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2008
Lacerda Lara, Herrero Maria A, Venner Kerrie, Bianco Alberto, Prato Maurizio, Kostarelos Kostas
Carbon-nanotube shape and individualization critical for renal excretion Journal Article
In: Small (Weinheim an Der Bergstrasse, Germany), vol. 4, no. 8, pp. 1130–1132, 2008, ISSN: 1613-6829.
Links | BibTeX | Tags: Animals, Biological Transport, carbon, Electron, Female, Glomerular Filtration Rate, I2CT, Inbred BALB C, Kidney Glomerulus, Mice, Microscopy, Nanoparticles, nanotechnology, Nanotubes, Team-Bianco, Transmission
@article{lacerda_carbon-nanotube_2008,
title = {Carbon-nanotube shape and individualization critical for renal excretion},
author = {Lara Lacerda and Maria A Herrero and Kerrie Venner and Alberto Bianco and Maurizio Prato and Kostas Kostarelos},
doi = {10.1002/smll.200800323},
issn = {1613-6829},
year = {2008},
date = {2008-08-01},
journal = {Small (Weinheim an Der Bergstrasse, Germany)},
volume = {4},
number = {8},
pages = {1130--1132},
keywords = {Animals, Biological Transport, carbon, Electron, Female, Glomerular Filtration Rate, I2CT, Inbred BALB C, Kidney Glomerulus, Mice, Microscopy, Nanoparticles, nanotechnology, Nanotubes, Team-Bianco, Transmission},
pubstate = {published},
tppubtype = {article}
}
Parietti Véronique, Monneaux Fanny, Décossas Marion, Muller Sylviane
Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector Ŧ cells Journal Article
In: Arthritis and Rheumatism, vol. 58, no. 6, pp. 1751–1761, 2008, ISSN: 0004-3591.
Abstract | Links | BibTeX | Tags: Animal, Animals, Antigen-Presenting Cells, Antigens, B7-1 Antigen, B7-2 Antigen, CD, Cell Communication, Cells, Coculture Techniques, CTLA-4 Antigen, Cultured, Disease Models, Female, I2CT, Interleukin-1, Interleukin-2 Receptor alpha Subunit, Lupus Erythematosus, Mice, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier
@article{parietti_function_2008,
title = {Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector Ŧ cells},
author = {Véronique Parietti and Fanny Monneaux and Marion Décossas and Sylviane Muller},
doi = {10.1002/art.23464},
issn = {0004-3591},
year = {2008},
date = {2008-06-01},
journal = {Arthritis and Rheumatism},
volume = {58},
number = {6},
pages = {1751--1761},
abstract = {OBJECTIVE: Naturally occurring CD4+,CD25+ Treg cells are central in the maintenance of peripheral tolerance. Impaired activity and/or a lower frequency of these cells is involved in the emergence of autoimmunity. We undertook this study to analyze relative proportions and functional alterations of Treg cells in MRL/lpr mice.
METHODS: The frequency of CD4+,CD25+ T cells in the peripheral blood of healthy and autoimmune mice was compared by flow cytometry. The capacity of CD4+,CD25+ T cells to inhibit the proliferation and cytokine secretion of CD4+,CD25- T cells was assessed after polyclonal activation.
RESULTS: MRL/lpr mice exhibited a normal percentage of CD4+,CD25 high T cells, and forkhead box P3 messenger RNA and protein expression in Treg cells was not altered. However, MRL/lpr Treg cells displayed a reduced capacity to suppress proliferation and to inhibit interferon-gamma secretion by syngeneic effector CD4+,CD25- T cells, as compared with syngeneic cocultures of CBA/J T cells. Moreover, effector MRL/lpr CD4+,CD25- T cells were substantially less susceptible to suppression even when cultured with CBA/J or MRL/lpr Treg cells. Crossover experiments led us to conclude that in MRL/lpr mice, each partner engaged in T cell regulation displays altered functions. Molecules involved in suppressive mechanisms (CTLA-4 and CD80/CD86) are underexpressed, and antigen-presenting cells (APCs) produce raised levels of interleukin-6, which is known to abrogate suppression.
CONCLUSION: Our results suggest that although the frequency and phenotype of Treg cells in MRL/lpr mice are similar to those in normal mice, Treg cells in MRL/lpr mice are not properly stimulated by APCs and are unable to suppress proinflammatory cytokine secretion from effector T cells.},
keywords = {Animal, Animals, Antigen-Presenting Cells, Antigens, B7-1 Antigen, B7-2 Antigen, CD, Cell Communication, Cells, Coculture Techniques, CTLA-4 Antigen, Cultured, Disease Models, Female, I2CT, Interleukin-1, Interleukin-2 Receptor alpha Subunit, Lupus Erythematosus, Mice, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: Naturally occurring CD4+,CD25+ Treg cells are central in the maintenance of peripheral tolerance. Impaired activity and/or a lower frequency of these cells is involved in the emergence of autoimmunity. We undertook this study to analyze relative proportions and functional alterations of Treg cells in MRL/lpr mice.
METHODS: The frequency of CD4+,CD25+ T cells in the peripheral blood of healthy and autoimmune mice was compared by flow cytometry. The capacity of CD4+,CD25+ T cells to inhibit the proliferation and cytokine secretion of CD4+,CD25- T cells was assessed after polyclonal activation.
RESULTS: MRL/lpr mice exhibited a normal percentage of CD4+,CD25 high T cells, and forkhead box P3 messenger RNA and protein expression in Treg cells was not altered. However, MRL/lpr Treg cells displayed a reduced capacity to suppress proliferation and to inhibit interferon-gamma secretion by syngeneic effector CD4+,CD25- T cells, as compared with syngeneic cocultures of CBA/J T cells. Moreover, effector MRL/lpr CD4+,CD25- T cells were substantially less susceptible to suppression even when cultured with CBA/J or MRL/lpr Treg cells. Crossover experiments led us to conclude that in MRL/lpr mice, each partner engaged in T cell regulation displays altered functions. Molecules involved in suppressive mechanisms (CTLA-4 and CD80/CD86) are underexpressed, and antigen-presenting cells (APCs) produce raised levels of interleukin-6, which is known to abrogate suppression.
CONCLUSION: Our results suggest that although the frequency and phenotype of Treg cells in MRL/lpr mice are similar to those in normal mice, Treg cells in MRL/lpr mice are not properly stimulated by APCs and are unable to suppress proinflammatory cytokine secretion from effector T cells.
METHODS: The frequency of CD4+,CD25+ T cells in the peripheral blood of healthy and autoimmune mice was compared by flow cytometry. The capacity of CD4+,CD25+ T cells to inhibit the proliferation and cytokine secretion of CD4+,CD25- T cells was assessed after polyclonal activation.
RESULTS: MRL/lpr mice exhibited a normal percentage of CD4+,CD25 high T cells, and forkhead box P3 messenger RNA and protein expression in Treg cells was not altered. However, MRL/lpr Treg cells displayed a reduced capacity to suppress proliferation and to inhibit interferon-gamma secretion by syngeneic effector CD4+,CD25- T cells, as compared with syngeneic cocultures of CBA/J T cells. Moreover, effector MRL/lpr CD4+,CD25- T cells were substantially less susceptible to suppression even when cultured with CBA/J or MRL/lpr Treg cells. Crossover experiments led us to conclude that in MRL/lpr mice, each partner engaged in T cell regulation displays altered functions. Molecules involved in suppressive mechanisms (CTLA-4 and CD80/CD86) are underexpressed, and antigen-presenting cells (APCs) produce raised levels of interleukin-6, which is known to abrogate suppression.
CONCLUSION: Our results suggest that although the frequency and phenotype of Treg cells in MRL/lpr mice are similar to those in normal mice, Treg cells in MRL/lpr mice are not properly stimulated by APCs and are unable to suppress proinflammatory cytokine secretion from effector T cells.
Lacerda Lara, Ali-Boucetta Hanene, Herrero Maria A, Pastorin Giorgia, Bianco Alberto, Prato Maurizio, Kostarelos Kostas
Tissue histology and physiology following intravenous administration of different types of functionalized multiwalled carbon nanotubes Journal Article
In: Nanomedicine (London, England), vol. 3, no. 2, pp. 149–161, 2008, ISSN: 1748-6963.
Abstract | Links | BibTeX | Tags: Animals, carbon, Female, I2CT, Inbred BALB C, Injections, Intravenous, Mice, Nanotubes, Organ Specificity, Team-Bianco, Tissue Distribution
@article{lacerda_tissue_2008,
title = {Tissue histology and physiology following intravenous administration of different types of functionalized multiwalled carbon nanotubes},
author = {Lara Lacerda and Hanene Ali-Boucetta and Maria A Herrero and Giorgia Pastorin and Alberto Bianco and Maurizio Prato and Kostas Kostarelos},
doi = {10.2217/17435889.3.2.149},
issn = {1748-6963},
year = {2008},
date = {2008-04-01},
journal = {Nanomedicine (London, England)},
volume = {3},
number = {2},
pages = {149--161},
abstract = {BACKGROUND: Carbon nanotubes (CNTs) constitute one of the most important types of nanomaterials, increasingly gaining interest as tools for nanomedicine applications, such as sensors, implants or delivery systems. Our groups have reported previously that chemical functionalization of CNTs can lead to their almost complete elimination from the body of animals through the urinary excretion route. The administration of CNTs may, however, impact the physiological function of organs through which CNTs traverse or accumulate. AIM: The present study addresses the short-term impact (first 24 h) of intravenous administration of various types of multiwalled nanotubes (MWNTs) on the physiology of healthy mice. MATERIALS & METHODS: Nonfunctionalized, purified MWNTs (pMWNTs) and different types of water-dispersible, functionalized MWNTs (f-MWNTs) were tail-vein injected. Histological examination of tissues (kidney, liver, spleen and lung) harvested 24 h post-administration indicated that organ accumulation depended on the degree of ammonium (NH(3)(+)) functionalization at the f-MWNT surface. RESULTS: The higher the degree of functionalization of MWNT-NH(3)(+), the less their accumulation in tissues. pMWNTs coated with autologous serum proteins prior to injection accumulated almost entirely in the lung and liver in large dark clusters. Moreover, various indicators of serum and urine analyses also confirmed that MWNT-NH(3)(+) injections did not induce any physiological abnormality in all major organs within the first 24 h post-injection. Interestingly, no abnormalities were observed either for f-MWNTs highly functionalized with carboxylate groups (diethylentriaminepentaacetic-functionalized MWNTs) or by upscaling to the highest doses ever injected so far in vivo (20 mg/kg). CONCLUSION: The high degree of f-MWNT functionalization responsible for adequate individualization of nanotubes and not the nature of the functional groups was the critical factor leading to less tissue accumulation and normal tissue physiology at least within the first 24 h post-administration, even at the highest carbon nanotube doses ever administered in any study today.},
keywords = {Animals, carbon, Female, I2CT, Inbred BALB C, Injections, Intravenous, Mice, Nanotubes, Organ Specificity, Team-Bianco, Tissue Distribution},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Carbon nanotubes (CNTs) constitute one of the most important types of nanomaterials, increasingly gaining interest as tools for nanomedicine applications, such as sensors, implants or delivery systems. Our groups have reported previously that chemical functionalization of CNTs can lead to their almost complete elimination from the body of animals through the urinary excretion route. The administration of CNTs may, however, impact the physiological function of organs through which CNTs traverse or accumulate. AIM: The present study addresses the short-term impact (first 24 h) of intravenous administration of various types of multiwalled nanotubes (MWNTs) on the physiology of healthy mice. MATERIALS & METHODS: Nonfunctionalized, purified MWNTs (pMWNTs) and different types of water-dispersible, functionalized MWNTs (f-MWNTs) were tail-vein injected. Histological examination of tissues (kidney, liver, spleen and lung) harvested 24 h post-administration indicated that organ accumulation depended on the degree of ammonium (NH(3)(+)) functionalization at the f-MWNT surface. RESULTS: The higher the degree of functionalization of MWNT-NH(3)(+), the less their accumulation in tissues. pMWNTs coated with autologous serum proteins prior to injection accumulated almost entirely in the lung and liver in large dark clusters. Moreover, various indicators of serum and urine analyses also confirmed that MWNT-NH(3)(+) injections did not induce any physiological abnormality in all major organs within the first 24 h post-injection. Interestingly, no abnormalities were observed either for f-MWNTs highly functionalized with carboxylate groups (diethylentriaminepentaacetic-functionalized MWNTs) or by upscaling to the highest doses ever injected so far in vivo (20 mg/kg). CONCLUSION: The high degree of f-MWNT functionalization responsible for adequate individualization of nanotubes and not the nature of the functional groups was the critical factor leading to less tissue accumulation and normal tissue physiology at least within the first 24 h post-administration, even at the highest carbon nanotube doses ever administered in any study today.
Flacher Vincent, Douillard Patrice, Aït-Yahia Smina, Stoitzner Patrizia, Clair-Moninot Valérie, Romani Nikolaus, Saeland Sem
Expression of langerin/CD207 reveals dendritic cell heterogeneity between inbred mouse strains Journal Article
In: Immunology, vol. 123, no. 3, pp. 339–347, 2008, ISSN: 1365-2567.
Abstract | Links | BibTeX | Tags: Animals, Antigen, Antigens, C-Type, CD, Cell Surface, Dendritic Cells, DERMATOLOGY, Epidermis, Expression, Immunology, Immunophenotyping, Inbred Strains, inflammation, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Lymphoid Tissue, Mannose-Binding Lectins, Maturation, metabolism, Mice, Minor Histocompatibility Antigens, mouse, Phenotype, Protein, Receptor, Receptors, Species Specificity, SPLEEN, SUBSETS, Surface, Team-Mueller
@article{flacher_expression_2008,
title = {Expression of langerin/CD207 reveals dendritic cell heterogeneity between inbred mouse strains},
author = {Vincent Flacher and Patrice Douillard and Smina Aït-Yahia and Patrizia Stoitzner and Valérie Clair-Moninot and Nikolaus Romani and Sem Saeland},
doi = {10.1111/j.1365-2567.2007.02785.x},
issn = {1365-2567},
year = {2008},
date = {2008-03-01},
journal = {Immunology},
volume = {123},
number = {3},
pages = {339--347},
abstract = {Langerin/CD207 is expressed by a subset of dendritic cells (DC), the epithelial Langerhans cells. However, langerin is also detected among lymphoid tissue DC. Here, we describe striking differences in langerin-expressing cells between inbred mouse strains. While langerin+ cells are observed in comparable numbers and with comparable phenotypes in the epidermis, two distinct DC subsets bear langerin in peripheral, skin-draining lymph nodes of BALB/c mice (CD11c(high) CD8alpha(high) and CD11c(low) CD8alpha(low)), whereas only the latter subset is present in C57BL/6 mice. The CD11c(high) subset is detected in mesenteric lymph nodes and spleen of BALB/c mice, but is virtually absent from C57BL/6 mice. Similar differences are observed in other mouse strains. CD11c(low) langerin+ cells represent skin-derived Langerhans cells, as demonstrated by their high expression of DEC-205/CD205, maturation markers, and recruitment to skin-draining lymph nodes upon imiquimod-induced inflammation. It will be of interest to determine the role of lymphoid tissue-resident compared to skin-derived langerin+ DC.},
keywords = {Animals, Antigen, Antigens, C-Type, CD, Cell Surface, Dendritic Cells, DERMATOLOGY, Epidermis, Expression, Immunology, Immunophenotyping, Inbred Strains, inflammation, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Lymphoid Tissue, Mannose-Binding Lectins, Maturation, metabolism, Mice, Minor Histocompatibility Antigens, mouse, Phenotype, Protein, Receptor, Receptors, Species Specificity, SPLEEN, SUBSETS, Surface, Team-Mueller},
pubstate = {published},
tppubtype = {article}
}
Langerin/CD207 is expressed by a subset of dendritic cells (DC), the epithelial Langerhans cells. However, langerin is also detected among lymphoid tissue DC. Here, we describe striking differences in langerin-expressing cells between inbred mouse strains. While langerin+ cells are observed in comparable numbers and with comparable phenotypes in the epidermis, two distinct DC subsets bear langerin in peripheral, skin-draining lymph nodes of BALB/c mice (CD11c(high) CD8alpha(high) and CD11c(low) CD8alpha(low)), whereas only the latter subset is present in C57BL/6 mice. The CD11c(high) subset is detected in mesenteric lymph nodes and spleen of BALB/c mice, but is virtually absent from C57BL/6 mice. Similar differences are observed in other mouse strains. CD11c(low) langerin+ cells represent skin-derived Langerhans cells, as demonstrated by their high expression of DEC-205/CD205, maturation markers, and recruitment to skin-draining lymph nodes upon imiquimod-induced inflammation. It will be of interest to determine the role of lymphoid tissue-resident compared to skin-derived langerin+ DC.
Goto Akira, Matsushita Kazufumi, Gesellchen Viola, Chamy Laure El, Kuttenkeuler David, Takeuchi Osamu, Hoffmann Jules A, Akira Shizuo, Boutros Michael, Reichhart Jean-Marc
Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice Journal Article
In: Nat. Immunol., vol. 9, no. 1, pp. 97–104, 2008, ISSN: 1529-2916.
Abstract | Links | BibTeX | Tags: Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha
@article{goto_akirins_2008,
title = {Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice},
author = {Akira Goto and Kazufumi Matsushita and Viola Gesellchen and Laure El Chamy and David Kuttenkeuler and Osamu Takeuchi and Jules A Hoffmann and Shizuo Akira and Michael Boutros and Jean-Marc Reichhart},
doi = {10.1038/ni1543},
issn = {1529-2916},
year = {2008},
date = {2008-01-01},
journal = {Nat. Immunol.},
volume = {9},
number = {1},
pages = {97--104},
abstract = {During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.},
keywords = {Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha},
pubstate = {published},
tppubtype = {article}
}
During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.
Barbaroux J B, Beleut M, Brisken C, Mueller C G, Groves R W
Epidermal receptor activator of NF-kappaB ligand controls Langerhans cells numbers and proliferation Journal Article
In: Journal of Immunology, vol. 181, no. 1550-6606 (Electronic), pp. 1103–1108, 2008.
Abstract | BibTeX | Tags: APC, Apoptosis, BLOOD, Cell Count, Cell Proliferation, Cell Survival, Culture, cytology, Dendritic Cells, DERMATOLOGY, Differentiation, Epidermis, Expression, Homeostasis, Human, Humans, Immunology, IN VITRO, In vivo, KERATINOCYTES, Langerhans Cells, ligand, metabolism, Mice, NF-kappa B, NF-kappaB, OSTEOCLAST, Osteoclasts, Proliferation, Protein, rank, RANK ligand, Receptor, Receptor Activator of Nuclear Factor-kappa B, Regulation, Signal Transduction, Skin, survival, Team-Mueller, viability
@article{barbaroux_epidermal_2008,
title = {Epidermal receptor activator of NF-kappaB ligand controls Langerhans cells numbers and proliferation},
author = {J B Barbaroux and M Beleut and C Brisken and C G Mueller and R W Groves},
year = {2008},
date = {2008-01-01},
journal = {Journal of Immunology},
volume = {181},
number = {1550-6606 (Electronic)},
pages = {1103--1108},
abstract = {Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-kappaB ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34(+) progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 +/- 1% vs 55.2 +/- 5.7% live cells, respectively; n = 4; p textless 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 +/- 77.2 vs 873.6 +/- 41.6 LC per mm(2); n = 9; p textless 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis},
keywords = {APC, Apoptosis, BLOOD, Cell Count, Cell Proliferation, Cell Survival, Culture, cytology, Dendritic Cells, DERMATOLOGY, Differentiation, Epidermis, Expression, Homeostasis, Human, Humans, Immunology, IN VITRO, In vivo, KERATINOCYTES, Langerhans Cells, ligand, metabolism, Mice, NF-kappa B, NF-kappaB, OSTEOCLAST, Osteoclasts, Proliferation, Protein, rank, RANK ligand, Receptor, Receptor Activator of Nuclear Factor-kappa B, Regulation, Signal Transduction, Skin, survival, Team-Mueller, viability},
pubstate = {published},
tppubtype = {article}
}
Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-kappaB ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34(+) progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 +/- 1% vs 55.2 +/- 5.7% live cells, respectively; n = 4; p textless 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 +/- 77.2 vs 873.6 +/- 41.6 LC per mm(2); n = 9; p textless 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis
Tripp Christoph H, Haid Bernhard, Flacher Vincent, Sixt Michael, Peter Hannes, Farkas Julia, Gschwentner Robert, Sorokin Lydia, Romani Nikolaus, Stoitzner Patrizia
The lymph vessel network in mouse skin visualised with antibodies against the hyaluronan receptor LYVE-1 Journal Article
In: Immunobiology, vol. 213, no. 9-10, pp. 715–728, 2008, ISSN: 0171-2985.
Abstract | Links | BibTeX | Tags: anatomy & histology, Animals, Antibodies, antibody, BLOOD, Blood Vessels, CD31, Cell Movement, Culture, cytology, Dendritic Cells, DERMAL DENDRITIC CELLS, DERMATOLOGY, DERMIS, EAR, electron microscopy, ENDOTHELIUM, Expression, GLYCOPROTEIN, Glycoproteins, hyaluronan, imiquimod, Immunology, Immunotherapy, In vivo, Inbred BALB C, Inbred C57BL, Langerhans Cells, ligand, LYMPH, LYMPH NODE, Lymph Nodes, LYMPHATIC VESSEL, Lymphatic Vessels, LYVE-1, Membrane Transport Proteins, metabolism, MHC, Mice, migration, mouse, murine, physiology, priming, Protein, Receptor, Skin, tape stripping, Team-Mueller, tolerance
@article{tripp_lymph_2008,
title = {The lymph vessel network in mouse skin visualised with antibodies against the hyaluronan receptor LYVE-1},
author = {Christoph H Tripp and Bernhard Haid and Vincent Flacher and Michael Sixt and Hannes Peter and Julia Farkas and Robert Gschwentner and Lydia Sorokin and Nikolaus Romani and Patrizia Stoitzner},
doi = {10.1016/j.imbio.2008.07.025},
issn = {0171-2985},
year = {2008},
date = {2008-01-01},
journal = {Immunobiology},
volume = {213},
number = {9-10},
pages = {715--728},
abstract = {Langerhans cells and dermal dendritic cells migrate to the draining lymph nodes through dermal lymphatic vessels. They do so in the steady-state and under inflammatory conditions. Peripheral T cell tolerance or T cell priming, respectively, are the consequences of migration. The nature of dendritic cell-containing vessels was mostly defined by electron microscopy or by their lack of blood endothelial markers. Selective markers for murine lymph endothelium were hitherto rare or not available. Here, we utilised recently developed antibodies against the murine hyaluronan receptor, LYVE-1, to study the lymph vessel network in mouse skin in more detail. In hairless skin from the ears, lymph vessels were spread out in a horizontal plane. They formed anastomoses, and they possessed frequent blind endings that were occasionally open. Lymph vessels were wider than blood vessels, which were identified by their strong CD31 expression. In body wall skin LYVE-1 reactive vessels did not extend laterally but they dived straight down into the deeper dermis. There, they are connected to each other and formed a network similar to ear skin. The number and width of lymph vessels did not grossly change upon inflammatory stimuli such as skin explant culture or tape stripping. There were also no marked changes in caliber in response to the TLR 7/8 ligand Imiquimod. Double-labelling experiments of cultured skin showed that most of the strongly cell surface MHC II-expressing (i.e. activated) dendritic cells were confined to the lymph vessels. Langerin/CD207(+) cells within this population appeared later than dermal dendritic cells, i.e. langerin-negative cells. Comparable results were obtained after stimulating the skin in vivo with the TLR 7/8 ligand Imiquimod or by tape stripping. In untreated skin (i.e. steady state) a few MHC II(+) and Langerin/CD207(+) cells, presumably migrating skin dendritic cells including epidermal Langerhans cells, were consistently observed within the lymph vessels. The novel antibody reagents may serve as important tools to further study the dendritic cell traffic in the skin under physiological conditions as well as in conditions of adoptive dendritic cell transfer in immunotherapy.},
keywords = {anatomy & histology, Animals, Antibodies, antibody, BLOOD, Blood Vessels, CD31, Cell Movement, Culture, cytology, Dendritic Cells, DERMAL DENDRITIC CELLS, DERMATOLOGY, DERMIS, EAR, electron microscopy, ENDOTHELIUM, Expression, GLYCOPROTEIN, Glycoproteins, hyaluronan, imiquimod, Immunology, Immunotherapy, In vivo, Inbred BALB C, Inbred C57BL, Langerhans Cells, ligand, LYMPH, LYMPH NODE, Lymph Nodes, LYMPHATIC VESSEL, Lymphatic Vessels, LYVE-1, Membrane Transport Proteins, metabolism, MHC, Mice, migration, mouse, murine, physiology, priming, Protein, Receptor, Skin, tape stripping, Team-Mueller, tolerance},
pubstate = {published},
tppubtype = {article}
}
Langerhans cells and dermal dendritic cells migrate to the draining lymph nodes through dermal lymphatic vessels. They do so in the steady-state and under inflammatory conditions. Peripheral T cell tolerance or T cell priming, respectively, are the consequences of migration. The nature of dendritic cell-containing vessels was mostly defined by electron microscopy or by their lack of blood endothelial markers. Selective markers for murine lymph endothelium were hitherto rare or not available. Here, we utilised recently developed antibodies against the murine hyaluronan receptor, LYVE-1, to study the lymph vessel network in mouse skin in more detail. In hairless skin from the ears, lymph vessels were spread out in a horizontal plane. They formed anastomoses, and they possessed frequent blind endings that were occasionally open. Lymph vessels were wider than blood vessels, which were identified by their strong CD31 expression. In body wall skin LYVE-1 reactive vessels did not extend laterally but they dived straight down into the deeper dermis. There, they are connected to each other and formed a network similar to ear skin. The number and width of lymph vessels did not grossly change upon inflammatory stimuli such as skin explant culture or tape stripping. There were also no marked changes in caliber in response to the TLR 7/8 ligand Imiquimod. Double-labelling experiments of cultured skin showed that most of the strongly cell surface MHC II-expressing (i.e. activated) dendritic cells were confined to the lymph vessels. Langerin/CD207(+) cells within this population appeared later than dermal dendritic cells, i.e. langerin-negative cells. Comparable results were obtained after stimulating the skin in vivo with the TLR 7/8 ligand Imiquimod or by tape stripping. In untreated skin (i.e. steady state) a few MHC II(+) and Langerin/CD207(+) cells, presumably migrating skin dendritic cells including epidermal Langerhans cells, were consistently observed within the lymph vessels. The novel antibody reagents may serve as important tools to further study the dendritic cell traffic in the skin under physiological conditions as well as in conditions of adoptive dendritic cell transfer in immunotherapy.
2007
Habib Mohammed, Rivas Magali Noval, Chamekh Mustapha, Wieckowski Sébastien, Sun Weimin, Bianco Alberto, Trouche Nathalie, Chaloin Olivier, Dumortier Hélène, Goldman Michel, Guichard Gilles, Fournel Sylvie, Vray Bernard
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 178, no. 11, pp. 6700–6704, 2007, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Animals, CD40 Antigens, CD40 Ligand, Cell Line, Cells, Chagas Disease, Cultured, Dumortier, I2CT, Inbred BALB C, Inbred C57BL, Interferon-gamma, Knockout, Mice, Molecular Mimicry, Parasitemia, T-Lymphocyte Subsets, Team-Bianco, Team-Dumortier, Trypanosoma cruzi
@article{habib_cutting_2007,
title = {Cutting edge: small molecule CD40 ligand mimetics promote control of parasitemia and enhance Ŧ cells producing IFN-gamma during experimental Trypanosoma cruzi infection},
author = {Mohammed Habib and Magali Noval Rivas and Mustapha Chamekh and Sébastien Wieckowski and Weimin Sun and Alberto Bianco and Nathalie Trouche and Olivier Chaloin and Hélène Dumortier and Michel Goldman and Gilles Guichard and Sylvie Fournel and Bernard Vray},
doi = {10.4049/jimmunol.178.11.6700},
issn = {0022-1767},
year = {2007},
date = {2007-06-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {178},
number = {11},
pages = {6700--6704},
abstract = {Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-gamma. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (textless3 kDa) mimicking trimeric CD40L (mini CD40Ls(-1) and (-2)) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8(+) T cells, and IFN-gamma production. Mice surviving T. cruzi infection in the presence of miniCD40L(-1) were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites.},
keywords = {Animals, CD40 Antigens, CD40 Ligand, Cell Line, Cells, Chagas Disease, Cultured, Dumortier, I2CT, Inbred BALB C, Inbred C57BL, Interferon-gamma, Knockout, Mice, Molecular Mimicry, Parasitemia, T-Lymphocyte Subsets, Team-Bianco, Team-Dumortier, Trypanosoma cruzi},
pubstate = {published},
tppubtype = {article}
}
Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-gamma. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (textless3 kDa) mimicking trimeric CD40L (mini CD40Ls(-1) and (-2)) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8(+) T cells, and IFN-gamma production. Mice surviving T. cruzi infection in the presence of miniCD40L(-1) were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites.
Croker Ben, Crozat Karine, Berger Michael, Xia Yu, Sovath Sosathya, Schaffer Lana, Eleftherianos Ioannis, Imler Jean-Luc, Beutler Bruce
ATP-sensitive potassium channels mediate survival during infection in mammals and insects Journal Article
In: Nature Genetics, vol. 39, no. 12, pp. 1453–1460, 2007, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags: Animals, ATP-Binding Cassette Transporters, Cloning, Coronary Vessels, Crosses, Ethylnitrosourea, Genetic, Homozygote, imler, infection, Inwardly Rectifying, KATP Channels, Lipopolysaccharides, M3i, Mice, Molecular, Mutagenesis, Potassium Channels, Sulfonylurea Receptors
@article{croker_atp-sensitive_2007,
title = {ATP-sensitive potassium channels mediate survival during infection in mammals and insects},
author = {Ben Croker and Karine Crozat and Michael Berger and Yu Xia and Sosathya Sovath and Lana Schaffer and Ioannis Eleftherianos and Jean-Luc Imler and Bruce Beutler},
doi = {10.1038/ng.2007.25},
issn = {1546-1718},
year = {2007},
date = {2007-01-01},
journal = {Nature Genetics},
volume = {39},
number = {12},
pages = {1453--1460},
abstract = {Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and approximately 20,000-fold sensitization to lipopolysaccharide (LPS), poly(I.C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (K(ATP)) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, K(ATP) evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.},
keywords = {Animals, ATP-Binding Cassette Transporters, Cloning, Coronary Vessels, Crosses, Ethylnitrosourea, Genetic, Homozygote, imler, infection, Inwardly Rectifying, KATP Channels, Lipopolysaccharides, M3i, Mice, Molecular, Mutagenesis, Potassium Channels, Sulfonylurea Receptors},
pubstate = {published},
tppubtype = {article}
}
Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and approximately 20,000-fold sensitization to lipopolysaccharide (LPS), poly(I.C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (K(ATP)) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, K(ATP) evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.
Monneaux F, Muller S
[The spliceosome and its interest for lupus therapy] Journal Article
In: La Revue De Medecine Interne, vol. 28, no. 10, pp. 725–728, 2007, ISSN: 0248-8663.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Animals, Antibodies, CD4-Positive T-Lymphocytes, Conserved Sequence, DNA, Epitopes, Haplotypes, Humans, I2CT, Immune Tolerance, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Phosphoserine, Protein, Recombinant, Ribonucleoprotein, Sequence Analysis, Serine, Spliceosomes, Systemic, Team-Dumortier, U1 Small Nuclear
@article{monneaux_spliceosome_2007,
title = {[The spliceosome and its interest for lupus therapy]},
author = {F Monneaux and S Muller},
doi = {10.1016/j.revmed.2007.05.003},
issn = {0248-8663},
year = {2007},
date = {2007-01-01},
journal = {La Revue De Medecine Interne},
volume = {28},
number = {10},
pages = {725--728},
abstract = {INTRODUCTION: The spliceosome, which is a particle containing a molecule of U-RNA and proteins that are specific to each U ribonuclear particle (U-snRNP) or common to every U-snRNPs, is one of the numerous nuclear targets recognized by the antibodies (Abs) and CD4+ T cells from patients with systemic lupus erythematosus and lupus mice.
EXEGESIS: We recently characterized a peptide from the spliceosomal protein U1-70K (sequence 131-151), which is recognized by the Abs and CD4+ T cells from lupus mice and patients. This peptide contains a conserved RNP1 motif, which is also present in other spliceosomal proteins targeted by the Abs from individuals with lupus. We further showed that peptide 131-151 containing a phosphoserine at position 140 (peptide P140) possessed tolerogenic properties in lupus mice and was recognized by the Abs and CD4+ T cells from lupus patients.
CONCLUSION: Thanks to its RNP1 motif, the peptide P140 might play an important role in the initiation and perpetuation steps of the humoral and cellular immune response diversification in lupus individuals. Therapeutic and particularly immunomodulating properties of P140 peptide are being evaluated in humans (a phase III clinical trial will be undertaken in the next weeks).},
keywords = {Amino Acid Motifs, Animals, Antibodies, CD4-Positive T-Lymphocytes, Conserved Sequence, DNA, Epitopes, Haplotypes, Humans, I2CT, Immune Tolerance, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Phosphoserine, Protein, Recombinant, Ribonucleoprotein, Sequence Analysis, Serine, Spliceosomes, Systemic, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
INTRODUCTION: The spliceosome, which is a particle containing a molecule of U-RNA and proteins that are specific to each U ribonuclear particle (U-snRNP) or common to every U-snRNPs, is one of the numerous nuclear targets recognized by the antibodies (Abs) and CD4+ T cells from patients with systemic lupus erythematosus and lupus mice.
EXEGESIS: We recently characterized a peptide from the spliceosomal protein U1-70K (sequence 131-151), which is recognized by the Abs and CD4+ T cells from lupus mice and patients. This peptide contains a conserved RNP1 motif, which is also present in other spliceosomal proteins targeted by the Abs from individuals with lupus. We further showed that peptide 131-151 containing a phosphoserine at position 140 (peptide P140) possessed tolerogenic properties in lupus mice and was recognized by the Abs and CD4+ T cells from lupus patients.
CONCLUSION: Thanks to its RNP1 motif, the peptide P140 might play an important role in the initiation and perpetuation steps of the humoral and cellular immune response diversification in lupus individuals. Therapeutic and particularly immunomodulating properties of P140 peptide are being evaluated in humans (a phase III clinical trial will be undertaken in the next weeks).
EXEGESIS: We recently characterized a peptide from the spliceosomal protein U1-70K (sequence 131-151), which is recognized by the Abs and CD4+ T cells from lupus mice and patients. This peptide contains a conserved RNP1 motif, which is also present in other spliceosomal proteins targeted by the Abs from individuals with lupus. We further showed that peptide 131-151 containing a phosphoserine at position 140 (peptide P140) possessed tolerogenic properties in lupus mice and was recognized by the Abs and CD4+ T cells from lupus patients.
CONCLUSION: Thanks to its RNP1 motif, the peptide P140 might play an important role in the initiation and perpetuation steps of the humoral and cellular immune response diversification in lupus individuals. Therapeutic and particularly immunomodulating properties of P140 peptide are being evaluated in humans (a phase III clinical trial will be undertaken in the next weeks).
Woods Anne, Monneaux Fanny, Soulas-Sprauel Pauline, Muller Sylviane, Martin Thierry, Korganow Anne-Sophie, Pasquali Jean-Louis
Influenza virus-induced type I interferon leads to polyclonal B-cell activation but does not break down B-cell tolerance Journal Article
In: Journal of Virology, vol. 81, no. 22, pp. 12525–12534, 2007, ISSN: 0022-538X.
Abstract | Links | BibTeX | Tags: Animals, Antibody Formation, Autoantibodies, Autoantigens, Autoimmunity, B-Lymphocytes, Humans, I2CT, Immune Tolerance, Immunoglobulin M, Inbred Strains, Influenza A virus, Interferon Type I, Lymphocyte Activation, Mice, Monneaux, Rheumatoid Factor, Team-Dumortier, transgenic
@article{woods_influenza_2007,
title = {Influenza virus-induced type I interferon leads to polyclonal B-cell activation but does not break down B-cell tolerance},
author = {Anne Woods and Fanny Monneaux and Pauline Soulas-Sprauel and Sylviane Muller and Thierry Martin and Anne-Sophie Korganow and Jean-Louis Pasquali},
doi = {10.1128/JVI.00839-07},
issn = {0022-538X},
year = {2007},
date = {2007-01-01},
journal = {Journal of Virology},
volume = {81},
number = {22},
pages = {12525--12534},
abstract = {The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB x NZW)F(1)] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB x NZW)F(1) mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.},
keywords = {Animals, Antibody Formation, Autoantibodies, Autoantigens, Autoimmunity, B-Lymphocytes, Humans, I2CT, Immune Tolerance, Immunoglobulin M, Inbred Strains, Influenza A virus, Interferon Type I, Lymphocyte Activation, Mice, Monneaux, Rheumatoid Factor, Team-Dumortier, transgenic},
pubstate = {published},
tppubtype = {article}
}
The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB x NZW)F(1)] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB x NZW)F(1) mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.
Monneaux Fanny, Parietti Véronique, Briand Jean-Paul, Muller Sylviane
Importance of spliceosomal RNP1 motif for intermolecular Ŧ-B cell spreading and tolerance restoration in lupus Journal Article
In: Arthritis Research & Therapy, vol. 9, no. 5, pp. R111, 2007, ISSN: 1478-6362.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Amino Acid Sequence, Animals, B-Lymphocytes, I2CT, Immune Tolerance, Inbred MRL lpr, Lupus Erythematosus, Mice, Molecular Sequence Data, Monneaux, Ribonucleoproteins, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier
@article{monneaux_importance_2007,
title = {Importance of spliceosomal RNP1 motif for intermolecular Ŧ-B cell spreading and tolerance restoration in lupus},
author = {Fanny Monneaux and Véronique Parietti and Jean-Paul Briand and Sylviane Muller},
doi = {10.1186/ar2317},
issn = {1478-6362},
year = {2007},
date = {2007-01-01},
journal = {Arthritis Research & Therapy},
volume = {9},
number = {5},
pages = {R111},
abstract = {We previously demonstrated the importance of the RNP1 motif-bearing region 131-151 of the U1-70K spliceosomal protein in the intramolecular T-B spreading that occurs in MRL/lpr lupus mice. Here, we analyze the involvement of RNP1 motif in the development and prevention of naturally-occurring intermolecular T-B cell diversification. We found that MRL/lpr peripheral blood lymphocytes proliferated in response to peptides containing or corresponding exactly to the RNP1 motif of spliceosomal U1-70K, U1-A and hnRNP-A2 proteins. We also demonstrated that rabbit antibodies to peptide 131-151 cross-reacted with U1-70K, U1-A and hnRNP-A2 RNP1-peptides. These antibodies recognized the U1-70K and U1-A proteins, and also U1-C and SmD1 proteins, which are devoid of RNP1 motif. Repeated administration of phosphorylated peptide P140 into MRL/lpr mice abolished T-cell response to several peptides from the U1-70K, U1-A and SmD1 proteins without affecting antibody and T-cell responses to foreign (viral) antigen in treated mice challenged with infectious virus. These results emphasized the importance of the dominant RNP1 region, which seems to be central in the activation cascade of B and T cells reacting with spliceosomal RNP1+ and RNP1- spliceosomal proteins. The tolerogenic peptide P140, which is recognized by lupus patients' CD4+ T cells and known to protect MRL/lpr mice, is able to thwart emergence of intermolecular T-cell spreading in treated animals.},
keywords = {Amino Acid Motifs, Amino Acid Sequence, Animals, B-Lymphocytes, I2CT, Immune Tolerance, Inbred MRL lpr, Lupus Erythematosus, Mice, Molecular Sequence Data, Monneaux, Ribonucleoproteins, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
We previously demonstrated the importance of the RNP1 motif-bearing region 131-151 of the U1-70K spliceosomal protein in the intramolecular T-B spreading that occurs in MRL/lpr lupus mice. Here, we analyze the involvement of RNP1 motif in the development and prevention of naturally-occurring intermolecular T-B cell diversification. We found that MRL/lpr peripheral blood lymphocytes proliferated in response to peptides containing or corresponding exactly to the RNP1 motif of spliceosomal U1-70K, U1-A and hnRNP-A2 proteins. We also demonstrated that rabbit antibodies to peptide 131-151 cross-reacted with U1-70K, U1-A and hnRNP-A2 RNP1-peptides. These antibodies recognized the U1-70K and U1-A proteins, and also U1-C and SmD1 proteins, which are devoid of RNP1 motif. Repeated administration of phosphorylated peptide P140 into MRL/lpr mice abolished T-cell response to several peptides from the U1-70K, U1-A and SmD1 proteins without affecting antibody and T-cell responses to foreign (viral) antigen in treated mice challenged with infectious virus. These results emphasized the importance of the dominant RNP1 region, which seems to be central in the activation cascade of B and T cells reacting with spliceosomal RNP1+ and RNP1- spliceosomal proteins. The tolerogenic peptide P140, which is recognized by lupus patients' CD4+ T cells and known to protect MRL/lpr mice, is able to thwart emergence of intermolecular T-cell spreading in treated animals.
2006
Singh Ravi, Pantarotto Davide, Lacerda Lara, Pastorin Giorgia, Klumpp Cédric, Prato Maurizio, Bianco Alberto, Kostarelos Kostas
Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 9, pp. 3357–3362, 2006, ISSN: 0027-8424.
Abstract | Links | BibTeX | Tags: Animals, carbon, Electron, Female, Half-Life, I2CT, Inbred BALB C, Indium Radioisotopes, Injections, Intravenous, Mice, Microscopy, Molecular Structure, Nanotubes, Pentetic Acid, Team-Bianco, Tissue Distribution, Transmission
@article{singh_tissue_2006,
title = {Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers},
author = {Ravi Singh and Davide Pantarotto and Lara Lacerda and Giorgia Pastorin and Cédric Klumpp and Maurizio Prato and Alberto Bianco and Kostas Kostarelos},
doi = {10.1073/pnas.0509009103},
issn = {0027-8424},
year = {2006},
date = {2006-02-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {103},
number = {9},
pages = {3357--3362},
abstract = {Carbon nanotubes (CNT) are intensively being developed for biomedical applications including drug and gene delivery. Although all possible clinical applications will require compatibility of CNT with the biological milieu, their in vivo capabilities and limitations have not yet been explored. In this work, water-soluble, single-walled CNT (SWNT) have been functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) and labeled with indium ((111)In) for imaging purposes. Intravenous (i.v.) administration of these functionalized SWNT (f-SWNT) followed by radioactivity tracing using gamma scintigraphy indicated that f-SWNT are not retained in any of the reticuloendothelial system organs (liver or spleen) and are rapidly cleared from systemic blood circulation through the renal excretion route. The observed rapid blood clearance and half-life (3 h) of f-SWNT has major implications for all potential clinical uses of CNT. Moreover, urine excretion studies using both f-SWNT and functionalized multiwalled CNT followed by electron microscopy analysis of urine samples revealed that both types of nanotubes were excreted as intact nanotubes. This work describes the pharmacokinetic parameters of i.v. administered functionalized CNT relevant for various therapeutic and diagnostic applications.},
keywords = {Animals, carbon, Electron, Female, Half-Life, I2CT, Inbred BALB C, Indium Radioisotopes, Injections, Intravenous, Mice, Microscopy, Molecular Structure, Nanotubes, Pentetic Acid, Team-Bianco, Tissue Distribution, Transmission},
pubstate = {published},
tppubtype = {article}
}
Carbon nanotubes (CNT) are intensively being developed for biomedical applications including drug and gene delivery. Although all possible clinical applications will require compatibility of CNT with the biological milieu, their in vivo capabilities and limitations have not yet been explored. In this work, water-soluble, single-walled CNT (SWNT) have been functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) and labeled with indium ((111)In) for imaging purposes. Intravenous (i.v.) administration of these functionalized SWNT (f-SWNT) followed by radioactivity tracing using gamma scintigraphy indicated that f-SWNT are not retained in any of the reticuloendothelial system organs (liver or spleen) and are rapidly cleared from systemic blood circulation through the renal excretion route. The observed rapid blood clearance and half-life (3 h) of f-SWNT has major implications for all potential clinical uses of CNT. Moreover, urine excretion studies using both f-SWNT and functionalized multiwalled CNT followed by electron microscopy analysis of urine samples revealed that both types of nanotubes were excreted as intact nanotubes. This work describes the pharmacokinetic parameters of i.v. administered functionalized CNT relevant for various therapeutic and diagnostic applications.
2005
Fournel Sylvie, Wieckowski Sébastien, Sun Weimin, Trouche Nathalie, Dumortier Hélène, Bianco Alberto, Chaloin Olivier, Habib Mohammed, Peter Jean-Christophe, Schneider Pascal, Vray Bernard, Toes René E, Offringa Rienk, Melief Cornelis J M, Hoebeke Johan, Guichard Gilles
C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L Journal Article
In: Nature Chemical Biology, vol. 1, no. 7, pp. 377–382, 2005, ISSN: 1552-4450.
Abstract | Links | BibTeX | Tags: Animals, Apoptosis, Biological, CD40 Antigens, CD40 Ligand, Cell Line, Dumortier, Humans, I2CT, Inbred BALB C, Mice, Models, Molecular Mimicry, Molecular Structure, Peptides, Protein Conformation, Protein Structure, Quaternary, Structure-Activity Relationship, Team-Bianco, Team-Dumortier, Time Factors, tumor
@article{fournel_c3-symmetric_2005,
title = {C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L},
author = {Sylvie Fournel and Sébastien Wieckowski and Weimin Sun and Nathalie Trouche and Hélène Dumortier and Alberto Bianco and Olivier Chaloin and Mohammed Habib and Jean-Christophe Peter and Pascal Schneider and Bernard Vray and René E Toes and Rienk Offringa and Cornelis J M Melief and Johan Hoebeke and Gilles Guichard},
doi = {10.1038/nchembio746},
issn = {1552-4450},
year = {2005},
date = {2005-12-01},
journal = {Nature Chemical Biology},
volume = {1},
number = {7},
pages = {377--382},
abstract = {Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.},
keywords = {Animals, Apoptosis, Biological, CD40 Antigens, CD40 Ligand, Cell Line, Dumortier, Humans, I2CT, Inbred BALB C, Mice, Models, Molecular Mimicry, Molecular Structure, Peptides, Protein Conformation, Protein Structure, Quaternary, Structure-Activity Relationship, Team-Bianco, Team-Dumortier, Time Factors, tumor},
pubstate = {published},
tppubtype = {article}
}
Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.
Hayer Silvia, Tohidast-Akrad Makiyeh, Haralambous Silva, Jahn-Schmid Beatrice, Skriner Karl, Trembleau Sylvie, Dumortier Hélène, Pinol-Roma Serafin, Redlich Kurt, Schett Georg, Muller Sylviane, Kollias George, Smolen Josef, Steiner Günter
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 175, no. 12, pp. 8327–8336, 2005, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Animals, Antibody Formation, arthritis, Autoantibodies, Autoantigens, Dumortier, Gene Expression Regulation, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Humans, I2CT, Joints, Mice, rheumatoid, Team-Dumortier, Tissue Distribution, transgenic, Tumor Necrosis Factor-alpha
@article{hayer_aberrant_2005,
title = {Aberrant expression of the autoantigen heterogeneous nuclear ribonucleoprotein-A2 (RA33) and spontaneous formation of rheumatoid arthritis-associated anti-RA33 autoantibodies in TNF-alpha transgenic mice},
author = {Silvia Hayer and Makiyeh Tohidast-Akrad and Silva Haralambous and Beatrice Jahn-Schmid and Karl Skriner and Sylvie Trembleau and Hélène Dumortier and Serafin Pinol-Roma and Kurt Redlich and Georg Schett and Sylviane Muller and George Kollias and Josef Smolen and Günter Steiner},
doi = {10.4049/jimmunol.175.12.8327},
issn = {0022-1767},
year = {2005},
date = {2005-12-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {175},
number = {12},
pages = {8327--8336},
abstract = {Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, textgreater50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.},
keywords = {Animals, Antibody Formation, arthritis, Autoantibodies, Autoantigens, Dumortier, Gene Expression Regulation, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Humans, I2CT, Joints, Mice, rheumatoid, Team-Dumortier, Tissue Distribution, transgenic, Tumor Necrosis Factor-alpha},
pubstate = {published},
tppubtype = {article}
}
Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, textgreater50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.
Dumortier Hélène, van Mierlo Geertje J D, Egan Deirdre, van Ewijk Willem, Toes René E M, Offringa Rienk, Melief Cornelis J M
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 175, no. 2, pp. 855–863, 2005, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Adenovirus E1A Proteins, Animals, Antigen, Antigen Presentation, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Line, Cell Movement, Clonal Deletion, Cytotoxic, Cytotoxicity, Dendritic Cells, Down-Regulation, Dumortier, Epitopes, Female, I2CT, Immunologic, Immunologic Memory, Inbred C57BL, Lipopolysaccharides, Lymphocyte Activation, Mice, Myeloid Cells, Receptors, Regulatory, T-Cell, T-Lymphocyte, T-Lymphocytes, Team-Dumortier, transgenic
@article{dumortier_antigen_2005,
title = {Antigen presentation by an immature myeloid dendritic cell line does not cause CTL deletion in vivo, but generates CD8+ central memory-like Ŧ cells that can be rescued for full effector function},
author = {Hélène Dumortier and Geertje J D van Mierlo and Deirdre Egan and Willem van Ewijk and René E M Toes and Rienk Offringa and Cornelis J M Melief},
doi = {10.4049/jimmunol.175.2.855},
issn = {0022-1767},
year = {2005},
date = {2005-01-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {175},
number = {2},
pages = {855--863},
abstract = {Immature dendritic cells (DC), in contrast to their mature counterparts, are incapable of mobilizing a CD8+ CTL response, and, instead, have been reported to induce CTL tolerance. We directly addressed the impact of immature vs mature DC on CTL responses by infusing adenovirus peptide-loaded DC (of the D1 cell line) into mice that had received adenovirus-specific naive TCR-transgenic CD8+ T cells. Whereas i.v. injection of mature DC triggered vigorous CTL expansion, immature DC elicited little proliferation involving only a minority of the TCR-transgenic CTL. Even though the latter CTL developed effector functions, including cytolytic activity and proinflammatory cytokine secretion, these cells differed significantly from CTL primed by mature DC in that they did not exhibit down-regulation of CD62L and CCR7, receptors involved in trapping of T cells in the lymphoid organs. Interestingly, adoptive transfer of CTL effector cells harvested after priming by either mature or immature DC into naive recipient mice, followed by exposure to adenovirus, yielded quantitatively and qualitatively indistinguishable CTL memory responses. Therefore, in vivo priming of naive CD8+ T cells by immature DC, although failing to induce a full-blown, systemic CTL response, resulted in the formation of central memory-like T cells that were able to expand and produce IFN-gamma upon secondary antigenic stimulation.},
keywords = {Adenovirus E1A Proteins, Animals, Antigen, Antigen Presentation, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Line, Cell Movement, Clonal Deletion, Cytotoxic, Cytotoxicity, Dendritic Cells, Down-Regulation, Dumortier, Epitopes, Female, I2CT, Immunologic, Immunologic Memory, Inbred C57BL, Lipopolysaccharides, Lymphocyte Activation, Mice, Myeloid Cells, Receptors, Regulatory, T-Cell, T-Lymphocyte, T-Lymphocytes, Team-Dumortier, transgenic},
pubstate = {published},
tppubtype = {article}
}
Immature dendritic cells (DC), in contrast to their mature counterparts, are incapable of mobilizing a CD8+ CTL response, and, instead, have been reported to induce CTL tolerance. We directly addressed the impact of immature vs mature DC on CTL responses by infusing adenovirus peptide-loaded DC (of the D1 cell line) into mice that had received adenovirus-specific naive TCR-transgenic CD8+ T cells. Whereas i.v. injection of mature DC triggered vigorous CTL expansion, immature DC elicited little proliferation involving only a minority of the TCR-transgenic CTL. Even though the latter CTL developed effector functions, including cytolytic activity and proinflammatory cytokine secretion, these cells differed significantly from CTL primed by mature DC in that they did not exhibit down-regulation of CD62L and CCR7, receptors involved in trapping of T cells in the lymphoid organs. Interestingly, adoptive transfer of CTL effector cells harvested after priming by either mature or immature DC into naive recipient mice, followed by exposure to adenovirus, yielded quantitatively and qualitatively indistinguishable CTL memory responses. Therefore, in vivo priming of naive CD8+ T cells by immature DC, although failing to induce a full-blown, systemic CTL response, resulted in the formation of central memory-like T cells that were able to expand and produce IFN-gamma upon secondary antigenic stimulation.
Fournel Sylvie, Wieckowski Sébastien, Sun Weimin, Trouche Nathalie, Dumortier Hélène, Bianco Alberto, Chaloin Olivier, Habib Mohammed, Peter Jean-Christophe, Schneider Pascal, Vray Bernard, Toes René E, Offringa Rienk, Melief Cornelis J M, Hoebeke Johan, Guichard Gilles
C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L Journal Article
In: Nature Chemical Biology, vol. 1, no. 7, pp. 377–382, 2005, ISSN: 1552-4450.
Abstract | Links | BibTeX | Tags: Animals, Apoptosis, Biological, CD40 Antigens, CD40 Ligand, Cell Line, Humans, I2CT, Inbred BALB C, Mice, Models, Molecular Mimicry, Molecular Structure, Peptides, Protein Conformation, Protein Structure, Quaternary, Structure-Activity Relationship, Team-Bianco, Time Factors, tumor
@article{fournel_c3-symmetric_2005b,
title = {C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L},
author = {Sylvie Fournel and Sébastien Wieckowski and Weimin Sun and Nathalie Trouche and Hélène Dumortier and Alberto Bianco and Olivier Chaloin and Mohammed Habib and Jean-Christophe Peter and Pascal Schneider and Bernard Vray and René E Toes and Rienk Offringa and Cornelis J M Melief and Johan Hoebeke and Gilles Guichard},
doi = {10.1038/nchembio746},
issn = {1552-4450},
year = {2005},
date = {2005-01-01},
journal = {Nature Chemical Biology},
volume = {1},
number = {7},
pages = {377--382},
abstract = {Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.},
keywords = {Animals, Apoptosis, Biological, CD40 Antigens, CD40 Ligand, Cell Line, Humans, I2CT, Inbred BALB C, Mice, Models, Molecular Mimicry, Molecular Structure, Peptides, Protein Conformation, Protein Structure, Quaternary, Structure-Activity Relationship, Team-Bianco, Time Factors, tumor},
pubstate = {published},
tppubtype = {article}
}
Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.
Bianco Alberto, Hoebeke Johan, Godefroy Sylvie, Chaloin Olivier, Pantarotto Davide, Briand Jean-Paul, Muller Sylviane, Prato Maurizio, Partidos Charalambos D
Cationic carbon nanotubes bind to CpG oligodeoxynucleotides and enhance their immunostimulatory properties Journal Article
In: Journal of the American Chemical Society, vol. 127, no. 1, pp. 58–59, 2005, ISSN: 0002-7863.
Abstract | Links | BibTeX | Tags: Adjuvants, Animals, carbon, Cations, CpG Islands, I2CT, Immunologic, Interferon-gamma, Interleukin-6, Kinetics, Lymphocytes, Mice, Nanotubes, oligonucleotides, Surface Plasmon Resonance, Team-Bianco
@article{bianco_cationic_2005,
title = {Cationic carbon nanotubes bind to CpG oligodeoxynucleotides and enhance their immunostimulatory properties},
author = {Alberto Bianco and Johan Hoebeke and Sylvie Godefroy and Olivier Chaloin and Davide Pantarotto and Jean-Paul Briand and Sylviane Muller and Maurizio Prato and Charalambos D Partidos},
doi = {10.1021/ja044293y},
issn = {0002-7863},
year = {2005},
date = {2005-01-01},
journal = {Journal of the American Chemical Society},
volume = {127},
number = {1},
pages = {58--59},
abstract = {Functionalized cationic carbon nanotubes are able to form a stable complex with CpG ODN based on charge interaction and to increase the immunostimulatory activity of CpG motifs.},
keywords = {Adjuvants, Animals, carbon, Cations, CpG Islands, I2CT, Immunologic, Interferon-gamma, Interleukin-6, Kinetics, Lymphocytes, Mice, Nanotubes, oligonucleotides, Surface Plasmon Resonance, Team-Bianco},
pubstate = {published},
tppubtype = {article}
}
Functionalized cationic carbon nanotubes are able to form a stable complex with CpG ODN based on charge interaction and to increase the immunostimulatory activity of CpG motifs.
2004
van Mierlo Geertje J D, Boonman Zita F H M, Dumortier Hélène M H, den Boer Annemieke Th, Fransen Marieke F, Nouta Jan, van der Voort Ellen I H, Offringa Rienk, Toes René E M, Melief Cornelis J M
Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 173, no. 11, pp. 6753–6759, 2004, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Adenovirus E1A Proteins, Animals, Antibodies, Antigen-Presenting Cells, Antigens, CD11c Antigen, CD40 Antigens, Cross-Priming, Cultured, Cytotoxic, Cytotoxicity, Dendritic Cells, Dumortier, Epitopes, Experimental, I2CT, Immunologic, Inbred C57BL, Injections, Intralesional, Intravenous, Knockout, Male, Mice, Monoclonal, Neoplasms, T-Lymphocyte, T-Lymphocytes, Team-Dumortier, transgenic, tumor, Tumor Cells, Viral
@article{van_mierlo_activation_2004,
title = {Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication},
author = {Geertje J D van Mierlo and Zita F H M Boonman and Hélène M H Dumortier and Annemieke Th den Boer and Marieke F Fransen and Jan Nouta and Ellen I H van der Voort and Rienk Offringa and René E M Toes and Cornelis J M Melief},
doi = {10.4049/jimmunol.173.11.6753},
issn = {0022-1767},
year = {2004},
date = {2004-12-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {173},
number = {11},
pages = {6753--6759},
abstract = {The fate of naive CD8(+) T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c(+) APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8(+) CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.},
keywords = {Adenovirus E1A Proteins, Animals, Antibodies, Antigen-Presenting Cells, Antigens, CD11c Antigen, CD40 Antigens, Cross-Priming, Cultured, Cytotoxic, Cytotoxicity, Dendritic Cells, Dumortier, Epitopes, Experimental, I2CT, Immunologic, Inbred C57BL, Injections, Intralesional, Intravenous, Knockout, Male, Mice, Monoclonal, Neoplasms, T-Lymphocyte, T-Lymphocytes, Team-Dumortier, transgenic, tumor, Tumor Cells, Viral},
pubstate = {published},
tppubtype = {article}
}
The fate of naive CD8(+) T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c(+) APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8(+) CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.
Monneaux Fanny, Parietti Véronique, Briand Jean-Paul, Muller Sylviane
Intramolecular Ŧ cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151 Journal Article
In: Arthritis and Rheumatism, vol. 50, no. 10, pp. 3232–3238, 2004, ISSN: 0004-3591.
Abstract | Links | BibTeX | Tags: Animals, Cell Division, Female, I2CT, Immunization, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lymphocytes, Mice, Monneaux, Peptides, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear
@article{monneaux_intramolecular_2004,
title = {Intramolecular Ŧ cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151},
author = {Fanny Monneaux and Véronique Parietti and Jean-Paul Briand and Sylviane Muller},
doi = {10.1002/art.20510},
issn = {0004-3591},
year = {2004},
date = {2004-10-01},
journal = {Arthritis and Rheumatism},
volume = {50},
number = {10},
pages = {3232--3238},
abstract = {OBJECTIVE: To analyze spontaneous T cell spreading against determinants of the U1-70K protein in young autoimmune MRL/lpr lupus mice, in comparison with the T cell spreading occurring in normal BALB/c mice immunized with peptide 131-151 of this protein.
METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2.
RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.
CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.},
keywords = {Animals, Cell Division, Female, I2CT, Immunization, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lymphocytes, Mice, Monneaux, Peptides, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: To analyze spontaneous T cell spreading against determinants of the U1-70K protein in young autoimmune MRL/lpr lupus mice, in comparison with the T cell spreading occurring in normal BALB/c mice immunized with peptide 131-151 of this protein.
METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2.
RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.
CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.
METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2.
RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.
CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.
Martineau Y., Bec C. Le, Monbrun L., Allo V., Chiu I. M., Danos O., Moine H., Prats H., Prats A. C.
Internal ribosome entry site structural motifs conserved among mammalian fibroblast growth factor 1 alternatively spliced mRNAs Journal Article
In: Mol Cell Biol, vol. 24, no. 17, pp. 7622-35, 2004, (0270-7306 Journal Article).
Abstract | BibTeX | Tags: (Genetics), *5', *Alternative, *Nucleic, *Promoter, 1/*genetics, Acid, Alignment, Animals, Base, Cell, Conformation, Data, EHRESMANN, Factor, Fibroblast, Gene, Genes, Genetic, Gov't, Growth, Human, Line, Messenger/chemistry/*genetics/metabolism, Mice, Molecular, Muscle, Mutagenesis, Non-U.S., Regions, Ribosomes/*metabolism, RNA, Sequence, Site-Directed, Skeletal/cytology/physiology, Splicing, Structural/genetics, Support, Techniques, Transfer, Untranslated, Vectors
@article{,
title = {Internal ribosome entry site structural motifs conserved among mammalian fibroblast growth factor 1 alternatively spliced mRNAs},
author = { Y. Martineau and C. Le Bec and L. Monbrun and V. Allo and I. M. Chiu and O. Danos and H. Moine and H. Prats and A. C. Prats},
year = {2004},
date = {2004-01-01},
journal = {Mol Cell Biol},
volume = {24},
number = {17},
pages = {7622-35},
abstract = {Fibroblast growth factor 1 (FGF-1) is a powerful angiogenic factor whose gene structure contains four promoters, giving rise to a process of alternative splicing resulting in four mRNAs with alternative 5' untranslated regions (5' UTRs). Here we have identified, by using double luciferase bicistronic vectors, the presence of internal ribosome entry sites (IRESs) in the human FGF-1 5' UTRs, particularly in leaders A and C, with distinct activities in mammalian cells. DNA electrotransfer in mouse muscle revealed that the IRES present in the FGF-1 leader A has a high activity in vivo. We have developed a new regulatable TET OFF bicistronic system, which allowed us to rule out the possibility of any cryptic promoter in the FGF-1 leaders. FGF-1 IRESs A and C, which were mapped in fragments of 118 and 103 nucleotides, respectively, are flexible in regard to the position of the initiation codon, making them interesting from a biotechnological point of view. Furthermore, we show that FGF-1 IRESs A of murine and human origins show similar IRES activity profiles. Enzymatic and chemical probing of the FGF-1 IRES A RNA revealed a structural domain conserved among mammals at both the nucleotide sequence and RNA structure levels. The functional role of this structural motif has been demonstrated by point mutagenesis, including compensatory mutations. These data favor an important role of IRESs in the control of FGF-1 expression and provide a new IRES structural motif that could help IRES prediction in 5' UTR databases.},
note = {0270-7306
Journal Article},
keywords = {(Genetics), *5', *Alternative, *Nucleic, *Promoter, 1/*genetics, Acid, Alignment, Animals, Base, Cell, Conformation, Data, EHRESMANN, Factor, Fibroblast, Gene, Genes, Genetic, Gov't, Growth, Human, Line, Messenger/chemistry/*genetics/metabolism, Mice, Molecular, Muscle, Mutagenesis, Non-U.S., Regions, Ribosomes/*metabolism, RNA, Sequence, Site-Directed, Skeletal/cytology/physiology, Splicing, Structural/genetics, Support, Techniques, Transfer, Untranslated, Vectors},
pubstate = {published},
tppubtype = {article}
}
Fibroblast growth factor 1 (FGF-1) is a powerful angiogenic factor whose gene structure contains four promoters, giving rise to a process of alternative splicing resulting in four mRNAs with alternative 5' untranslated regions (5' UTRs). Here we have identified, by using double luciferase bicistronic vectors, the presence of internal ribosome entry sites (IRESs) in the human FGF-1 5' UTRs, particularly in leaders A and C, with distinct activities in mammalian cells. DNA electrotransfer in mouse muscle revealed that the IRES present in the FGF-1 leader A has a high activity in vivo. We have developed a new regulatable TET OFF bicistronic system, which allowed us to rule out the possibility of any cryptic promoter in the FGF-1 leaders. FGF-1 IRESs A and C, which were mapped in fragments of 118 and 103 nucleotides, respectively, are flexible in regard to the position of the initiation codon, making them interesting from a biotechnological point of view. Furthermore, we show that FGF-1 IRESs A of murine and human origins show similar IRES activity profiles. Enzymatic and chemical probing of the FGF-1 IRES A RNA revealed a structural domain conserved among mammals at both the nucleotide sequence and RNA structure levels. The functional role of this structural motif has been demonstrated by point mutagenesis, including compensatory mutations. These data favor an important role of IRESs in the control of FGF-1 expression and provide a new IRES structural motif that could help IRES prediction in 5' UTR databases.
Imler Jean-Luc, Zheng Liangbiao
Biology of Toll receptors: lessons from insects and mammals Journal Article
In: Journal of Leukocyte Biology, vol. 75, no. 1, pp. 18–26, 2004, ISSN: 0741-5400.
Abstract | Links | BibTeX | Tags: Animals, Anopheles, Cell Surface, Humans, imler, M3i, Membrane Glycoproteins, Mice, Phylogeny, Plant Physiological Phenomena, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors
@article{imler_biology_2004,
title = {Biology of Toll receptors: lessons from insects and mammals},
author = {Jean-Luc Imler and Liangbiao Zheng},
doi = {10.1189/jlb.0403160},
issn = {0741-5400},
year = {2004},
date = {2004-01-01},
journal = {Journal of Leukocyte Biology},
volume = {75},
number = {1},
pages = {18--26},
abstract = {Toll receptors are type I transmembrane proteins that play important roles in development and immunity in animals. Comparison of the genomes of mouse and human on one side and of the fruitfly Drosophila and the mosquito Anopheles (two dipteran insects) on the other, revealed that the four species possess a similar number of Toll receptors (approximately 10). However, phylogenetic analyses indicate that the families of Toll receptors expanded independently in insects and mammals. We review recent results on these receptors, which point to differences in the activation and signaling between Tolls in insects and Toll-like receptors (TLRs) in mammals. Whereas mammalian TLRs appear to be solely dedicated to host-defense, insect Tolls may be predominantly linked to other functions, probably developmental.},
keywords = {Animals, Anopheles, Cell Surface, Humans, imler, M3i, Membrane Glycoproteins, Mice, Phylogeny, Plant Physiological Phenomena, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Toll receptors are type I transmembrane proteins that play important roles in development and immunity in animals. Comparison of the genomes of mouse and human on one side and of the fruitfly Drosophila and the mosquito Anopheles (two dipteran insects) on the other, revealed that the four species possess a similar number of Toll receptors (approximately 10). However, phylogenetic analyses indicate that the families of Toll receptors expanded independently in insects and mammals. We review recent results on these receptors, which point to differences in the activation and signaling between Tolls in insects and Toll-like receptors (TLRs) in mammals. Whereas mammalian TLRs appear to be solely dedicated to host-defense, insect Tolls may be predominantly linked to other functions, probably developmental.
Monneaux Fanny, Muller Sylviane
Peptide-based immunotherapy of systemic lupus erythematosus Journal Article
In: Autoimmunity Reviews, vol. 3, no. 1, pp. 16–24, 2004, ISSN: 1568-9972.
Abstract | Links | BibTeX | Tags: Animals, Antibodies, Antinuclear, Epitopes, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Mice, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier
@article{monneaux_peptide-based_2004,
title = {Peptide-based immunotherapy of systemic lupus erythematosus},
author = {Fanny Monneaux and Sylviane Muller},
doi = {10.1016/S1568-9972(03)00061-2},
issn = {1568-9972},
year = {2004},
date = {2004-01-01},
journal = {Autoimmunity Reviews},
volume = {3},
number = {1},
pages = {16--24},
abstract = {Current drug-based therapy for systemic lupus erythematosus (SLE) are non-specific and often counterbalanced by adverse effects. Current research aims at developing specific treatments that target deleterious cells only and not the whole immune system. This strategy requires the identification of sequences derived from major lupus autoantigens, responsible for the activation of autoreactive B and T cells. This review summarizes the identification and characterization of peptides, which are able to modulate T cells ex vivo, and describes the promising results obtained after administration of some of these peptides in lupus mice. Although these therapeutic trials are encouraging, the precise mode of action of peptide-based immunotherapy is still elusive. Here, we discuss the possible mechanisms leading to T-cell tolerance induction and the feasibility of extending the success of peptide-based therapy from animal models to human.},
keywords = {Animals, Antibodies, Antinuclear, Epitopes, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Mice, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Current drug-based therapy for systemic lupus erythematosus (SLE) are non-specific and often counterbalanced by adverse effects. Current research aims at developing specific treatments that target deleterious cells only and not the whole immune system. This strategy requires the identification of sequences derived from major lupus autoantigens, responsible for the activation of autoreactive B and T cells. This review summarizes the identification and characterization of peptides, which are able to modulate T cells ex vivo, and describes the promising results obtained after administration of some of these peptides in lupus mice. Although these therapeutic trials are encouraging, the precise mode of action of peptide-based immunotherapy is still elusive. Here, we discuss the possible mechanisms leading to T-cell tolerance induction and the feasibility of extending the success of peptide-based therapy from animal models to human.
Pantarotto Davide, Briand Jean-Paul, Prato Maurizio, Bianco Alberto
Translocation of bioactive peptides across cell membranes by carbon nanotubes Journal Article
In: Chemical Communications (Cambridge, England), no. 1, pp. 16–17, 2004, ISSN: 1359-7345.
Abstract | Links | BibTeX | Tags: 3T3 Cells, Animals, carbon, Cell Membrane, Confocal, Flow Cytometry, fluorescence, I2CT, Mice, Microscopy, Nanotubes, Particle Size, Peptides, Protein Transport, Team-Bianco
@article{pantarotto_translocation_2004,
title = {Translocation of bioactive peptides across cell membranes by carbon nanotubes},
author = {Davide Pantarotto and Jean-Paul Briand and Maurizio Prato and Alberto Bianco},
doi = {10.1039/b311254c},
issn = {1359-7345},
year = {2004},
date = {2004-01-01},
journal = {Chemical Communications (Cambridge, England)},
number = {1},
pages = {16--17},
abstract = {Functionalised carbon nanotubes are able to cross the cell membrane and to accumulate in the cytoplasm or reach the nucleus without being toxic for the cell up to 10 [micro sign]M.},
keywords = {3T3 Cells, Animals, carbon, Cell Membrane, Confocal, Flow Cytometry, fluorescence, I2CT, Mice, Microscopy, Nanotubes, Particle Size, Peptides, Protein Transport, Team-Bianco},
pubstate = {published},
tppubtype = {article}
}
Functionalised carbon nanotubes are able to cross the cell membrane and to accumulate in the cytoplasm or reach the nucleus without being toxic for the cell up to 10 [micro sign]M.
2003
Pantarotto Davide, Partidos Charalambos D, Hoebeke Johan, Brown Fred, Kramer Ed, Briand Jean-Paul, Muller Sylviane, Prato Maurizio, Bianco Alberto
Immunization with peptide-functionalized carbon nanotubes enhances virus-specific neutralizing antibody responses Journal Article
In: Chemistry & Biology, vol. 10, no. 10, pp. 961–966, 2003, ISSN: 1074-5521.
Links | BibTeX | Tags: Animals, Antibodies, Antigen-Antibody Reactions, carbon, Drug Delivery Systems, Epitopes, Foot-and-Mouth Disease Virus, I2CT, Immunization, Mice, Monoclonal, Nanotubes, Neutralization Tests, Peptides, Team-Bianco, Vaccines, Viral
@article{pantarotto_immunization_2003,
title = {Immunization with peptide-functionalized carbon nanotubes enhances virus-specific neutralizing antibody responses},
author = {Davide Pantarotto and Charalambos D Partidos and Johan Hoebeke and Fred Brown and Ed Kramer and Jean-Paul Briand and Sylviane Muller and Maurizio Prato and Alberto Bianco},
doi = {10.1016/j.chembiol.2003.09.011},
issn = {1074-5521},
year = {2003},
date = {2003-10-01},
journal = {Chemistry & Biology},
volume = {10},
number = {10},
pages = {961--966},
keywords = {Animals, Antibodies, Antigen-Antibody Reactions, carbon, Drug Delivery Systems, Epitopes, Foot-and-Mouth Disease Virus, I2CT, Immunization, Mice, Monoclonal, Nanotubes, Neutralization Tests, Peptides, Team-Bianco, Vaccines, Viral},
pubstate = {published},
tppubtype = {article}
}
Imler Jean-Luc, Hoffmann Jules A
Toll signaling: the TIReless quest for specificity Journal Article
In: Nature Immunology, vol. 4, no. 2, pp. 105–106, 2003, ISSN: 1529-2908.
Links | BibTeX | Tags: Animals, Cell Surface, Dendritic Cells, hoffmann, Humans, imler, Immunological, Interferon-beta, M3i, Membrane Glycoproteins, Mice, Models, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors
@article{imler_toll_2003,
title = {Toll signaling: the TIReless quest for specificity},
author = {Jean-Luc Imler and Jules A Hoffmann},
doi = {10.1038/ni0203-105},
issn = {1529-2908},
year = {2003},
date = {2003-02-01},
journal = {Nature Immunology},
volume = {4},
number = {2},
pages = {105--106},
keywords = {Animals, Cell Surface, Dendritic Cells, hoffmann, Humans, imler, Immunological, Interferon-beta, M3i, Membrane Glycoproteins, Mice, Models, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Monneaux Fanny, Lozano José Manuel, Patarroyo Manuel E, Briand Jean-Paul, Muller Sylviane
T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice Journal Article
In: European Journal of Immunology, vol. 33, no. 2, pp. 287–296, 2003, ISSN: 0014-2980.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animal, Animals, Autoantibodies, Autoantigens, Autoimmune Diseases, B-Lymphocytes, Cross Reactions, Disease Models, Female, HLA-DR Antigens, HLA-DR Serological Subtypes, HLA-DR1 Antigen, HLA-DR4 Antigen, Humans, I2CT, Immunization, Immunotherapy, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lupus Nephritis, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Protein Binding, Ribonucleoprotein, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear
@article{monneaux_t_2003,
title = {T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice},
author = {Fanny Monneaux and José Manuel Lozano and Manuel E Patarroyo and Jean-Paul Briand and Sylviane Muller},
doi = {10.1002/immu.200310002},
issn = {0014-2980},
year = {2003},
date = {2003-01-01},
journal = {European Journal of Immunology},
volume = {33},
number = {2},
pages = {287--296},
abstract = {Modifications of self antigens that occur during apoptosis might be involved in the generation of neo-antigens, which can break tolerance and induce autoimmunity. We have previously identified an epitope at residues 131-151 of the U1-70K snRNP protein, recognized by IgG antibodies and CD4+ T cells from at least two strains of lupus mice. With the aim of investigating the possible role of phosphorylation on the antigenicity of peptide 131-151 and to gain a better understanding of how this peptide can drive autoimmune response, we synthesized two peptides phosphorylated on Ser137 and 140, respectively. We show here that peptide P140 phosphorylated on Ser140 is recognized by both CD4+ T cells and antibodies from MRL/lpr mice. Furthermore, intravenous administration to lupus-prone MRL/lpr mice of P140 in saline (but not of the non-phosphorylated peptide) decreased proteinuria and anti-DNA antibody production, and significantly prolonged survival of treated mice. We further demonstrated that P140 is recognized by antibodies from lupus patients and binds to various HLA DR molecules, offering new hope for manipulating T cell response in humans.},
keywords = {Amino Acid Sequence, Animal, Animals, Autoantibodies, Autoantigens, Autoimmune Diseases, B-Lymphocytes, Cross Reactions, Disease Models, Female, HLA-DR Antigens, HLA-DR Serological Subtypes, HLA-DR1 Antigen, HLA-DR4 Antigen, Humans, I2CT, Immunization, Immunotherapy, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lupus Nephritis, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Protein Binding, Ribonucleoprotein, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
Modifications of self antigens that occur during apoptosis might be involved in the generation of neo-antigens, which can break tolerance and induce autoimmunity. We have previously identified an epitope at residues 131-151 of the U1-70K snRNP protein, recognized by IgG antibodies and CD4+ T cells from at least two strains of lupus mice. With the aim of investigating the possible role of phosphorylation on the antigenicity of peptide 131-151 and to gain a better understanding of how this peptide can drive autoimmune response, we synthesized two peptides phosphorylated on Ser137 and 140, respectively. We show here that peptide P140 phosphorylated on Ser140 is recognized by both CD4+ T cells and antibodies from MRL/lpr mice. Furthermore, intravenous administration to lupus-prone MRL/lpr mice of P140 in saline (but not of the non-phosphorylated peptide) decreased proteinuria and anti-DNA antibody production, and significantly prolonged survival of treated mice. We further demonstrated that P140 is recognized by antibodies from lupus patients and binds to various HLA DR molecules, offering new hope for manipulating T cell response in humans.
2002
Bates Elizabeth E M, Fridman Wolf H, Mueller Chris G F
The ADAMDEC1 (decysin) gene structure: evolution by duplication in a metalloprotease gene cluster on chromosome 8p12 Journal Article
In: Immunogenetics, vol. 54, no. 2, pp. 96–105, 2002, ISSN: 0093-7711.
Abstract | Links | BibTeX | Tags: ADAM Proteins, Amino Acid Sequence, Animals, Base Sequence, Chromosomes, Evolution, Gene Dosage, Gene Duplication, Genetic, Human, Humans, Inbred BALB C, Macaca mulatta, Membrane Glycoproteins, Metalloendopeptidases, Mice, Molecular, Molecular Sequence Data, Multigene Family, Pair 8, Promoter Regions, Sequence Alignment, Team-Mueller
@article{bates_adamdec1_2002,
title = {The ADAMDEC1 (decysin) gene structure: evolution by duplication in a metalloprotease gene cluster on chromosome 8p12},
author = {Elizabeth E M Bates and Wolf H Fridman and Chris G F Mueller},
doi = {10.1007/s00251-002-0430-3},
issn = {0093-7711},
year = {2002},
date = {2002-05-01},
journal = {Immunogenetics},
volume = {54},
number = {2},
pages = {96--105},
abstract = {Members of the ADAM superfamily of metalloprotease genes are involved in a number of biological processes, including fertilization, neurogenesis, muscle development, and the immune response. These proteins have been classified into several groups. The prototypic ADAM family is comprised of a pro-domain, a metalloprotease domain, a disintegrin domain, a cysteine-rich region, a transmembrane domain, and a variable cytoplasmic tail. We recently identified a novel member of this superfamily, ADAMDEC1 (decysin). Due to the partial lack of a disintegrin domain and the total lack of a cysteine-rich domain, this protein has been placed in a novel subclass of the ADAM gene family. We have investigated the gene structure of the human and mouse ADAMDEC1 and have revealed a metalloprotease gene cluster on human Chromosome 8p12 comprising ADAMDEC1, ADAM7, and ADAM28. Our results suggest that ADAMDEC1 has arisen by partial gene duplication from an ancestral gene at this locus and has acquired a novel function. ADAMDEC1 is expressed in the immune system, by dendritic cells and macrophages. The relatedness of ADAMDEC1, ADAM7, and ADAM28 suggests that these proteases share a similar function.},
keywords = {ADAM Proteins, Amino Acid Sequence, Animals, Base Sequence, Chromosomes, Evolution, Gene Dosage, Gene Duplication, Genetic, Human, Humans, Inbred BALB C, Macaca mulatta, Membrane Glycoproteins, Metalloendopeptidases, Mice, Molecular, Molecular Sequence Data, Multigene Family, Pair 8, Promoter Regions, Sequence Alignment, Team-Mueller},
pubstate = {published},
tppubtype = {article}
}
Members of the ADAM superfamily of metalloprotease genes are involved in a number of biological processes, including fertilization, neurogenesis, muscle development, and the immune response. These proteins have been classified into several groups. The prototypic ADAM family is comprised of a pro-domain, a metalloprotease domain, a disintegrin domain, a cysteine-rich region, a transmembrane domain, and a variable cytoplasmic tail. We recently identified a novel member of this superfamily, ADAMDEC1 (decysin). Due to the partial lack of a disintegrin domain and the total lack of a cysteine-rich domain, this protein has been placed in a novel subclass of the ADAM gene family. We have investigated the gene structure of the human and mouse ADAMDEC1 and have revealed a metalloprotease gene cluster on human Chromosome 8p12 comprising ADAMDEC1, ADAM7, and ADAM28. Our results suggest that ADAMDEC1 has arisen by partial gene duplication from an ancestral gene at this locus and has acquired a novel function. ADAMDEC1 is expressed in the immune system, by dendritic cells and macrophages. The relatedness of ADAMDEC1, ADAM7, and ADAM28 suggests that these proteases share a similar function.
Micillino J. C., Coulais C., Binet S., Bottin M. C., Keith G., Moulin D., Rihn B. H.
Lack of genotoxicity of bitumen fumes in transgenic mouse lung Journal Article
In: Toxicology, vol. 170, no. 1-2, pp. 11-20, 2002, (0300-483x Journal Article).
Abstract | BibTeX | Tags: Adducts/drug, Aerosols, Animals, C57BL, Chromatography, DNA, DNA/drug, effects, effects/metabolism, Gases/*toxicity, Genes, Hydrocarbons/*toxicity, Inbred, Lac, Layer, Lung/*drug, Mice, Mutagenicity, Mutagens/*toxicity, Mutation/drug, Operon/genetics, Reporter/genetics, Tests, Thin, transgenic
@article{,
title = {Lack of genotoxicity of bitumen fumes in transgenic mouse lung},
author = { J. C. Micillino and C. Coulais and S. Binet and M. C. Bottin and G. Keith and D. Moulin and B. H. Rihn},
year = {2002},
date = {2002-01-01},
journal = {Toxicology},
volume = {170},
number = {1-2},
pages = {11-20},
abstract = {During hot application of bitumen containing materials, e.g. in hot paving or roofing, fumes are emitted that contain polycyclic aromatic compounds. Previous studies with rodents exposed to bitumen and coal-tar fume condensates showed formation of DNA adducts. In order to clarify the genotoxicity of bitumen fumes, we designed a study by using mice carrying a reporter gene for mutagenesis analysis and exposed by nose-only to a constant and reproducible aerosol of bitumen fumes. We analyzed the genotoxic activity of inhaled bitumen fumes generated under those controlled conditions through the induction of mutation and DNA adducts in Big Blue mice. Mice were exposed to bitumen fumes (100 mg/m(3) total particulate matter) 6 h per day during 5 days by nose-only in an inhalation chamber designed in our laboratory. Following a 30-day fixation period, the experiment was terminated and lung DNA was extracted for mutant frequency and adduct determinations. The mutant frequency was determined using the cII and the lacI mutant analysis systems. In, addition, 61 and 54 mutants were sequenced in control and exposed groups, respectively. The study did not show any mutation or adduct induction in the exposed group compared to the control group: cII mutant frequencies were 11.0+/-4.5x10(-5) and 11.0+/-4.8x10(-5) in control and exposed lungs, respectively. Identically, using the lacI mutation detection system, the mutant frequencies were 6.4+/-3.1x10(-5) and 5.8+/-2.0x10(-5). The mutation spectra of both series were quite similar with regard to transition and transversion frequencies. The absence of genotoxicity in the group exposed to 100 mg/m(3) bitumen is discussed with regard to dosage of inhaled polycyclic aromatic compounds and species.},
note = {0300-483x
Journal Article},
keywords = {Adducts/drug, Aerosols, Animals, C57BL, Chromatography, DNA, DNA/drug, effects, effects/metabolism, Gases/*toxicity, Genes, Hydrocarbons/*toxicity, Inbred, Lac, Layer, Lung/*drug, Mice, Mutagenicity, Mutagens/*toxicity, Mutation/drug, Operon/genetics, Reporter/genetics, Tests, Thin, transgenic},
pubstate = {published},
tppubtype = {article}
}
During hot application of bitumen containing materials, e.g. in hot paving or roofing, fumes are emitted that contain polycyclic aromatic compounds. Previous studies with rodents exposed to bitumen and coal-tar fume condensates showed formation of DNA adducts. In order to clarify the genotoxicity of bitumen fumes, we designed a study by using mice carrying a reporter gene for mutagenesis analysis and exposed by nose-only to a constant and reproducible aerosol of bitumen fumes. We analyzed the genotoxic activity of inhaled bitumen fumes generated under those controlled conditions through the induction of mutation and DNA adducts in Big Blue mice. Mice were exposed to bitumen fumes (100 mg/m(3) total particulate matter) 6 h per day during 5 days by nose-only in an inhalation chamber designed in our laboratory. Following a 30-day fixation period, the experiment was terminated and lung DNA was extracted for mutant frequency and adduct determinations. The mutant frequency was determined using the cII and the lacI mutant analysis systems. In, addition, 61 and 54 mutants were sequenced in control and exposed groups, respectively. The study did not show any mutation or adduct induction in the exposed group compared to the control group: cII mutant frequencies were 11.0+/-4.5x10(-5) and 11.0+/-4.8x10(-5) in control and exposed lungs, respectively. Identically, using the lacI mutation detection system, the mutant frequencies were 6.4+/-3.1x10(-5) and 5.8+/-2.0x10(-5). The mutation spectra of both series were quite similar with regard to transition and transversion frequencies. The absence of genotoxicity in the group exposed to 100 mg/m(3) bitumen is discussed with regard to dosage of inhaled polycyclic aromatic compounds and species.
2001
Mueller C G, Cremer I, Paulet P E, Niida S, Maeda N, Lebeque S, Fridman W H, Sautès-Fridman C
Mannose receptor ligand-positive cells express the metalloprotease decysin in the B cell follicle Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 167, no. 9, pp. 5052–5060, 2001, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: ADAM Proteins, Amino Acid Sequence, Animals, B-Lymphocytes, C-Type, Cell Surface, Cloning, Dendritic Cells, Follicular, Germinal Center, Humans, Inbred BALB C, Lectins, ligands, Macrophage Colony-Stimulating Factor, Macrophages, Mannose-Binding Lectins, Metalloendopeptidases, Mice, Molecular, Molecular Sequence Data, Receptors, SPLEEN, Team-Mueller
@article{mueller_mannose_2001,
title = {Mannose receptor ligand-positive cells express the metalloprotease decysin in the B cell follicle},
author = {C G Mueller and I Cremer and P E Paulet and S Niida and N Maeda and S Lebeque and W H Fridman and C Sautès-Fridman},
doi = {10.4049/jimmunol.167.9.5052},
issn = {0022-1767},
year = {2001},
date = {2001-11-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {167},
number = {9},
pages = {5052--5060},
abstract = {Decysin, a gene encoding a disintegrin metalloprotease, is transcribed in human dendritic cells (DC) and germinal centers (GC). We have cloned its murine homologue and show that it is processed by the endoprotease furin before secretion of the catalytic domain. We have defined the cell types that express decysin in mouse spleen in the course of an immune response to T cell-dependent Ags. Like in humans, decysin is transcribed by activated CD11c(+) DC that enter the T cell zone from the marginal zone (MZ). In the GC, decysin is expressed by follicular DC and tingible body macrophages. In addition, a MZ cell population expresses decysin and appears to migrate into the B cell follicle. The majority of these follicle-homing cells express the mannose receptor ligand, a marker for the macrophage-like MZ metallophils. The follicle-homing cells are M-CSF dependent, as they are absent in op/op mice that lack functional M-CSF. This suggests that mannose receptor ligand(+) MZ metallophils differentiate into cells that migrate from the MZ into the B cell follicle. Decysin represents the first marker for this previously unrecognized cell population of the mouse spleen, which may represent a precursor for GCDC and may be specialized in the transport of unprocessed Ag from the MZ into developing GC.},
keywords = {ADAM Proteins, Amino Acid Sequence, Animals, B-Lymphocytes, C-Type, Cell Surface, Cloning, Dendritic Cells, Follicular, Germinal Center, Humans, Inbred BALB C, Lectins, ligands, Macrophage Colony-Stimulating Factor, Macrophages, Mannose-Binding Lectins, Metalloendopeptidases, Mice, Molecular, Molecular Sequence Data, Receptors, SPLEEN, Team-Mueller},
pubstate = {published},
tppubtype = {article}
}
Decysin, a gene encoding a disintegrin metalloprotease, is transcribed in human dendritic cells (DC) and germinal centers (GC). We have cloned its murine homologue and show that it is processed by the endoprotease furin before secretion of the catalytic domain. We have defined the cell types that express decysin in mouse spleen in the course of an immune response to T cell-dependent Ags. Like in humans, decysin is transcribed by activated CD11c(+) DC that enter the T cell zone from the marginal zone (MZ). In the GC, decysin is expressed by follicular DC and tingible body macrophages. In addition, a MZ cell population expresses decysin and appears to migrate into the B cell follicle. The majority of these follicle-homing cells express the mannose receptor ligand, a marker for the macrophage-like MZ metallophils. The follicle-homing cells are M-CSF dependent, as they are absent in op/op mice that lack functional M-CSF. This suggests that mannose receptor ligand(+) MZ metallophils differentiate into cells that migrate from the MZ into the B cell follicle. Decysin represents the first marker for this previously unrecognized cell population of the mouse spleen, which may represent a precursor for GCDC and may be specialized in the transport of unprocessed Ag from the MZ into developing GC.
Moine H., Mandel J. L.
Biomedicine. Do G quartets orchestrate fragile X pathology? Journal Article
In: Science, vol. 294, no. 5551, pp. 2487-8, 2001, (0036-8075 Journal Article).
BibTeX | Tags: Acid, Analysis, Animals, Array, Binding, Brain/metabolism, Conformation, Crystallography, Expression, Fragile, Gene, Genetic, Human, Messenger/*chemistry/genetics/*metabolism, Mice, Nerve, Nucleic, Oligonucleotide, Protein, Proteins/chemistry/genetics/*metabolism, Regions, Regulation, RNA, Sequence, Sites, structure, Synapses/physiology, Syndrome/genetics/*metabolism, Tertiary, Tissue, Translation, Untranslated, X, X-Ray
@article{,
title = {Biomedicine. Do G quartets orchestrate fragile X pathology?},
author = { H. Moine and J. L. Mandel},
year = {2001},
date = {2001-01-01},
journal = {Science},
volume = {294},
number = {5551},
pages = {2487-8},
note = {0036-8075
Journal Article},
keywords = {Acid, Analysis, Animals, Array, Binding, Brain/metabolism, Conformation, Crystallography, Expression, Fragile, Gene, Genetic, Human, Messenger/*chemistry/genetics/*metabolism, Mice, Nerve, Nucleic, Oligonucleotide, Protein, Proteins/chemistry/genetics/*metabolism, Regions, Regulation, RNA, Sequence, Sites, structure, Synapses/physiology, Syndrome/genetics/*metabolism, Tertiary, Tissue, Translation, Untranslated, X, X-Ray},
pubstate = {published},
tppubtype = {article}
}
Monneaux F, Muller S
Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins Journal Article
In: Scandinavian Journal of Immunology, vol. 54, no. 1-2, pp. 45–54, 2001, ISSN: 0300-9475.
Abstract | Links | BibTeX | Tags: Animals, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocyte, Epitopes, Humans, I2CT, Mice, Monneaux, Ribonucleoproteins, Spliceosomes, Team-Dumortier
@article{monneaux_key_2001,
title = {Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins},
author = {F Monneaux and S Muller},
doi = {10.1046/j.1365-3083.2001.00942.x},
issn = {0300-9475},
year = {2001},
date = {2001-01-01},
journal = {Scandinavian Journal of Immunology},
volume = {54},
number = {1-2},
pages = {45--54},
abstract = {Immune spreading to multiple intracellular antigens is likely to be of primary importance in organ-specific and systemic autoimmune diseases. A number of mechanisms by which immune spreading may occur from only a single autoreactive epitope have been proposed. Search for an initiator or early epitope thus represents an important area of investigation. For example, many studies have focused on the identification of epitopes recognized by the antibodies from both patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Recently, an autoepitope present in the 70K U1 ribonucleo protein (RNP) and recognized by CD4+ T cells from lupus mice has also been identified. Here, we analyze the results of B- and T-cell-epitope mapping studies of several RNPs present in the spliceosome and propose a model of epitope spreading. In this model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar and cytoplasmic antigens, might play a role as 'driver' epitope. This hypothesis is based on the observation that this sequence is recognized by CD4+ T cells from lupus mice and is often targeted by autoantibodies, very early during the course of the disease. Targeting this region that is repeated in different self-antigens, might represent an interesting strategy to interfere with the continuous T-cell stimulation and exposure to specific antigens.},
keywords = {Animals, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocyte, Epitopes, Humans, I2CT, Mice, Monneaux, Ribonucleoproteins, Spliceosomes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Immune spreading to multiple intracellular antigens is likely to be of primary importance in organ-specific and systemic autoimmune diseases. A number of mechanisms by which immune spreading may occur from only a single autoreactive epitope have been proposed. Search for an initiator or early epitope thus represents an important area of investigation. For example, many studies have focused on the identification of epitopes recognized by the antibodies from both patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Recently, an autoepitope present in the 70K U1 ribonucleo protein (RNP) and recognized by CD4+ T cells from lupus mice has also been identified. Here, we analyze the results of B- and T-cell-epitope mapping studies of several RNPs present in the spliceosome and propose a model of epitope spreading. In this model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar and cytoplasmic antigens, might play a role as 'driver' epitope. This hypothesis is based on the observation that this sequence is recognized by CD4+ T cells from lupus mice and is often targeted by autoantibodies, very early during the course of the disease. Targeting this region that is repeated in different self-antigens, might represent an interesting strategy to interfere with the continuous T-cell stimulation and exposure to specific antigens.
Monneaux F, Dumortier H, Steiner G, Briand J P, Muller S
In: International Immunology, vol. 13, no. 9, pp. 1155–1163, 2001, ISSN: 0953-8178.
Abstract | Links | BibTeX | Tags: Animals, Antibody Specificity, B-Lymphocytes, Crosses, Dumortier, fas Receptor, Female, Genetic, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Histocompatibility Antigens Class II, I2CT, Immunoglobulin G, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, Ribonucleoproteins, Small Nuclear, Species Specificity, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear
@article{monneaux_murine_2001,
title = {Murine models of systemic lupus erythematosus: B and Ŧ cell responses to spliceosomal ribonucleoproteins in MRL/Fas(lpr) and (NZB x NZW)F(1) lupus mice},
author = {F Monneaux and H Dumortier and G Steiner and J P Briand and S Muller},
doi = {10.1093/intimm/13.9.1155},
issn = {0953-8178},
year = {2001},
date = {2001-01-01},
journal = {International Immunology},
volume = {13},
number = {9},
pages = {1155--1163},
abstract = {(NZB x NZW)F(1) and MRL/Fas(lpr) lupus mice present a similar phenotype with a spectrum of autoantibodies associated with very severe nephritis. It is thought, however, that in contrast to other lupus-prone mice such as MRL/Fas(lpr) mice, (NZB x NZW)F(1) mice do not generate autoantibodies to ribonucleoproteins (RNP) Sm/RNP. In this study, we demonstrate that contrary to previous reports, the autoimmune response directed against Sm/RNP antigens also occurs in NZB x NZW mice. CD4(+) T cells from unprimed 10-week-old NZB x NZW mice proliferate and secrete IL-2 in response to peptide 131-151 of the U1-70K protein, which is known to contain a T(h) epitope recognized by CD4(+) T cells from MRL/Fas(lpr) mice. Peptide 131-151, which was found to bind I-A(k) and I-E(k) class II MHC molecules, also bound both I-A(d) and I-E(d) molecules. This result led us to also re-evaluate longitudinally the anti-Sm/RNP antibody response in NZB x NZW mice. We found that 25-week-old mice do produce antibodies reacting with several small nuclear and heterogeneous nuclear (hn) RNP proteins, such as SmD1, U1-70K and hnRNP A2/B1 proteins. The fine specificity of these antibodies was studied with overlapping synthetic peptides. The same antigenically positive and negative peptides were characterized in MRL/Fas(lpr) and NZB x NZW mice in the three proteins. This new finding can help to understand the mechanisms involved in the development of the anti-Sm/RNP antibody response and, particularly, the role played by non-MHC genes in this autoimmune response.},
keywords = {Animals, Antibody Specificity, B-Lymphocytes, Crosses, Dumortier, fas Receptor, Female, Genetic, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Histocompatibility Antigens Class II, I2CT, Immunoglobulin G, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, Ribonucleoproteins, Small Nuclear, Species Specificity, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
(NZB x NZW)F(1) and MRL/Fas(lpr) lupus mice present a similar phenotype with a spectrum of autoantibodies associated with very severe nephritis. It is thought, however, that in contrast to other lupus-prone mice such as MRL/Fas(lpr) mice, (NZB x NZW)F(1) mice do not generate autoantibodies to ribonucleoproteins (RNP) Sm/RNP. In this study, we demonstrate that contrary to previous reports, the autoimmune response directed against Sm/RNP antigens also occurs in NZB x NZW mice. CD4(+) T cells from unprimed 10-week-old NZB x NZW mice proliferate and secrete IL-2 in response to peptide 131-151 of the U1-70K protein, which is known to contain a T(h) epitope recognized by CD4(+) T cells from MRL/Fas(lpr) mice. Peptide 131-151, which was found to bind I-A(k) and I-E(k) class II MHC molecules, also bound both I-A(d) and I-E(d) molecules. This result led us to also re-evaluate longitudinally the anti-Sm/RNP antibody response in NZB x NZW mice. We found that 25-week-old mice do produce antibodies reacting with several small nuclear and heterogeneous nuclear (hn) RNP proteins, such as SmD1, U1-70K and hnRNP A2/B1 proteins. The fine specificity of these antibodies was studied with overlapping synthetic peptides. The same antigenically positive and negative peptides were characterized in MRL/Fas(lpr) and NZB x NZW mice in the three proteins. This new finding can help to understand the mechanisms involved in the development of the anti-Sm/RNP antibody response and, particularly, the role played by non-MHC genes in this autoimmune response.
2000
Casimir J R, Iterbeke K, Nest W Van Den, Trescol-Biémont M C, Dumortier H, Muller S, Gerlier D, Rabourdin-Combe C, Tourwé D, Paris J
Conformational restriction of the Tyr53 side-chain in the decapeptide HE Journal Article
In: The Journal of Peptide Research: Official Journal of the American Peptide Society, vol. 56, no. 6, pp. 398–408, 2000, ISSN: 1397-002X.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animals, Antigen, Antigen-Presenting Cells, B-Lymphocytes, Chemical, Chickens, Dumortier, I2CT, Major Histocompatibility Complex, Mice, Models, Molecular Sequence Data, Muramidase, Peptide Biosynthesis, Peptides, Phenylalanine, Protein Binding, Protein Conformation, Receptors, T-Cell, Team-Dumortier, Temperature, Tyrosine
@article{casimir_conformational_2000,
title = {Conformational restriction of the Tyr53 side-chain in the decapeptide HE},
author = {J R Casimir and K Iterbeke and W Van Den Nest and M C Trescol-Biémont and H Dumortier and S Muller and D Gerlier and C Rabourdin-Combe and D Tourwé and J Paris},
doi = {10.1034/j.1399-3011.2000.00777.x},
issn = {1397-002X},
year = {2000},
date = {2000-12-01},
journal = {The Journal of Peptide Research: Official Journal of the American Peptide Society},
volume = {56},
number = {6},
pages = {398--408},
abstract = {A series of conformationally restricted analogs of the hen egg lysozyme (HEL) decapeptide 52-61 in which the conformationally flexible Tyr53 residue was replaced by several more constrained tyrosine and phenylalanine analogs was prepared. Among these tyrosine and phenylalanine analogs were 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (Htc), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), 4-amino- 1,2,4,5-tetrahydro-8-hydroxy-2-benzazepine-3-one (Hba), 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-one (Aba), 2-amino-6-hydroxytetralin-2-carboxylic acid (Hat) and 2-amino-5-hydroxyindan-2-carboxylic acid (Hai) in which the rotations around Calpha-Cbeta and Cbeta-Cgamma were restricted because of cyclization of the side-chain to the backbone. Synthesis of Pht-Hba-Gly-OH using a modification of the Flynn and de Laszlo procedure is described. Analogs of beta-methyltyrosine (beta-MeTyr) in which the side-chains were biased to particular side-chain torsional angles because of substitution at the beta-hydrogens were also prepared. These analogs of HEL[52-61] peptide were tested for their ability to bind to the major histocompatibility complex class II I-Ak molecule and to be recognized in this context by two T-cell hybridomas, specific for the parent peptide HEL[52-61]. The data showed that the conformation and also the configuration of the Tyr53 residue influenced both the binding of the peptide to I-Ak and the recognition of the peptide/I-Ak complex by a T-cell receptor.},
keywords = {Amino Acid Sequence, Animals, Antigen, Antigen-Presenting Cells, B-Lymphocytes, Chemical, Chickens, Dumortier, I2CT, Major Histocompatibility Complex, Mice, Models, Molecular Sequence Data, Muramidase, Peptide Biosynthesis, Peptides, Phenylalanine, Protein Binding, Protein Conformation, Receptors, T-Cell, Team-Dumortier, Temperature, Tyrosine},
pubstate = {published},
tppubtype = {article}
}
A series of conformationally restricted analogs of the hen egg lysozyme (HEL) decapeptide 52-61 in which the conformationally flexible Tyr53 residue was replaced by several more constrained tyrosine and phenylalanine analogs was prepared. Among these tyrosine and phenylalanine analogs were 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (Htc), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), 4-amino- 1,2,4,5-tetrahydro-8-hydroxy-2-benzazepine-3-one (Hba), 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-one (Aba), 2-amino-6-hydroxytetralin-2-carboxylic acid (Hat) and 2-amino-5-hydroxyindan-2-carboxylic acid (Hai) in which the rotations around Calpha-Cbeta and Cbeta-Cgamma were restricted because of cyclization of the side-chain to the backbone. Synthesis of Pht-Hba-Gly-OH using a modification of the Flynn and de Laszlo procedure is described. Analogs of beta-methyltyrosine (beta-MeTyr) in which the side-chains were biased to particular side-chain torsional angles because of substitution at the beta-hydrogens were also prepared. These analogs of HEL[52-61] peptide were tested for their ability to bind to the major histocompatibility complex class II I-Ak molecule and to be recognized in this context by two T-cell hybridomas, specific for the parent peptide HEL[52-61]. The data showed that the conformation and also the configuration of the Tyr53 residue influenced both the binding of the peptide to I-Ak and the recognition of the peptide/I-Ak complex by a T-cell receptor.
Monneaux F, Muller S
Laboratory protocols for the identification of Th cell epitopes on self-antigens in mice with systemic autoimmune diseases Journal Article
In: Journal of Immunological Methods, vol. 244, no. 1-2, pp. 195–204, 2000, ISSN: 0022-1759.
Abstract | Links | BibTeX | Tags: Animals, Antigen Presentation, Antigen-Presenting Cells, Autoantigens, B-Lymphocytes, Coculture Techniques, Epitopes, Female, Flow Cytometry, I2CT, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Lymphocyte Activation, Mice, Monneaux, Ribonucleoproteins, Small Nuclear, Systemic, T-Lymphocyte, Team-Dumortier, Th1 Cells, Th2 Cells
@article{monneaux_laboratory_2000,
title = {Laboratory protocols for the identification of Th cell epitopes on self-antigens in mice with systemic autoimmune diseases},
author = {F Monneaux and S Muller},
doi = {10.1016/s0022-1759(00)00256-8},
issn = {0022-1759},
year = {2000},
date = {2000-10-01},
journal = {Journal of Immunological Methods},
volume = {244},
number = {1-2},
pages = {195--204},
abstract = {T cells play a critical role in both the immunological and clinical manifestations of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although in normal mice multiple T cell epitopes have been characterized in several self-proteins, there is little information on the fine specificity of autoreactive T cells in lupus model mice and humans. In SLE-prone mice and humans, the only Th cell epitopes identified at the molecular level in self-antigens concern histones and nucleosomes, and the 70-kD U1-snRNP protein. T cell characterization in certain autoimmune mice such as MRL lpr/lpr and NZB/NZW mice has been largely impaired by their hyporesponsiveness in response to mitogen and minimal IL-2 secretion. In addition, MRL lpr/lpr mice also develop lymphadenopathy characterized by the progressive accumulation of functionally immature CD4(-) CD8(-) T cells. It is therefore important to optimize the methods used to measure T cell proliferation and cytokine production ex vivo in order to identify minimal activation in the presence of appropriate antigen. The protocol described in this article has been used for identifying in young MRL lpr/lpr and NZB/NZW mice a CD4(+) T cell epitope in the murine 70-kD U1-RNP protein.},
keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Autoantigens, B-Lymphocytes, Coculture Techniques, Epitopes, Female, Flow Cytometry, I2CT, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Lymphocyte Activation, Mice, Monneaux, Ribonucleoproteins, Small Nuclear, Systemic, T-Lymphocyte, Team-Dumortier, Th1 Cells, Th2 Cells},
pubstate = {published},
tppubtype = {article}
}
T cells play a critical role in both the immunological and clinical manifestations of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although in normal mice multiple T cell epitopes have been characterized in several self-proteins, there is little information on the fine specificity of autoreactive T cells in lupus model mice and humans. In SLE-prone mice and humans, the only Th cell epitopes identified at the molecular level in self-antigens concern histones and nucleosomes, and the 70-kD U1-snRNP protein. T cell characterization in certain autoimmune mice such as MRL lpr/lpr and NZB/NZW mice has been largely impaired by their hyporesponsiveness in response to mitogen and minimal IL-2 secretion. In addition, MRL lpr/lpr mice also develop lymphadenopathy characterized by the progressive accumulation of functionally immature CD4(-) CD8(-) T cells. It is therefore important to optimize the methods used to measure T cell proliferation and cytokine production ex vivo in order to identify minimal activation in the presence of appropriate antigen. The protocol described in this article has been used for identifying in young MRL lpr/lpr and NZB/NZW mice a CD4(+) T cell epitope in the murine 70-kD U1-RNP protein.
Dumortier H, Monneaux F, Jahn-Schmid B, Briand J P, Skriner K, Cohen P L, Smolen J S, Steiner G, Muller S
B and Ŧ cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 165, no. 4, pp. 2297–2305, 2000, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animals, Autoantibodies, B-Lymphocytes, Dumortier, Epitope Mapping, Female, Heterogeneous Nuclear, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Humans, I2CT, Immunoglobulin G, Inbred BALB C, Inbred C57BL, Inbred CBA, Inbred MRL lpr, Injections, Lupus Nephritis, Lymphocyte Activation, Male, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Recombinant Proteins, Ribonucleoproteins, RNA, Spliceosomes, Subcutaneous, T-Lymphocytes, Team-Dumortier, transgenic
@article{dumortier_b_2000,
title = {B and Ŧ cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice},
author = {H Dumortier and F Monneaux and B Jahn-Schmid and J P Briand and K Skriner and P L Cohen and J S Smolen and G Steiner and S Muller},
doi = {10.4049/jimmunol.165.4.2297},
issn = {0022-1767},
year = {2000},
date = {2000-08-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {165},
number = {4},
pages = {2297--2305},
abstract = {Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid arthritis, systemic lupus erythematosus, and mixed-connective tissue disease. With the aim of investigating a potential pathogenic role of these Abs, we have studied the Ab response to A2/B1 hnRNPs in different murine models of lupus. The specificity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthetic peptides covering the region 1-206 of A2 that contains most of the epitopes recognized by patients' Abs. A major epitope recognized very early during the course of the disease by Abs from most of MRL lpr/lpr mice but not from other lupus mice and from mice of different MHC haplotypes immunized against B1 was identified in residues 50-70. This peptide contains a highly conserved sequence RGFGFVTF also present in other hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second A2 epitope identified in residues 35-55 were detectable several weeks later, suggesting an intramolecular B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35-175 that generated an effective Th cell response with IL-2 and IFN-gamma secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2k as MRL/lpr mice. None of the peptides stimulated T cells primed in vivo with B1. Because Abs to peptide 50-70 were detected significantly earlier than Abs reacting with other A2 peptides and the protein itself, it is possible that within the protein, this segment contains residues playing an initiator role in the induction of the anti-A2/B1 and antispliceosome Ab response.},
keywords = {Amino Acid Sequence, Animals, Autoantibodies, B-Lymphocytes, Dumortier, Epitope Mapping, Female, Heterogeneous Nuclear, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Humans, I2CT, Immunoglobulin G, Inbred BALB C, Inbred C57BL, Inbred CBA, Inbred MRL lpr, Injections, Lupus Nephritis, Lymphocyte Activation, Male, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Recombinant Proteins, Ribonucleoproteins, RNA, Spliceosomes, Subcutaneous, T-Lymphocytes, Team-Dumortier, transgenic},
pubstate = {published},
tppubtype = {article}
}
Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid arthritis, systemic lupus erythematosus, and mixed-connective tissue disease. With the aim of investigating a potential pathogenic role of these Abs, we have studied the Ab response to A2/B1 hnRNPs in different murine models of lupus. The specificity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthetic peptides covering the region 1-206 of A2 that contains most of the epitopes recognized by patients' Abs. A major epitope recognized very early during the course of the disease by Abs from most of MRL lpr/lpr mice but not from other lupus mice and from mice of different MHC haplotypes immunized against B1 was identified in residues 50-70. This peptide contains a highly conserved sequence RGFGFVTF also present in other hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second A2 epitope identified in residues 35-55 were detectable several weeks later, suggesting an intramolecular B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35-175 that generated an effective Th cell response with IL-2 and IFN-gamma secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2k as MRL/lpr mice. None of the peptides stimulated T cells primed in vivo with B1. Because Abs to peptide 50-70 were detected significantly earlier than Abs reacting with other A2 peptides and the protein itself, it is possible that within the protein, this segment contains residues playing an initiator role in the induction of the anti-A2/B1 and antispliceosome Ab response.
Monneaux F, Briand J P, Muller S
In: European Journal of Immunology, vol. 30, no. 8, pp. 2191–2200, 2000, ISSN: 0014-2980.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Animals, Antigen-Presenting Cells, Autoimmunity, B-Lymphocytes, CD4-Positive T-Lymphocytes, Epitopes, Female, I2CT, Inbred BALB C, Inbred CBA, Inbred MRL lpr, Lupus Vulgaris, Lymphocyte Activation, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, T-Lymphocyte, Team-Dumortier, U1 Small Nuclear
@article{monneaux_b_2000,
title = {B and Ŧ cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) Ŧ cells recognize a Ŧ cell epitope located within the RNP80 motif of the 70K protein},
author = {F Monneaux and J P Briand and S Muller},
doi = {10.1002/1521-4141(2000)30:8<2191::AID-IMMU2191>3.0.CO;2-R},
issn = {0014-2980},
year = {2000},
date = {2000-08-01},
journal = {European Journal of Immunology},
volume = {30},
number = {8},
pages = {2191--2200},
abstract = {Systemic lupus erythematosus is characterized by the presence of high titers of autoantibodies reacting with various components of the U1 small nuclear ribonucleoprotein particle (snRNP). It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought, with 20 overlapping peptides, the Th epitopes on the U1-70K snRNP in unprimed H-2(k) MRL / lpr lupus mice and immunized CBA normal mice. The peptide 131 - 151 was recognized by both IgG autoantibodies and CD4(+) T cells from 7 - 9-week-old MRL / lpr mice. In this test, antigen-presenting cells (APC) from MRL / lpr mice were required; APC from naive CBA mice failed to stimulate CD4(+) cells from MRL / lpr mice. The potential role of MRL / lpr B cells as APC, the expression of MHC class II molecules at their surface and their activation state (expression of CD69, CD80 / B7-1 and CD86 / B7-2 molecules) were studied. Peptide 131 - 151 bound both I-A(k) and I-E(k) class II molecules and favored an IL-2-positive T cell response but not IFN-gamma, IL-6 and IL-10 secretion. Segment 131 - 151 is localized within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins.},
keywords = {Amino Acid Motifs, Animals, Antigen-Presenting Cells, Autoimmunity, B-Lymphocytes, CD4-Positive T-Lymphocytes, Epitopes, Female, I2CT, Inbred BALB C, Inbred CBA, Inbred MRL lpr, Lupus Vulgaris, Lymphocyte Activation, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, T-Lymphocyte, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
Systemic lupus erythematosus is characterized by the presence of high titers of autoantibodies reacting with various components of the U1 small nuclear ribonucleoprotein particle (snRNP). It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought, with 20 overlapping peptides, the Th epitopes on the U1-70K snRNP in unprimed H-2(k) MRL / lpr lupus mice and immunized CBA normal mice. The peptide 131 - 151 was recognized by both IgG autoantibodies and CD4(+) T cells from 7 - 9-week-old MRL / lpr mice. In this test, antigen-presenting cells (APC) from MRL / lpr mice were required; APC from naive CBA mice failed to stimulate CD4(+) cells from MRL / lpr mice. The potential role of MRL / lpr B cells as APC, the expression of MHC class II molecules at their surface and their activation state (expression of CD69, CD80 / B7-1 and CD86 / B7-2 molecules) were studied. Peptide 131 - 151 bound both I-A(k) and I-E(k) class II molecules and favored an IL-2-positive T cell response but not IFN-gamma, IL-6 and IL-10 secretion. Segment 131 - 151 is localized within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins.
Obrecht-Pflumio S., Dirheimer G.
In vitro DNA and dGMP adducts formation caused by ochratoxin A Journal Article
In: Chem Biol Interact, vol. 127, no. 1, pp. 29-44, 2000, (0009-2797 Journal Article).
Abstract | BibTeX | Tags: Acid/metabolism, Adducts/*metabolism, Agents/pharmacology, Animals, Arachidonic, Carcinogens/pharmacology, Chelating, Chromatography, Deferoxamine/pharmacology, Deoxyguanine, DNA, Female, Kidney/ultrastructure, Liver/metabolism, Male, Mice, Microsomes, Microsomes/metabolism, Mycotoxins/pharmacology, NADP/metabolism, Nucleotides/*metabolism, Nucleotides/metabolism, Ochratoxins/*pharmacology, Peroxidase/metabolism, Rabbits, Spectrophotometry
@article{,
title = {In vitro DNA and dGMP adducts formation caused by ochratoxin A},
author = { S. Obrecht-Pflumio and G. Dirheimer},
year = {2000},
date = {2000-01-01},
journal = {Chem Biol Interact},
volume = {127},
number = {1},
pages = {29-44},
abstract = {Ochratoxin A (OTA), a nephrotoxic and nephrocarcinogenic mycotoxin, leads to the formation of DNA adducts after administration to animals. This could be due to an epigenetic effect. In vitro assays can exclude an indirect effect, where the xenobiotic can generate, in vivo, endogenous reactive compounds which give adducts on DNA. Microsomes prepared from mice or rabbit kidney and liver, used as metabolic activators, were incubated in the presence of commercial salmon testes DNA and OTA, with NADPH or arachidonic acid used as cofactors. Upto 126 DNA adducts for 10(9) nucleotides were detected using the 32P postlabeling method after incubation with the mouse kidney system. Similar results were obtained with rabbit kidney microsomes. Using liver microsomes, the number of DNA adducts detected was much lower. When NADPH was used as a cosubstrate (to explore the cytochrome P450 metabolic pathways), with mice kidney microsomes, the adduct level was only 44% of the one obtained with arachidonic acid. These results lend support to the hypothesis of the preferential activation of OTA by the peroxidase activity of prostaglandin synthases and/or lipoxygenases to direct genotoxic metabolites, and are in agreement with the previously obtained results after in vivo treatment of mice. In order to identify the nucleotides of DNA modified by the OTA metabolites, dAMP, dGMP, dTMP and dCMP were used as substrates under the same conditions as with DNA. The adducts were found only on dGMP. The total adduct level was of 344 adducts per 10(9) nucleotides with the appearance of three major adducts in the presence of arachidonic acid. With NADPH, 271 adducts were obtained per 10(9) nucleotides, with again three major adducts, but only two of them were similar to two adducts obtained in the presence of arachidonic acid. Desferal (desferrioxamine B methanesulphonate), at a 50 microM concentration, did not reduce the adduct level. Adducts were also obtained when polydG, polydC and dG-p-dG were used as alternative substrates, whereas no adducts were obtained with polydA, polydT and polydC. The major adduct obtained after incubation of DNA with OTA, comigrated with the major adduct obtained with dGMP, in two chromatographic solvents. These results show that OTA is metabolized to genotoxic metabolite(s) which interact with the guanine residues of DNA.},
note = {0009-2797
Journal Article},
keywords = {Acid/metabolism, Adducts/*metabolism, Agents/pharmacology, Animals, Arachidonic, Carcinogens/pharmacology, Chelating, Chromatography, Deferoxamine/pharmacology, Deoxyguanine, DNA, Female, Kidney/ultrastructure, Liver/metabolism, Male, Mice, Microsomes, Microsomes/metabolism, Mycotoxins/pharmacology, NADP/metabolism, Nucleotides/*metabolism, Nucleotides/metabolism, Ochratoxins/*pharmacology, Peroxidase/metabolism, Rabbits, Spectrophotometry},
pubstate = {published},
tppubtype = {article}
}
Ochratoxin A (OTA), a nephrotoxic and nephrocarcinogenic mycotoxin, leads to the formation of DNA adducts after administration to animals. This could be due to an epigenetic effect. In vitro assays can exclude an indirect effect, where the xenobiotic can generate, in vivo, endogenous reactive compounds which give adducts on DNA. Microsomes prepared from mice or rabbit kidney and liver, used as metabolic activators, were incubated in the presence of commercial salmon testes DNA and OTA, with NADPH or arachidonic acid used as cofactors. Upto 126 DNA adducts for 10(9) nucleotides were detected using the 32P postlabeling method after incubation with the mouse kidney system. Similar results were obtained with rabbit kidney microsomes. Using liver microsomes, the number of DNA adducts detected was much lower. When NADPH was used as a cosubstrate (to explore the cytochrome P450 metabolic pathways), with mice kidney microsomes, the adduct level was only 44% of the one obtained with arachidonic acid. These results lend support to the hypothesis of the preferential activation of OTA by the peroxidase activity of prostaglandin synthases and/or lipoxygenases to direct genotoxic metabolites, and are in agreement with the previously obtained results after in vivo treatment of mice. In order to identify the nucleotides of DNA modified by the OTA metabolites, dAMP, dGMP, dTMP and dCMP were used as substrates under the same conditions as with DNA. The adducts were found only on dGMP. The total adduct level was of 344 adducts per 10(9) nucleotides with the appearance of three major adducts in the presence of arachidonic acid. With NADPH, 271 adducts were obtained per 10(9) nucleotides, with again three major adducts, but only two of them were similar to two adducts obtained in the presence of arachidonic acid. Desferal (desferrioxamine B methanesulphonate), at a 50 microM concentration, did not reduce the adduct level. Adducts were also obtained when polydG, polydC and dG-p-dG were used as alternative substrates, whereas no adducts were obtained with polydA, polydT and polydC. The major adduct obtained after incubation of DNA with OTA, comigrated with the major adduct obtained with dGMP, in two chromatographic solvents. These results show that OTA is metabolized to genotoxic metabolite(s) which interact with the guanine residues of DNA.
Rihn B., Coulais C., Kauffer E., Bottin M. C., Martin P., Yvon F., Vigneron J. C., Binet S., Monhoven N., Steiblen G., Keith G.
Inhaled crocidolite mutagenicity in lung DNA Journal Article
In: Environ Health Perspect, vol. 108, no. 4, pp. 341-6, 2000, (0091-6765 Journal Article).
Abstract | BibTeX | Tags: &, Adducts/*genetics, Air, Alveolar/physiology, Animals, Asbestos, Crocidolite/administration, Damage/*genetics, DNA, dosage/*adverse, effects, effects/pathology, Exposure, Gov't, Inhalation, Lung/*drug, Macrophages, Male, Mice, Mutagenicity, Non-U.S., Pollutants/*adverse, Support, Tests, transgenic
@article{,
title = {Inhaled crocidolite mutagenicity in lung DNA},
author = { B. Rihn and C. Coulais and E. Kauffer and M. C. Bottin and P. Martin and F. Yvon and J. C. Vigneron and S. Binet and N. Monhoven and G. Steiblen and G. Keith},
year = {2000},
date = {2000-01-01},
journal = {Environ Health Perspect},
volume = {108},
number = {4},
pages = {341-6},
abstract = {We used transgenic mice carrying the lacI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-only inhalation to an aerosol containing 5.75 mg/m(3) crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacI reporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 +/- 103 ng/mg lung). There was evidence of a typical inflammatory response consisting of multinucleate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonuclear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 [time] 10(-5) in the exposed group versus 6. 9 10(-5) in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the (32)P-postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.},
note = {0091-6765
Journal Article},
keywords = {&, Adducts/*genetics, Air, Alveolar/physiology, Animals, Asbestos, Crocidolite/administration, Damage/*genetics, DNA, dosage/*adverse, effects, effects/pathology, Exposure, Gov't, Inhalation, Lung/*drug, Macrophages, Male, Mice, Mutagenicity, Non-U.S., Pollutants/*adverse, Support, Tests, transgenic},
pubstate = {published},
tppubtype = {article}
}
We used transgenic mice carrying the lacI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-only inhalation to an aerosol containing 5.75 mg/m(3) crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacI reporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 +/- 103 ng/mg lung). There was evidence of a typical inflammatory response consisting of multinucleate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonuclear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 [time] 10(-5) in the exposed group versus 6. 9 10(-5) in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the (32)P-postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.
Rihn B. H., Bottin M. C., Coulais C., Rouget R., Monhoven N., Baranowski W., Edorh A., Keith G.
Genotoxicity of 3-methylcholanthrene in liver of transgenic big Blue mice Journal Article
In: Environ Mol Mutagen, vol. 36, no. 4, pp. 266-73, 2000, (0893-6692 Journal Article).
Abstract | BibTeX | Tags: *Escherichia, Adducts, Animals, Bacterial, Base, C57BL, Cell, coli, Division/drug, DNA, effects, Gov't, Inbred, Liver/cytology/*drug, Methylcholanthrene/*toxicity, Mice, Mutagens/*toxicity, Mutation, Non-U.S., Organ, Primers, Proteins, Proteins/genetics, Repressor, Sequence, Support, transgenic, Weight
@article{,
title = {Genotoxicity of 3-methylcholanthrene in liver of transgenic big Blue mice},
author = { B. H. Rihn and M. C. Bottin and C. Coulais and R. Rouget and N. Monhoven and W. Baranowski and A. Edorh and G. Keith},
year = {2000},
date = {2000-01-01},
journal = {Environ Mol Mutagen},
volume = {36},
number = {4},
pages = {266-73},
abstract = {Transgenic mice provide a unique tool for studying the tissue specificity and mutagenic potential of chemicals. Because 3-methylcholanthrene (3MC) was found mutagenic in bacteria, clastogenic in bone marrow, and induces DNA adducts in animals, we were interested to determinine whether this xenobiotic provokes (1) cell proliferation, (2) transcriptional activity changes, (3) DNA adducts, and (4) hepatic mutations in transgenic Big Blue mice carrying the lambdaLIZ phage shuttle vector. Big Blue C57/Bl male mice were treated with a single intraperitoneal dose of 80 mg/kg 3MC for 1, 3, 6, 14, or 30 days. Cell proliferation was checked by 5-bromo-2-deoxyuridine labeling and immunohistochemical detection. The maximal increase of the mitotic index was evidenced after 3 days (2.9 times the control value; P < 0.01). The relative nucleus area, reflecting the transcriptional activity, was also the highest in the treated group after 3 days: 1.86 times the control value, on average (P < 0.01). Four major DNA adducts, determined according to the [(32)P]-postlabeling method, were evidenced in liver DNA of treated mice, 6 days after the treatment: the spot intensities increased in a time-dependent manner. The mutant frequency of liver DNA was the highest after 14 days: 20.3 +/- 2.9 x 10(-5) in the treated vs. 7.6 +/- 2.7 x 10(-5) in the control mice (P < 0.01). Sequencing of the lambda lacI mutant plaques showed mainly G:C --> T:A and C:G --> A:T transversions. In conclusion, 3MC at first induced nuclear enlargement and a slight increase of cell proliferation in liver, followed by parallel formation of DNA adducts and mutations. This study shows how transgenic models allow in vivo evaluation of mechanistically simultaneous endpoints.},
note = {0893-6692
Journal Article},
keywords = {*Escherichia, Adducts, Animals, Bacterial, Base, C57BL, Cell, coli, Division/drug, DNA, effects, Gov't, Inbred, Liver/cytology/*drug, Methylcholanthrene/*toxicity, Mice, Mutagens/*toxicity, Mutation, Non-U.S., Organ, Primers, Proteins, Proteins/genetics, Repressor, Sequence, Support, transgenic, Weight},
pubstate = {published},
tppubtype = {article}
}
Transgenic mice provide a unique tool for studying the tissue specificity and mutagenic potential of chemicals. Because 3-methylcholanthrene (3MC) was found mutagenic in bacteria, clastogenic in bone marrow, and induces DNA adducts in animals, we were interested to determinine whether this xenobiotic provokes (1) cell proliferation, (2) transcriptional activity changes, (3) DNA adducts, and (4) hepatic mutations in transgenic Big Blue mice carrying the lambdaLIZ phage shuttle vector. Big Blue C57/Bl male mice were treated with a single intraperitoneal dose of 80 mg/kg 3MC for 1, 3, 6, 14, or 30 days. Cell proliferation was checked by 5-bromo-2-deoxyuridine labeling and immunohistochemical detection. The maximal increase of the mitotic index was evidenced after 3 days (2.9 times the control value; P < 0.01). The relative nucleus area, reflecting the transcriptional activity, was also the highest in the treated group after 3 days: 1.86 times the control value, on average (P < 0.01). Four major DNA adducts, determined according to the [(32)P]-postlabeling method, were evidenced in liver DNA of treated mice, 6 days after the treatment: the spot intensities increased in a time-dependent manner. The mutant frequency of liver DNA was the highest after 14 days: 20.3 +/- 2.9 x 10(-5) in the treated vs. 7.6 +/- 2.7 x 10(-5) in the control mice (P < 0.01). Sequencing of the lambda lacI mutant plaques showed mainly G:C --> T:A and C:G --> A:T transversions. In conclusion, 3MC at first induced nuclear enlargement and a slight increase of cell proliferation in liver, followed by parallel formation of DNA adducts and mutations. This study shows how transgenic models allow in vivo evaluation of mechanistically simultaneous endpoints.
Imler Jean-Luc, Hoffmann Jules A
Toll and Toll-like proteins: an ancient family of receptors signaling infection Journal Article
In: Reviews in Immunogenetics, vol. 2, no. 3, pp. 294–304, 2000, ISSN: 1398-1714.
Abstract | BibTeX | Tags: Adaptor Proteins, Animals, Antigens, Autoantigens, CD14, Cell Adhesion Molecules, Cell Surface, Differentiation, DNA-Binding Proteins, Gene Expression Regulation, hoffmann, I-kappa B Proteins, imler, Immunity, Immunologic, infection, Innate, Insect Proteins, Interleukin-1 Receptor-Associated Kinases, Knockout, Larva, Lipopolysaccharides, M3i, Mammals, MAP Kinase Signaling System, Membrane Glycoproteins, Membrane Proteins, Mice, Multigene Family, Myeloid Differentiation Factor 88, NF-kappa B, peptidoglycan, Phosphorylation, Post-Translational, Protein Kinases, Protein Processing, Protein Structure, Receptors, Recombinant Fusion Proteins, Signal Transducing, Signal Transduction, Teichoic Acids, Tertiary, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 6, Toll-Like Receptor 9, Toll-Like Receptors, Ubiquitins
@article{imler_toll_2000,
title = {Toll and Toll-like proteins: an ancient family of receptors signaling infection},
author = {Jean-Luc Imler and Jules A Hoffmann},
issn = {1398-1714},
year = {2000},
date = {2000-01-01},
journal = {Reviews in Immunogenetics},
volume = {2},
number = {3},
pages = {294--304},
abstract = {Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals.},
keywords = {Adaptor Proteins, Animals, Antigens, Autoantigens, CD14, Cell Adhesion Molecules, Cell Surface, Differentiation, DNA-Binding Proteins, Gene Expression Regulation, hoffmann, I-kappa B Proteins, imler, Immunity, Immunologic, infection, Innate, Insect Proteins, Interleukin-1 Receptor-Associated Kinases, Knockout, Larva, Lipopolysaccharides, M3i, Mammals, MAP Kinase Signaling System, Membrane Glycoproteins, Membrane Proteins, Mice, Multigene Family, Myeloid Differentiation Factor 88, NF-kappa B, peptidoglycan, Phosphorylation, Post-Translational, Protein Kinases, Protein Processing, Protein Structure, Receptors, Recombinant Fusion Proteins, Signal Transducing, Signal Transduction, Teichoic Acids, Tertiary, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 6, Toll-Like Receptor 9, Toll-Like Receptors, Ubiquitins},
pubstate = {published},
tppubtype = {article}
}
Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals.
1997
Mézière C, Viguier M, Dumortier H, Lo-Man R, Leclerc C, Guillet J G, Briand J P, Muller S
In vivo Ŧ helper cell response to retro-inverso peptidomimetics Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 159, no. 7, pp. 3230–3237, 1997, ISSN: 0022-1767.
Abstract | BibTeX | Tags: Amino Acid Sequence, Animals, Antibodies, Antigen, Capsid, Capsid Proteins, Dumortier, Female, Helper-Inducer, Histocompatibility Antigens Class II, I2CT, Immunoglobulin Allotypes, Immunoglobulin G, Inbred BALB C, Injections, Intraperitoneal, Lymphocyte Activation, Mice, Molecular Sequence Data, Peptide Fragments, Poliovirus, Protein Binding, Receptors, T-Cell, T-Lymphocytes, Team-Dumortier, Viral
@article{meziere_vivo_1997,
title = {In vivo Ŧ helper cell response to retro-inverso peptidomimetics},
author = {C Mézière and M Viguier and H Dumortier and R Lo-Man and C Leclerc and J G Guillet and J P Briand and S Muller},
issn = {0022-1767},
year = {1997},
date = {1997-10-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {159},
number = {7},
pages = {3230--3237},
abstract = {Peptide analogues containing reversed peptide bonds between each residue along the peptide sequence (retro-inverso modification) have been analyzed for their antigenic and in vivo immunogenic properties in the MHC II and Th cell response context. Two antigenic peptides were selected for this study, namely peptide 103-115 of poliovirus VP1, which is involved in the production of Abs that neutralize the infectivity of the virus, and peptide 435-446 from the third constant region of mouse heavy chain IgG2a allopeptide gamma 2ab, which mimics a corneal Ag implicated in autoimmune keratitis. In a competition assay performed in vitro using reference hybridomas of known MHC class II restriction, both retro-inverso analogues bound (although more weakly in our test) to I-Ad and/or I-Ed class II molecules. However, in both cases, this lower affinity was apparently largely compensated in vivo, as a T cell response (with IL-2 secretion), equivalent to that obtained with the wild-type peptides, was observed following immunization of BALB/c mice with the retro-inverso analogues. Moreover, these T cells proliferated and produced IL-2 in response to the cognate peptides. It is concluded that the T cell receptors of T cells primed in vivo with the retro-inverso analogues readily cross-react with parent and retro-inverso analogue-MHC complexes. The approach of using pseudopeptides containing changes involving the backbone, and not the orientation of side chains, may thus be promising to design potent immunogens for class II-restricted T cells.},
keywords = {Amino Acid Sequence, Animals, Antibodies, Antigen, Capsid, Capsid Proteins, Dumortier, Female, Helper-Inducer, Histocompatibility Antigens Class II, I2CT, Immunoglobulin Allotypes, Immunoglobulin G, Inbred BALB C, Injections, Intraperitoneal, Lymphocyte Activation, Mice, Molecular Sequence Data, Peptide Fragments, Poliovirus, Protein Binding, Receptors, T-Cell, T-Lymphocytes, Team-Dumortier, Viral},
pubstate = {published},
tppubtype = {article}
}
Peptide analogues containing reversed peptide bonds between each residue along the peptide sequence (retro-inverso modification) have been analyzed for their antigenic and in vivo immunogenic properties in the MHC II and Th cell response context. Two antigenic peptides were selected for this study, namely peptide 103-115 of poliovirus VP1, which is involved in the production of Abs that neutralize the infectivity of the virus, and peptide 435-446 from the third constant region of mouse heavy chain IgG2a allopeptide gamma 2ab, which mimics a corneal Ag implicated in autoimmune keratitis. In a competition assay performed in vitro using reference hybridomas of known MHC class II restriction, both retro-inverso analogues bound (although more weakly in our test) to I-Ad and/or I-Ed class II molecules. However, in both cases, this lower affinity was apparently largely compensated in vivo, as a T cell response (with IL-2 secretion), equivalent to that obtained with the wild-type peptides, was observed following immunization of BALB/c mice with the retro-inverso analogues. Moreover, these T cells proliferated and produced IL-2 in response to the cognate peptides. It is concluded that the T cell receptors of T cells primed in vivo with the retro-inverso analogues readily cross-react with parent and retro-inverso analogue-MHC complexes. The approach of using pseudopeptides containing changes involving the backbone, and not the orientation of side chains, may thus be promising to design potent immunogens for class II-restricted T cells.
1995
Briand J P, Guichard G, Dumortier H, Muller S
Retro-inverso peptidomimetics as new immunological probes. Validation and application to the detection of antibodies in rheumatic diseases Journal Article
In: The Journal of Biological Chemistry, vol. 270, no. 35, pp. 20686–20691, 1995, ISSN: 0021-9258.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animals, Antibodies, Autoantibodies, Autoimmune Diseases, Dumortier, Enzyme-Linked Immunosorbent Assay, Humans, I2CT, Immunoassay, Lupus Erythematosus, Mice, Molecular Sequence Data, Monoclonal, Peptide Fragments, Peptides, Rheumatic Diseases, Stereoisomerism, Structure-Activity Relationship, Systemic, Team-Dumortier
@article{briand_retro-inverso_1995,
title = {Retro-inverso peptidomimetics as new immunological probes. Validation and application to the detection of antibodies in rheumatic diseases},
author = {J P Briand and G Guichard and H Dumortier and S Muller},
doi = {10.1074/jbc.270.35.20686},
issn = {0021-9258},
year = {1995},
date = {1995-09-01},
journal = {The Journal of Biological Chemistry},
volume = {270},
number = {35},
pages = {20686--20691},
abstract = {Retro-inverso peptides which contain NH-CO bonds instead of CO-NH peptide bonds are much more resistant to proteolysis than L-peptides. Moreover, they have been shown recently to be able to mimic natural L-peptides with respect to poly- and monoclonal antibodies (Guichard, G., Benkirane, N., Zeder-Lutz, G., Van Regenmortel, M. H. V., Briand, J. P., and Muller, S. (1994b) Proc. Natl. Acad. Sci. U.S.A. 91, 9765-9769). We have further tested the capacity of retro-inverso peptidomimetics to serve as possible targets for antibodies produced by lupus mice and by patients with rheumatic autoimmune diseases. Several retro-inverso peptides corresponding to sequences known to be recognized by autoantibodies were synthesized, namely peptides 28-45 and 130-135 of H3, 277-291 of the Ro/SSA 52-kDa protein, and 304-324 of the Ro/SSA 60-kDa protein, and tested with autoimmune sera by enzyme-linked immunosorbent assay. We have found that retro-inverso peptides are recognized as well as or even better than natural peptides by antibodies from autoimmune patients and lupus mice. This new approach may lead to important progress in the future development of immunodiagnostic assays, particularly in the case of diseases characterized by inflammatory reactions in the course of which the level of degradative enzymes is increased.},
keywords = {Amino Acid Sequence, Animals, Antibodies, Autoantibodies, Autoimmune Diseases, Dumortier, Enzyme-Linked Immunosorbent Assay, Humans, I2CT, Immunoassay, Lupus Erythematosus, Mice, Molecular Sequence Data, Monoclonal, Peptide Fragments, Peptides, Rheumatic Diseases, Stereoisomerism, Structure-Activity Relationship, Systemic, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Retro-inverso peptides which contain NH-CO bonds instead of CO-NH peptide bonds are much more resistant to proteolysis than L-peptides. Moreover, they have been shown recently to be able to mimic natural L-peptides with respect to poly- and monoclonal antibodies (Guichard, G., Benkirane, N., Zeder-Lutz, G., Van Regenmortel, M. H. V., Briand, J. P., and Muller, S. (1994b) Proc. Natl. Acad. Sci. U.S.A. 91, 9765-9769). We have further tested the capacity of retro-inverso peptidomimetics to serve as possible targets for antibodies produced by lupus mice and by patients with rheumatic autoimmune diseases. Several retro-inverso peptides corresponding to sequences known to be recognized by autoantibodies were synthesized, namely peptides 28-45 and 130-135 of H3, 277-291 of the Ro/SSA 52-kDa protein, and 304-324 of the Ro/SSA 60-kDa protein, and tested with autoimmune sera by enzyme-linked immunosorbent assay. We have found that retro-inverso peptides are recognized as well as or even better than natural peptides by antibodies from autoimmune patients and lupus mice. This new approach may lead to important progress in the future development of immunodiagnostic assays, particularly in the case of diseases characterized by inflammatory reactions in the course of which the level of degradative enzymes is increased.
