129 results on '"Philippe Druet"'
Search Results
2. Effect of the thiol group on experimental gold-induced autoimmunity
- Author
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Jean-Charles Guéry, Lucette Pelletier, Philippe Druet, M. C. Vial, E. Druet, Chantal Mandet, H. Tournade, Patrick M. Dansette, and Régine Pasquier
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Propanols ,Immunology ,Autoimmunity ,Systemic autoimmunity ,medicine.disease_cause ,Thiol group ,Autoimmune Diseases ,Rheumatology ,Rats, Inbred BN ,Organometallic Compounds ,Animals ,Immunology and Allergy ,Medicine ,Pharmacology (medical) ,Sulfhydryl Compounds ,chemistry.chemical_classification ,Autoimmune disease ,Experimental model ,business.industry ,BROWN NORWAY ,medicine.disease ,Rats ,Sodium salt ,Disease Models, Animal ,chemistry ,Antirheumatic Agents ,Thiol ,Dimercaprol ,Female ,business ,Organogold Compounds - Abstract
Brown Norway rats injected with aurothiopro-panolsulfonate sodium salt develop systemic autoimmunity. The aim of this study was to assess the influence of the sulfur-containing group in this experimental model of gold-induced autoimmunity. It was shown that the sulfur-containing group does not induce autoimmunity of itself, but potentiates the immunotoxic effects of gold.
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- 2010
3. Mercury-Induced Autoimmune Glomerulonephritis in Animals
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Régine Pasquier, François Hirsch, Catherine Sapin, Lucette Pelletier, Jerome Rossert, Philippe Druet, and E. Druet
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chemistry ,business.industry ,Immunology ,Medicine ,chemistry.chemical_element ,Glomerulonephritis ,business ,medicine.disease ,Mercury (element) - Published
- 2015
4. IgA Nephropathy in Chronic Liver Disease
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D. Nochy, Philippe Druet, and J. Bariety
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medicine.medical_specialty ,Text mining ,business.industry ,Internal medicine ,medicine ,Chronic liver disease ,medicine.disease ,business ,Gastroenterology ,Nephropathy - Published
- 2015
5. The immunosuppressant LF 15-0195 prevents experimental autoimmune myasthenia gravis in Brown-Norway rats
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Abdelhadi Saoudi, P Dutartre, Valérie Duplan, and Philippe Druet
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Male ,B-Lymphocytes ,Transplantation ,Chemotherapy ,business.industry ,T-Lymphocytes ,medicine.medical_treatment ,BROWN NORWAY ,medicine.disease ,medicine.disease_cause ,Guanidines ,Myasthenia gravis ,Rats ,Autoimmunity ,Disease Models, Animal ,Animal model ,Rats, Inbred BN ,Antibody Formation ,Myasthenia Gravis ,Immunology ,medicine ,Animals ,Surgery ,business ,Immunosuppressive Agents - Published
- 2002
6. Beneficial effect of the immunosuppressant LF 15-0195 on passively induced rat experimental autoimmune encephalomyelitis
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Aline Stennevin, P Dutartre, K Ipinazar, Valérie Duplan, Abdelhadi Saoudi, and Philippe Druet
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Male ,Adoptive cell transfer ,Encephalomyelitis, Autoimmune, Experimental ,Encephalomyelitis ,Lymphocyte Activation ,medicine.disease_cause ,Guanidines ,Autoimmunity ,Interferon-gamma ,Immune system ,Antigen ,In vivo ,medicine ,Animals ,Autoimmune disease ,Transplantation ,business.industry ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Interleukin-10 ,Rats ,Rats, Inbred Lew ,Immunology ,Surgery ,Lymph Nodes ,business ,Immunosuppressive Agents - Abstract
EXPERIMENTAL allergic encephalomyelitis (EAE), an inflammatory autoimmune disease of the central nervous system (CNS), serves as an experimental model for multiple sclerosis. EAE is a T-cell-dependent paralytic disease that can be induced in experimental animals by injection of myelin-derived antigens emulsified in Complete Freund’s Adjuvant (CFA) or following adoptive transfer of T-cell lines or clones specific for various myelin proteins. The clinical course of EAE varies with the animal model and the protocol. In most models, acute EAE is followed by permanent remission and concomitant resistance to further disease induction or by a transient remission that is followed by subsequent relapses and remissions. A large body of evidence correlates the induction phase of EAE to a Th1-type immune response, whereas the remission phase as well as the subsequent resistance is characterized by an up-regulation of the anti-inflammatory cytokines IL-4, IL-10, and TGF. Deoxyspergualin (DSG) is a synthetic analogue of the anti-tumor antibiotic spergualin, a natural product isolated from Bacillus laterosporus. DSG is claimed to have potent immunosuppressive effects and several advantages compared to available immunosuppressive drugs. However, preclinical and clinical use of DSG is limited by its chemical and metabolic instability. Several analogues of DSG have been recently prepared through organic synthesis, such as LF 15-0195, an analogue that is more potent than DSG due to improved activity and increased metabolic resistance to oxidative metabolism in vivo. This new immunosuppressant is currently in clinical development for autoimmune diseases. The present study was undertaken to analyze the capacity of LF 15-0195 to inhibit the pathogenicity of differentiated effector T cells. We tested (i) the effect of LF 15-0195 administration in vivo on development of EAE induced by adoptive transfer of anti-myelin basic protein (MBP) pathogenic CD4 T cells and (ii) the effect of stimulation of immune lymph node cells in the presence of LF 15-0195 in vitro on their ability to transfer EAE. We showed that LF 15-0195, both in vitro and in vivo, reduced the pathogenicity of autoreactive effector anti-MBP CD4 T cells. This beneficial effect could not be explained by inhibition of the expansion of pathogenic CD4 T cells or by the inhibition of their production of effector cytokines. MATERIALS AND METHODS Animals
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- 2002
7. LF 15-0195 prevents from the development and inhibits the progression of rat experimental autoimmune myasthenia gravis
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Patrick Dutartre, Valérie Duplan, Abdelhadi Saoudi, and Philippe Druet
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Male ,Drug ,T-Lymphocytes ,media_common.quotation_subject ,Immunology ,Lymphocyte Activation ,medicine.disease_cause ,Guanidines ,Autoimmunity ,Antigen specific ,medicine ,Animals ,Immunology and Allergy ,Receptors, Cholinergic ,Autoantibodies ,media_common ,Acetylcholine receptor ,Autoimmune disease ,B-Lymphocytes ,Dose-Response Relationship, Drug ,Effector ,business.industry ,Interleukins ,Autoantibody ,Cell Differentiation ,medicine.disease ,Myasthenia gravis ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,Disease Models, Animal ,Neurology ,Rats, Inbred Lew ,Immunoglobulin G ,Neurology (clinical) ,business ,Cell Division ,Immunosuppressive Agents - Abstract
Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent antibody-mediated neuromuscular autoimmune disease induced in susceptible rats by a single immunisation with torpedo acetylcholine receptor (AChR). Here, we report that subcutaneous administration of a novel immunosuppressant, LF 15-0195, is effective in inhibiting the induction and the progression of rat EAMG—suggesting that this drug may be used for preventive and curative treatment. The beneficial effect of LF 15-0195 is accompanied by decreased production of pathogenic autoantibodies and inhibition of the differentiation of antigen specific T cells into effector lymphocytes. These finding suggest that LF 15-0195 is a promising therapeutic for this autoimmune disease.
- Published
- 2002
8. Cellular and genetic factors involved in the difference between Brown Norway and Lewis rats to develop respectively type-2 and type-1 immune-mediated diseases
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Magali Mas, Jean-François Subra, Lucette Pelletier, Dominique Lagrange, Abdelhadi Saoudi, Isabelle Bernard, Gilbert J. Fournié, Philippe Druet, Bastien Cautain, Jan Damoiseaux, and Emmanuel Xystrakis
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Autoimmune disease ,medicine.medical_specialty ,T cell ,Immunology ,Experimental autoimmune encephalomyelitis ,Biology ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,Immune tolerance ,Endocrinology ,Immune system ,medicine.anatomical_structure ,Internal medicine ,medicine ,Gold salts ,Immunology and Allergy ,Cytotoxic T cell ,medicine.drug - Abstract
Summary: The understanding of the mechanisms of immune tolerance and the unravelling of the pathophysiology of autoimmune diseases rely on animal models. In this respect, BN and LEW rats represent models of choice to study immune-mediated diseases from the cellular and genetic points of view. Indeed, BN and LEW rats are extremes with respect to their polarisation of the immune response as well as their susceptibility to autoimmune diseases. LEW rats are susceptible to Th1-mediated autoimmune diseases while BN rats are highly susceptible to Th2-mediated autoimmune disease. Comparison of the T cell compartment between LEW and BN rats revealed several important differences. 1) A MHC-dependent quantitative difference that is due to a defect in the CD8 T cell compartment in BN rats. 2) A qualitative MHC-independent difference that is related to a high frequency of CD45RClow CD4 and CD8 T cell subsets, producing IL-4, IL-13, IL-10 and TGF-β in BN rats as compared to LEW rats. 3) Interestingly, the genetic studies showed that susceptibility to Th1-mediated experimental autoimmune encephalomyelitis, and to Th2-mediated disorders triggered by gold salts as well as the difference in the CD45RChigh/CD45RClow ratio between LEW and BN rats are genetically determined by regions on chromosomes 9, 10 and 20.
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- 2001
9. Self major histocompatibility complex class-II-specific regulatory CD4 T cells prevent both Th1- and Th2-mediated autoimmune diseases in the rat
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Saoudi Abdelhadi, Philippe Druet, Valérie Duplan, Emmanuel Xystrakis, Magali Savignac, and Lucette Pelletier
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CD4-Positive T-Lymphocytes ,Cellular immunity ,medicine.medical_treatment ,Immunology ,Down-Regulation ,Biology ,medicine.disease_cause ,Microbiology ,Autoimmune Diseases ,Autoimmunity ,Th2 Cells ,Immune system ,Downregulation and upregulation ,medicine ,Animals ,Humans ,IL-2 receptor ,Autoimmune disease ,Histocompatibility Antigens Class II ,T lymphocyte ,Th1 Cells ,medicine.disease ,Rats ,Infectious Diseases ,Cytokine ,Rats, Inbred Lew ,Mercuric Chloride - Abstract
It is clear that functional heterogeneity of T cells may be explained by differential cytokine production. The aim of this paper was to review evidence for regulatory cells, generated after HgCl(2)-exposure. They differ from classical Th1 and Th2 cells, produce transforming growth factor-beta and interleukin-10 and exert their regulatory functions in a Th1/Th2-unrestricted fashion.
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- 2001
10. Gold is a T cell polyclonal activator in BN and LEW rats but favors IL-4 expression only in autoimmune prone BN rats
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Philippe Druet, Abdelhadi Saoudi, Magali Savignac, Lucette Pelletier, Jean-François Subra, Abdallah Badou, Christelle Delmas, Pierre Paulet, Stéphane De Cramer, and Georges Cassar
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medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,Autoimmunity ,Spleen ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Interferon-gamma ,Th2 Cells ,Chlorides ,Rats, Inbred BN ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Calcium Signaling ,RNA, Messenger ,Phosphorylation ,Interleukin 4 ,B-Lymphocytes ,Antibodies, Monoclonal ,Immunoglobulin E ,Gold Compounds ,In vitro ,Rats ,medicine.anatomical_structure ,Cytokine ,Endocrinology ,Gene Expression Regulation ,Rats, Inbred Lew ,Immunoglobulin G ,Gold salts ,Calcium ,Gold ,Interleukin-4 ,CD8 ,medicine.drug - Abstract
Gold salts are beneficial in the treatment of rheumatoid arthritis but may induce immune-mediated disorders in predisposed patients. Gold salts induce Th2-dependent autoimmunity in Brown-Norway (BN) rats but not in Lewis (LEW) rats. The aim of this study was to define molecular targets of gold salts and to approach why LEW rats are resistant. Gold salts act on early steps of transduction in T cells from BN and LEW rats since they trigger tyrosine phosphorylation of numerous proteins including p56(lck) and a calcium signal which results in IL-4 and IFN-gamma expression by BN and LEW T cells. However, the IL-4 response was favored in BN spleen cells in vitro and in vivo. IFN-gamma, produced in part by CD8(+) cells, contributes to the resistance of LEW rats since gold salt-injected LEW rats receiving anti-CD8 or anti-IFN-gamma mAb displayed the parameters characteristics of gold salt-induced Th2 autoimmunity although to a lesser extent than in BN rats. Gold salts transduce a signal in BN and LEW spleen cells resulting in IL-4 and IFN-gamma gene transcription with a preferential IL-4 response in BN rats, a Th2-prone strain, while IFN-gamma contributes to the resistance of LEW rats.
- Published
- 2001
11. Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-γ production
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Jean-Charles Guéry, Catherine Leclerc, Dominique Lagrange, Gilles Foucras, Pierre Paulet, Abdallah Badou, Marc Moreau, George Cassar, Magali Savignac, Lucette Pelletier, and Philippe Druet
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MAPK/ERK pathway ,Cellular differentiation ,T cell ,Immunology ,T-cell receptor ,chemistry.chemical_element ,chemical and pharmacologic phenomena ,Stimulation ,Biology ,Calcium ,Cell biology ,medicine.anatomical_structure ,chemistry ,medicine ,Immunology and Allergy ,Signal transduction ,Calcium signaling - Abstract
Th1 and Th2 cells produce different cytokines and have distinct functions. Th1/Th2 cell differentiation is influenced, among other factors, by the nature of TCR-MHC interactions. However, how the TCR transduces a signal resulting in IFN-gamma or IL-4 production is a matter of debate. For example, some authors reported a loss of calcium signaling pathway in Th2 cells. We used a T cell hybridoma producing IL-4 upon weak TCR stimulation and both IL-4 and IFN-gamma for strong TCR engagement as a model to study how TCR signaling pathways are differentially activated in both conditions of stimulation and how this influences the production of cytokines. We show that: (1) the calcium response is identical following weak and strong TCR stimulation; (2) mitogen-activated protein kinase(MAPK) activation is a gradual phenomenon depending upon the strength of TCR activation; (3) a calcium response, even weak, triggers IL-4 expression; (4) IFN-gamma synthesis requires not only a calcium response but also MAPK activation. The MAPK pathway is dispensable for IL-4 production, although it amplifies IL-4 synthesis upon strong TCR stimulation; (5) TCR-induced IL-4 production also depends on calcium signaling in Th2 cells, while IFN-gamma synthesis is dependent, in addition, on MAPK activation in Th1 cells.
- Published
- 2001
12. Identification of μ-Opioid Receptor Epitopes Recognized by Agonistic IgG
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Philippe Druet, E. Druet, Catherine Blanpied, Gilles Dietrich, Gaëtane Macé, Martial Jaume, and Christophe Nguyen
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Male ,medicine.drug_class ,Molecular Sequence Data ,Dose-Response Relationship, Immunologic ,Receptors, Opioid, mu ,Biophysics ,Enzyme-Linked Immunosorbent Assay ,CHO Cells ,Ligands ,Biochemistry ,Antibodies ,Epitope ,Epitopes ,Antibody Specificity ,Opioid receptor ,Cricetinae ,Cyclic AMP ,medicine ,Agonistic behaviour ,Extracellular ,Enzyme-linked receptor ,Animals ,5-HT5A receptor ,Amino Acid Sequence ,Molecular Biology ,Sequence Homology, Amino Acid ,biology ,Chemistry ,Cell Biology ,Antigen binding ,Molecular biology ,Protein Structure, Tertiary ,Rats ,Immunoglobulin G ,biology.protein ,Antibody ,Peptides ,Protein Binding - Abstract
We have previously reported the presence of IgG antibodies with a morphine-like activity in the serum of healthy individuals. The agonistic activity of IgG was dependent on their binding to the first and the third extracellular loops of the human mu opioid receptor. In this study we show that IgG antibodies obtained by immunizing rats with peptides corresponding to these two loops exhibited a similar morphine-like activity. Residues corresponding to Y(130), M(132), G(133), T(134) within the first and F(315) within the third extracellular segment were required for antibody binding and conferred to IgG a high mu-opioid selectivity.
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- 2001
13. Les voies dépendantes du calcium impliquées dans la production de cytokines dans les lymphocytes
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Magali Savignac, Lucette Pelletier, Catherine Leclerc, Pierre Paulet, Marc Moreau, and Philippe Druet
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Aging ,Cell Biology - Abstract
Les lymphocytes T CD4+ sont heterogenes en termes de fonctions et de production de cytokines. Les lymphocytes Thl produisent de l’IL-2 et de l’IFNγ et sont impliques dans l’elimination des agents pathogenes intracellulaires. Au contraire, les lymphocytes Th2 produisent de l’IL-4 et de l’IL-5 et contribuent a l’eradication des helminthes. Cet article decrit les voies de signalisation activees apres stimulation via le recepteur T pour l’antigene (TCR) et tente de comprendre lesquelles interviennent dans la synthese de telle ou telle cytokine. Une nouvelle voie impliquee dans la production d’IL-4 est decrite. Elle couple le TCR a une PKC qui controle une entree de calcium via des canaux calciques sensibles a la dihydropyridine, vraisemblablement apparentes aux canaux de type L des cellules excitables. Ce signal calcique est suffisant pour initier la transcription d’IL-4. Au contraire, la production d’IFNγ requiert absolument l’activation des MAP-kinases.
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- 2001
14. Rat chromosome 9 bears a major susceptibility locus for IgE response
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Nathalie Kermarrec, Jean-François Subra, Sylvie Pilipenko-Appolinaire, Gilbert J. Fournié, Dominique Lagrange, Dominique Gauguier, Magali Mas, and Philippe Druet
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Male ,Propanols ,Immunology ,Chromosome 9 ,Locus (genetics) ,Immunoglobulin E ,Major histocompatibility complex ,Quantitative Trait, Heritable ,Gene mapping ,Rats, Inbred BN ,Organometallic Compounds ,medicine ,Animals ,Immunology and Allergy ,Sulfhydryl Compounds ,Gene ,Genetics ,biology ,Chromosome Mapping ,Rats ,Rats, Inbred Lew ,biology.protein ,Gold salts ,Dimercaprol ,Female ,Antibody ,Organogold Compounds ,medicine.drug - Abstract
Injection of Brown Norway (BN) rats with gold salts provides a model to analyze the genetic control of the IgE response. A cohort of F2 progeny of susceptible BN and resistant LEW strains has been studied to carry out a genome-wide search for loci controlling the IgE response. Genome scanning identified two previously described loci, Atps1 and Atps2, and a new locus, Atps3. Atps1 linked to the MHC and Atps2 linked to the cytokine gene cluster that included the IL-4 region have been previously associated with serum IgE concentrations and with other Th2-dependent immune manifestations triggered by gold salts. The new interval, Atps3, identified on chromosome 9 (Lod score = 16), appears to play a major role in the control of the IgE response since it accounts for 31% of the genetic variance. Moreover, Atps3 is linked to anti-laminin antibody response and to glomerular immunoglobulin deposits. The identification and functional characterization of genes involved in these regions, particularly in Atps3, may shed light on the pathogenesis of atopic diseases in man.
- Published
- 2000
15. Isolation and characterization of natural human IgG with a morphine-like activity
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Laurent J. Emorine, Catherine Blanpied, Philippe Druet, Gaëtane Macé, and Gilles Dietrich
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medicine.drug_class ,Immunology ,Receptors, Opioid, mu ,CHO Cells ,Pharmacology ,Ligands ,Pertussis toxin ,GTP-Binding Proteins ,Opioid receptor ,Cricetinae ,medicine ,Animals ,Humans ,Immunology and Allergy ,Receptor ,Autoantibodies ,Morphine ,biology ,Chinese hamster ovary cell ,Immunoglobulin G ,biology.protein ,μ-opioid receptor ,Antibody ,Cyclase activity ,Opioid antagonist ,Adenylyl Cyclases - Abstract
Although naturally occurring antibodies have been associated with numerous biological activities, their functional relevance is still a matter of debate. The presence of natural autoantibodies towards immune-related molecules such as cytokines and antibodies suggests a physiological immunomodulatory role. The neuroendocrine opioid system participates in the immune homeostasis. We report here the presence of antibodies with an agonist-like activity towards the human mu-type opioid receptor within a normal human IgG pool. Starting from an IgG pool, autoantibodies were affinity purified using Chinese hamster ovary cells expressing the human mu-opioid receptor. Their specificity was assessed by cytofluorometry and pharmacological analyses. The potency of these antibodies to recognize the mu-opioid receptor was similar to mu-opioid selective agonists. Furthermore, the functional opioid-like activity of the anti-opioid receptor IgG was demonstrated by their ability to inhibit adenylate cyclase activity by a Gi/o-protein-mediated mechanism as indicated by abrogation of the effect by either opioid antagonist or pertussis toxin. Five IgG pools, each from four unrelated healthy blood donors, and single IgG preparations from six other donors were prepared. Antibodies directed against the mu-opioid receptor were found in all IgG samples.
- Published
- 1999
16. β2-Microglobulin-Dependent T Cells Are Not Necessary for Alloantigen-Induced Th2 Responses After Neonatal Induction of Lymphoid Chimerism in Mice
- Author
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Gilles Foucras, Christiane Coureau, Leo Beijleveld, Philippe Druet, Abdelhadi Saoudi, and Jean-Charles Guéry
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Immunology ,Immunology and Allergy - Abstract
We have analyzed the requirement for β2-microglobulin (β2m)-dependent T cells in the generation of allogeneic Th2 responses in vivo. A neonatal injection of semiallogeneic cells in BALB/c mice induces a state of chimerism that promotes the differentiation of donor-specific CD4+ T cells toward the Th2 phenotype. Polyclonal T-B cell interactions occur in this model between host Th2 and donor B cells, resulting in the production of IgE Abs. IgE production and Th2-priming are critically dependent upon the early production of IL-4. Our data in the present paper demonstrate that: 1) IgE synthesis and the up-regulation of MHC class II and CD23 molecules on B cells are independent of β2m expression in the host, 2) no difference in the induction of CD4 alloreactive Th2 cells could be observed between β2m−/− and their wild-type control littermates when Th2-priming was measured in adult mice, and 3) the Th2 response and IgE production is induced in the complete absence of β2m-dependent T cells both in the host and in the inoculum. Therefore, using a variety of assays, we could not demonstrate diminished responses in mice with a disrupted β2m gene in this model of Th2-mediated allogeneic interaction, indicating that β2m-dependent NK1.1+ and CD8+ T cells are not required for the generation of alloreactive Th2 responses in vivo.
- Published
- 1998
17. Immunologic and renal markers among photogravure printers exposed to toluene
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Jean-Claude Limasset, François Diebold, Sylvie Cénée, Bénédicte Stengel, Denis Hémon, Philippe Druet, and Denis Michard
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Adult ,Male ,Physiology ,Renal function ,Cumulative Exposure ,Air Pollutants, Occupational ,Urine ,Kidney ,Kidney Function Tests ,Excretion ,chemistry.chemical_compound ,medicine ,Humans ,Longitudinal Studies ,Autoantibodies ,Creatinine ,business.industry ,Public Health, Environmental and Occupational Health ,Immunoglobulin E ,Middle Aged ,medicine.disease ,Increased IgE level ,Occupational Diseases ,chemistry ,Immunology ,Kidney Failure, Chronic ,Printing ,Microalbuminuria ,Laminin ,business ,Biomarkers ,Environmental Monitoring ,Toluene ,Kidney disease - Abstract
Objectives This study assessed immunologic and early renal effects of chronic toluene exposure. Methods In a longitudinal study of 92 printers and 74 referents, 145 subjects had pre- and poststudy samples of blood and urine taken for the following measurements: immunoglobulin E (IgE), antiglomerular basement membrane (anti-GBM) and antilaminin (anti-LAM) antibodies in blood; creatinine and s2-microglobulin in blood and urine; and microalbumin, N-acetyl-b-D-glucosaminidase (NAG) and alanine-aminopeptidase in urine. Creatinine clearance was calculated according to the Cockroft-Gault formula. Eight-hour personal air samples were collected twice to assess present exposure to toluene. A job-exposure matrix was developed to estimate past cumulative exposure. Information about potential confounders was recorded by questionnaire. Multiple regression analysis was performed to study dose-effect relations adjusted for age and smoking. Results No subject was positive for anti-GBM antibodies, and only 12 were positive for anti-LAM. No relation was observed between the markers studied and present exposure to toluene except that creatinine clearance was higher among the exposed subjects than among the referents. A dose-response relation was observed between cumulative toluene exposure and both IgE and NAG excretion. No interaction was observed between hypertension and exposure, but the relationship with NAG did not persist when subjects with hypertension were excluded. Past or present exposure did not alter the 2-year trend of any marker studied. Conclusion According to the results of this study, toluene at 50 ppm is not related to detectable renal dysfunction. The increased IgE levels associated with present and past exposure require further investigation.
- Published
- 1998
18. HgCl2-induced Interleukin-4 Gene Expression in T Cells Involves a Protein Kinase C-dependent Calcium Influx through L-type Calcium Channels
- Author
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Abdallah Badou, Régine Pasquier, Magali Savignac, Catherine Leclerc, Philippe Druet, Lucette Pelletier, and Marc Moreau
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T-Lymphocytes ,T cell ,Biology ,Biochemistry ,Interleukin 21 ,medicine ,Animals ,Cytotoxic T cell ,ASK1 ,RNA, Messenger ,IL-2 receptor ,Molecular Biology ,Protein Kinase C ,Interleukin 3 ,Hybridomas ,Ion Transport ,Cell-Free System ,Cyclin-dependent kinase 5 ,ZAP70 ,Cell Biology ,Molecular biology ,Rats ,Enzyme Activation ,medicine.anatomical_structure ,Gene Expression Regulation ,Mercuric Chloride ,Calcium ,Calcium Channels ,Interleukin-4 - Abstract
Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
- Published
- 1997
19. Transforming Growth Factor β (TGF-β)-dependent Inhibition of T Helper Cell 2 (Th2)-induced Autoimmunity by Self–Major Histocompatibility Complex (MHC) Class II–specific, Regulatory CD4+ T Cell Lines
- Author
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Régine Pasquier, E. Druet, Abdallah Badou, Abdelhadi Saoudi, Frank Bridoux, Philippe Druet, Lucette Pelletier, and Isabelle Bernard
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CD4-Positive T-Lymphocytes ,Interleukin 2 ,Encephalomyelitis, Autoimmune, Experimental ,T-Lymphocytes ,T cell ,Immunology ,Autoimmunity ,Major histocompatibility complex ,Article ,Major Histocompatibility Complex ,Interferon-gamma ,Interleukin 21 ,Th2 Cells ,Transforming Growth Factor beta ,Rats, Inbred BN ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,MHC class II ,biology ,Histocompatibility Antigens Class II ,Antibodies, Monoclonal ,Articles ,T helper cell ,Immunoglobulin E ,Th1 Cells ,Thymectomy ,Adoptive Transfer ,Molecular biology ,Rats ,medicine.anatomical_structure ,Rats, Inbred Lew ,Antibody Formation ,Mercury Poisoning ,biology.protein ,Interleukin-2 ,medicine.drug - Abstract
Autoreactive anti–MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW) rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast, T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN-γ and TGF-β, and the protective effect is TGF-β dependent since protection is abrogated by anti-TGF-β treatment. These results identify regulatory, TGF-β–producing, autoreactive T cells that are distinct from classical Th1 or Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.
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- 1997
20. Evidence for heterogeneous TCR V beta repertoire expression in mercury- induced immune disorders in rats
- Author
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Roberto Baccala, Philippe Druet, Christophe Pannetier, Jacqueline Fillion, B. Bellon, and Joëlle Kuhn
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Male ,CD8 Antigens ,Receptors, Antigen, T-Cell, alpha-beta ,T cell ,Immunology ,Immunoglobulin Variable Region ,Biology ,Autoimmune Diseases ,Flow cytometry ,Immune system ,T-Lymphocyte Subsets ,Rats, Inbred BN ,medicine ,Superantigen ,Animals ,Immunology and Allergy ,Lymphocyte Count ,medicine.diagnostic_test ,T-cell receptor ,Nuclease protection assay ,Mercury ,General Medicine ,T lymphocyte ,Flow Cytometry ,Molecular biology ,Rats ,medicine.anatomical_structure ,Rats, Inbred Lew ,CD4 Antigens ,Female ,Lymph Nodes ,CD8 - Abstract
Administration of subtoxic doses of HgCl2 affects differentially the immune system depending on the strain of rats tested. Susceptible Brown-Norway (BN) rats exhibit a CD4+ T cell-dependent polyclonal activation of B cells; in contrast, Lewis (LEW) rats are resistant and develop an immunosuppression mediated by CD8+ T cells recruited by CD4+ T cells. The mechanisms by which mercury induces immune disorders are poorly understood. We were interested in analyzing the diversity and mercury-mediated changes of the TCR Vbeta repertoire in the BN and LEW strains of rats at different times of HgCl2 exposure. Our results obtained after analysis of lymph node T cells by RNase protection assay, flow cytometry or immunoscope assay (i) were not consistent with a superantigen-like stimulus since we observed neither a V beta-selective expansion nor deletion that would have been expected and (ii) showed that in BN rats, as well as in LEW rats, an increase in the number of T cells was associated with the heterogeneous TCR V beta repertoire, thus supporting a polyclonal T cell activation. However, in BN rats the total number of T cells increased very rapidly, whereas in LEW rats only CD8+ T cells accumulated.
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- 1997
21. Mercuric Chloride-Induced Programmed Cell Death of a Murine T Cell Hybridoma
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Philippe Prigent, Catherine Blanpied, Pascal Poncet, François Hirsch, Philippe Druet, Jan Aten, Anwar Chand, and Michèle Février
- Subjects
Interleukin 2 ,Programmed cell death ,medicine.drug_class ,medicine.medical_treatment ,T cell ,Immunology ,Cell ,Biology ,Monoclonal antibody ,Molecular biology ,Cell biology ,medicine.anatomical_structure ,Cytokine ,medicine ,Incubation ,Interleukin 4 ,medicine.drug - Abstract
In susceptible animals evidence is accumulating for a primary role for Th2 cells in the course of HgCl2-induced autoimmunity, and for a contribution of Th1 cells in the self-regulated phase of this disease. We have reported that incubation of 2B4.11 T cell hybridoma with HgCl2 induced programmed cell death. This paper shows that recombinant IL-2 significantly diminished HgCl2-induced 2B4.11 cell death. Although no effect was observed upon incubation with exogenous IL-4, we observed a significant protection by adding an anti-IL-4 monoclonal antibody to the culture. Accordingly, by RT-PCR we found the presence of IL-2 receptor-encoding mRNA, and by cytofluorometry, the expression of the protein was detected only after exposure to HgCl2. Moreover, upon HgCl2 treatment, 2B4.11 cells were induced to produce IL-4. Altogether these findings showed that cytokine environment, IL-2, IL-4 otherwise defining the Th1/Th2 dichotomy, in conjunction with a chemical may differentially influence the fate of cell populations, death or survival.
- Published
- 1995
22. Mercuric Chloride-Induced Programmed Cell Death of a Murine T Cell Hybridoma
- Author
-
François Hirsch, Nike Claessen, Pascal Poncet, Catherine Blanpied, Philippe Prigent, Philippe Druet, and Jan Aten
- Subjects
Programmed cell death ,Necrosis ,medicine.diagnostic_test ,T cell ,Immunology ,Biology ,Molecular biology ,Flow cytometry ,Cell biology ,medicine.anatomical_structure ,UVB-induced apoptosis ,Cell Death Process ,Cell culture ,Apoptosis ,medicine ,medicine.symptom - Abstract
Mercuric chloride (HgCl 2 ) as well as several drugs can induce T cell activation leading to systemic immune-mediated diseases in genetically susceptible individuals or rodents. T cell hybridomas represent a well-characterized model system for in vivo mechanisms of various stimuli-induced cell death. The cellular response to HgCl 2 was examined using various T cell lines and particularly the murine T cell hybridoma 2B4.11. Exposure to HgCl 2 induced both necrosis and apoptosis in a dose- and time-dependent way as demonstrated by DNA fragmentation analysis, flow cytometry of the whole cells and of isolated nuclei, and morphological examination. HgCl 2 -induced cell death was partly inhibited by cycloheximide. The expression of human Bcl-2 in 2B4.11 cells after transfection significantly prevented HgCl 2 -induced cell death but did not affect the susceptibility to apoptosis induced by an anti-CD3ϵ mAb. Subcytotoxic doses of HgCl 2 enhanced metabolic activity of Bcl-2 transfectants in contrast with mock-transfected cell line. Thus, we conclude that apoptosis is part of the cell death process induced by HgCl 2 and that the ability of Bcl-2 to prevent the death of one particular cell line is stimulus-dependent suggesting the existence of different pathways leading to cell death.
- Published
- 1995
23. TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1-dependent autoimmune disease
- Author
-
T. Velu, Kris Huygen, Philippe Druet, Joëlle Kuhn, Michel Goldman, Abdelhadi Saoudi, B. Bellon, and Y. de Kozak
- Subjects
Male ,Cellular immunity ,medicine.medical_treatment ,Molecular Sequence Data ,Immunology ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Autoimmune Diseases ,Uveitis ,Interferon ,Rats, Inbred BN ,medicine ,Animals ,Immunology and Allergy ,Lymph node ,Autoimmune disease ,MHC class II ,Base Sequence ,biology ,Histocompatibility Antigens Class II ,Retinitis ,Interleukin ,T-Lymphocytes, Helper-Inducer ,Immunotherapy ,medicine.disease ,Molecular biology ,Rats ,Immunoglobulin Isotypes ,medicine.anatomical_structure ,Rats, Inbred Lew ,Mercuric Chloride ,biology.protein ,Cytokines ,Female ,Antibody ,medicine.drug - Abstract
Mercuric chloride (HgCl2) injections protect (Lewis x Brown-Norway) F1 (F1) rats against experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal S antigen (S-Ag); in contrast HgCl2-injected F1 rats develop EAU following transfer of lymph node (LN) cells from rats immunized with S-Ag alone. In the present study we demonstrate that the ability of LN cells from rats protected against EAU to transfer the disease into naive F1 rats was considerably reduced. These LN cells neither produced interleukin (IL)-2 nor (interferon (IFN)-gamma but exhibited mRNA for IL-4. In contrast, LN cells from diseased rats easily transferred EAU into naive F1 rats, produced significant IL-2 and IFN-gamma levels but barely exhibited mRNA for IL-4. Furthermore protected rats predominantly produced IgG1 anti-S-Ag antibodies, while diseased rats produced IgG2b anti-S-Ag antibodies and the increase in expression of MHC class II molecules on B cells was higher in protected rats than in diseased rats. These data suggest that (1) to exert a protective effect, HgCl2 must act at an early stage of differentiation of precursors of S-Ag specific T cells, and (2) this effect is related to the preferential activation of TH2 cells to the detriment of uveitogenic TH1 cells. Finally, these results indicate that activation of TH2 cells protect from a TH1-dependent autoimmune disease.
- Published
- 1993
24. Autoimmune glomerulonephritis induced by mercury vapour exposure in the Brown Norway rat
- Author
-
Lucette Pelletier, Jianyi Hua, Philippe Druet, and Maths Berlin
- Subjects
Male ,medicine.medical_specialty ,Injections, Subcutaneous ,Fluorescent Antibody Technique ,chemistry.chemical_element ,Kidney ,Toxicology ,Autoimmune Diseases ,Glomerulonephritis ,Rats, Inbred BN ,Internal medicine ,Administration, Inhalation ,medicine ,Animals ,Autoimmune disease ,Inhalation ,biology ,Chemistry ,Glomerular basement membrane ,Mercury ,medicine.disease ,Rats ,Mercury (element) ,Proteinuria ,medicine.anatomical_structure ,Endocrinology ,Mercuric Chloride ,Toxicity ,biology.protein ,Female ,Antibody - Abstract
Subcutaneous injections of mercuric chloride induce an autoimmune glomerulonephritis with both granular and linear IgG deposits along the glomerular capillary wall and proteinuria. This disease is due to a T cell dependent polyclonal B cell activation responsible for production of antibodies against self (glomerular basement membrane, immunoglobulins, DNA, myeloperoxydase) and non self (sheep red blood cells, trinitrophenol (TNP)) components. Increase in serum IgE concentration is the hallmark of this disease. To determine if mercury vapours have pathogenic effects is an important problem of public health. The aim of this study was, first to compare the effects of mercury vapour exposure to those of mercury injections and, second, to compare the effects of high doses to those of low doses of mercury. Two exposure levels were studied corresponding to a mercury absorption of 13.1 mumol/week per kg body wt. and 1.7 mumol/week per kg body wt. during a 5-week period. It will be shown that, whereas the mercury concentration in the kidneys was similar in injected--and vapour exposed--rats, the mercury concentration in blood at the end of the exposure was about twice as high in the injected animals. Blood concentration of mercury was related to dose level but kidney content of mercury was similar in all groups, in spite of a dose difference by a factor of seven between low and high exposure. Mercury vapour and HgCl2 injections both trigger autoimmunity to the same extent and, in both cases the extent of autoimmune manifestations was dose-dependent.
- Published
- 1993
25. Mercury-induced autoreactive anti-class II T cell line protects from experimental autoimmune encephalomyelitis by the bias of CD8+ antiergotypic cells in Lewis rats
- Author
-
Philippe Druet, Maria Castedo, Régine Pasquier, Lucette Pelletier, Henri Villarroya, and Jerome Rossert
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Interleukin 2 ,CD8 Antigens ,T-Lymphocytes ,T cell ,Immunology ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Autoimmune Diseases ,Autoimmunity ,Interleukin 21 ,medicine ,Animals ,Immunology and Allergy ,Cells, Cultured ,Autoimmune disease ,B-Lymphocytes ,Experimental autoimmune encephalomyelitis ,Histocompatibility Antigens Class II ,Articles ,T lymphocyte ,medicine.disease ,Rats ,medicine.anatomical_structure ,Rats, Inbred Lew ,Mercuric Chloride ,Encephalitis ,Female ,Cell Division ,CD8 ,medicine.drug - Abstract
Brown-Norway (BN) rats injected with HgCl2 develop a systemic autoimmune disease associated with a polyclonal B cell activation, due to autoreactive T cells specific for self-class II molecules, while Lewis (LEW) rats injected with HgCl2 do not exhibit autoimmunity and develop a non-antigen-specific, CD8-mediated immunosuppression assessed by a depression of T cell functions, and a protection against experimental autoimmune encephalomyelitis (EAE). Resistance to HgCl2-induced autoimmunity is not due to these suppressor cells since treatment with an anti-CD8 monoclonal antibody (mAb) did not allow autoimmunity to appear. The absence of autoimmunity in this strain could result from the absence of autoreactive T cells, or from quantitative or qualitative differences of these cells between susceptible and resistant strains. In the present study, we show that CD4+ anti-class II T cells are present in HgCl2-injected LEW rats and are as frequent as in BN rats when assessed by limiting dilution analysis. LEW CD4+ autoreactive T cell lines were derived. They proliferated in the presence of normal class II-bearing cells, secreted interleukin 2, and did not induce B cells to produce immunoglobulins. Transfer of one of these lines, LEW Hg A, into normal LEW rats led to the appearance of CD8+ cells responsible for a non-antigen-specific immunosuppression that induced complete protection from EAE. Immunosuppression was abrogated after treatment with an anti-CD8 mAb. In vitro, CD8+ cells from rats injected with the LEW Hg A T cell line proliferated in the presence of activated T cells whatever their origin. We conclude that HgCl2 induces CD4+ autoreactive T cells that proliferate in the presence of class II+ cells in susceptible BN as well as in resistant LEW rats. But while these cells collaborate with B cells to produce autoantibodies in BN rats, they initiate in LEW rats a suppressor circuit involving antiergotypic CD8+ suppressor cells.
- Published
- 1993
26. Anti-Interleukin-2 Receptor Monoclonal Antibody Therapy Supports a Role for Thl-Like Cells in HgCl2-Induced Autoimmunity in Rats
- Author
-
Philippe Druet, M. C. Vial, B. Bellon, D. Dubey, and Joëlle Kuhn
- Subjects
Interleukin 2 ,Autoimmune disease ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,General Medicine ,Immunotherapy ,Biology ,Monoclonal antibody ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,Cytokine ,Immune system ,medicine ,Monoclonal antibody therapy ,medicine.drug - Abstract
Brown-Norway (BN) rats injected with HgCl2 develop an autoimmune disease characterized by a T dependent polyclonal B-cell activation. Increase in major histocompatibility complex class II molecule expression on B cells concomitant with enhancement of serum IgE concentration supports the involvement of the T helper 2 (Th2)-like subset in the induction of the disease. The mercury disease is autoreguiated and does not develop in Lewis (LEW) rats. Considering the reciprocal regulation, well defined in mice, between the Th1 and Th2 subsets, we addressed the role of the Thl-like subset in this disease. Brown-Norway and LEW rats injected with HgCl2 were treated wilh NDS61, a mouse anti-ral-IL-2R MoAb that blocks mainly Th1 cells. Data reported herein show that: (1) HgCl2 treatment does not modify either the percentage of IL-2R+ cells or IL-2R expression in both BN and LEW rats; (2) treatment of BN rats with NDS61 MoAb does not modify the induction phase of the mercury disease but delays in parl the regulation phase; (3) such a treatment leads lo some immune abnormalities in LEW rals; (4) HgCl2 markedly potentiates the anti-mouse Ig antibody response in BN rats which probably limits the effect of this treatment. This study supports a role for the Th1-like subset in HgCl2-induced auloimmunity in the rat.
- Published
- 1993
27. Cellular Immunity in Interstitial Nephropathy
- Author
-
Frédérique Meeus, Jerome Rossert, and Philippe Druet
- Subjects
Cellular immunity ,Interstitial nephritis ,Guinea Pigs ,Kidney Glomerulus ,Critical Care and Intensive Care Medicine ,Basement Membrane ,Mice ,Immune system ,Antigen ,Immunity ,medicine ,Animals ,Humans ,Immunity, Cellular ,Kidney ,biology ,business.industry ,General Medicine ,equipment and supplies ,medicine.disease ,Rats ,Disease Models, Animal ,Kidney Tubules ,medicine.anatomical_structure ,Nephrology ,Antibody Formation ,Immunology ,biology.protein ,Kidney Failure, Chronic ,Nephritis, Interstitial ,Rabbits ,Antibody ,business ,Nephritis - Abstract
Inflammatory tubulointerstitial nephritis (TIN), either as a primary or as a secondary event, plays an essential role in the development of all forms of chronic renal failure. Experimental models of TIN should help in understanding TIN in humans. As in experimental glomerulopathies, the target antigen can be a kidney structural antigen, from the tubular basement membrane (TBM) or not, or a foreign antigen. While some models are due to deposits of free antibodies or circulating immune complexes, many others involve cell-mediated immunity. This last aspect explains the importance and the originality of experimental TIN.
- Published
- 1993
28. Anti-renin T cells trigger normal B cells to produce anti-renin antibodies and normalize blood pressure in spontaneously hypertensive rats
- Author
-
Jean-Baptiste Michel, Réglne Pasquler, Catherine Guettier, Maria Castedo, Lucette Pelletier, Philippe Druet, and Kris Huygen
- Subjects
Male ,medicine.medical_specialty ,Adoptive cell transfer ,Ovalbumin ,T-Lymphocytes ,Molecular Sequence Data ,Immunology ,Cell Communication ,Biology ,Lymphocyte Activation ,Interferon-gamma ,Immune system ,Rats, Inbred SHR ,Internal medicine ,Renin ,Renin–angiotensin system ,medicine ,Animals ,Immunology and Allergy ,Cells, Cultured ,Interleukin 4 ,B-Lymphocytes ,Base Sequence ,General Medicine ,T lymphocyte ,Flow Cytometry ,In vitro ,Rats ,Endocrinology ,Antibody Formation ,Hypertension ,biology.protein ,Interleukin-2 ,Immunization ,Antibody ,Homeostasis - Abstract
Spontaneously hypertensive (SH) rats immunized with mouse renin produce anti-renin antibodies, responsible for down-modulation of blood pressure, associated with an infiltration of kidneys by mononuclear cells. In this work, anti-renin T cells from SH rats immunized with renin have been stimulated in vitro, and we have studied in vitro and in vivo their effect on anti-renin antibody production by normal syngeneic B cells. We show that, in vitro, renin-activated T cells induce a renin-specific antibody response without addition of exogenous renin. Anti-renin T cells injected into naive SH rats trigger normal B cells to secrete high amounts of monospecific anti-renin IgG antibodies as early as day 5. These antibodies interfere with the homeostasis of the renin-angiotensin system leading to the normalization of blood pressure without any nephritis. These results show that anti-renin B cells are either not tolerant per se or in a reversible state of anergy. Our results also suggest that anti-renin B cells constitutively express renin-derived peptides in such a way that they may be stimulated by activated anti-renin T cells; these cells express IL-4 mRNA indicating that IL-4 could play a role in the differentiation of B cells.
- Published
- 1993
29. Diagnosis of autoimmune diseases
- Author
-
Philippe Druet
- Subjects
Autoimmune disease ,Anti-nuclear antibody ,business.industry ,Immunology ,Autoantibody ,Elisa assay ,medicine.disease ,Autoimmune Diseases ,Immunologic Technique ,Rheumatoid arthritis ,Immunologic Techniques ,medicine ,Humans ,Immunology and Allergy ,business ,Autoantibodies - Published
- 1992
30. HgCl2-induced perturbation of the T cell network in experimental allergic encephalomyelitis
- Author
-
Jerome Rossert, Lucette Pelletier, Henri Villarroya, Philippe Druet, Régine Pasquier, and Rafael Oriol
- Subjects
CD40 ,biology ,Encephalomyelitis ,T cell ,fungi ,Immunology ,Cell ,T lymphocyte ,medicine.disease ,Molecular biology ,Interleukin 21 ,Myelin ,medicine.anatomical_structure ,medicine ,biology.protein ,CD8 - Abstract
In the companion paper (J. Rossert et al., Cell. Immunol., 137, 1991), we showed by using limiting dilution analysis that Lewis (LEW) rats injected with HgCl2 and immunized with myelin ( LEWHg MYE ) exhibit anti-basic protein CD4+ T helper cells (Th), at least 10-fold more frequent CD8+ T suppressor cells (Ts), and T contrasuppressor cells (Tcs). These Tcs cells were shown to be CD4+ T cells adhering to Vicia villosa (VV) lectin and allowed Th cells to proliferate despite the presence of Ts cells. The CD8+ Ts cells might be responsible for the protection from experimental allergic encephalomyelitis (EAE) observed in about 70% of LEW rats injected with HgCl2. The concomitant presence of CD4+ Tcs cells might explain that 30% of the rats escaped this protection. The aim of this work is to demonstrate in vivo the roles of CD8+ Ts cells and Tcs cells in mercury-induced protection from EAE. It will be shown that LEWHg/MYE rats depleted of CD8+ cells as well as LEWHg/MYE rats transferred with VV lectin-adherent Tcs cells develop EAE. These data demonstrate that CD8+ Ts cells are responsible for HgCl2-induced protection and that Tcs cells are involved in the control of Ts cells in vivo.
- Published
- 1991
31. Increased expression of class II major histocompatibility complex molecules on B cells in rats susceptible or resistant to HgC12-induced autoimmunity
- Author
-
B. Bellon, Josée Kuhn, Michel Goldman, Philippe Druet, M. C. Vial, F. Hirsch, and C Dubey
- Subjects
Autoimmune disease ,biology ,Strain (chemistry) ,Immunology ,Spleen ,medicine.disease ,medicine.disease_cause ,Immunoglobulin E ,Major histocompatibility complex ,Autoimmunity ,medicine.anatomical_structure ,Immune system ,Polyclonal antibodies ,medicine ,biology.protein ,Immunology and Allergy - Abstract
SUMMARY Administration of HgCl2 to the susceptible Brown-Norway (BN)rais induces an autoimmune disease characterized by a T-dependent polyclonal activation of B cells responsible for a dramatic increase in serum IgE concentration. The resistant Lewis (LEW) rats injected with HgCi2. do not exhibit such autoimmune manifestations. We show here that, upon HgCl2 injections, major histocompalibility complex (MHC) class II molecule expression is increased very early in lymph nodes and spleen B cells from both strains. So far. it is the earliest marker (day 3)of the effect of HgCI2on the immune system. In both strains this enhancement is transient, but regulatory mechanisms arc much more efficient in the resistant LEW strain than in the susceptible BN strain, In addition, we observed that MHC class II molecule expression on B cells differs according to the organ and the rat strain tested. All these findings are discussed in an attempt to underline the role of MHC class II molecule expression in the occurrence of mercury-induced stutoimmunity.
- Published
- 1991
32. HgCl2-induced perturbation of the T cell network in experimental allergic encephalomyelitis
- Author
-
Philippe Druet, Rafael Oriol, Henri Villarroya, Lucette Pelletier, Régine Pasquier, and Jerome Rossert
- Subjects
CD40 ,biology ,T cell ,Immunology ,Natural killer T cell ,Molecular biology ,Interleukin 21 ,medicine.anatomical_structure ,biology.protein ,Interleukin 12 ,medicine ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell - Abstract
Mercuric chloride (HgCl 2 ) induces in Lewis (LEW) rats a non-antigen-specific immuno-suppression and is able to down-modulate experimental allergic encephalomyelitis in about 70% of the rats. The aim of the present study was to determine the frequencies of lymph node cells involved in the proliferative response to myelin basic protein in rats injected with HgCl 2 and immunized with myelin by using limiting dilution analysis (LDA). Highly frequent CD8+ T suppressor cells and at least 10-fold less frequent protein basic-specific T helper cells were detected in these rats. A third cell type allowing the proliferative response of Th cells in spite of Ts cells was also demonstrated. These cells, which could act as contrasuppressor cells, were CD4+ and adhered to Vicia villosa lectin; their frequency was in the same range as that of T helper cells. These data illustrate the potential role of different levels of T cell immunoregulatory activity in autoimmunity and the major interest of LDA in their analysis.
- Published
- 1991
33. Beneficial effect of human therapeutic intravenous immunoglobulins (IVIg) in mercuric-chloride-induced autoimmune disease of Brown-Norway rats
- Author
-
B. Bellon, M. D. Kazatchkine, M. C. Vial, Philippe Druet, and F. Rossi
- Subjects
medicine.medical_treatment ,Immunology ,Immunoglobulins ,Immunoglobulin E ,Glomerulonephritis, Membranous ,Autoimmune Diseases ,Immune system ,Rats, Inbred BN ,hemic and lymphatic diseases ,Immunopathology ,medicine ,Animals ,Immunology and Allergy ,Infusions, Intravenous ,Autoantibodies ,Autoimmune disease ,biology ,business.industry ,Immunization, Passive ,Glomerulonephritis ,Immunotherapy ,medicine.disease ,Rats ,Disease Models, Animal ,Proteinuria ,Rats, Inbred Lew ,Polyclonal antibodies ,Immunoglobulin G ,Mercuric Chloride ,biology.protein ,Antibody ,business ,Research Article - Abstract
SUMMARYAdministration of HgCl2 to the susceptible Brown–Norway (BN) strain of rats induces an autoimmune disease characterized by polyclonal B cell activation, increased serum levels of IgE and the occurrence of anti-glomerular basement membrane antibody-mediated glomerulonephritis. We have observed that the simultaneous administration to BN rats of normal human polyspeciric immunoglobulins for therapeutic use (IVIg) with HgCl2 significantly decreased the occurrence and severity of proteinuria, and reduced serum IgE levels in diseased animals. Hypergammaglobulinaemia was potentiated in animals receiving HgCl2 and IVIg, compared with animals receiving HgCl2 alone. In vitro experiments indicated that F(ab')2 fragments from IVIg inhibited the binding to laminin of pathogenic anti-laminin antibodies from diseased rats, as did antibodies from the resistant Lewis strain of rats but not antibodies from susceptible BN rats. These observations suggest that IVIg may interfere with the immune regulatory mechanisms involved in mercury-induced autoimmune disease in an analogous fashion to the ability of IVIg to suppress the expression of certain pathological autoimmune responses in humans.
- Published
- 1991
34. A spontaneous hybridoma producing autoanti-idiotypic antibodies that recognizea Vx−associated idiotope in mercury-induced autoimmunity
- Author
-
Philippe Druet and Jean-Charles Guéry
- Subjects
Idiotype ,Renal glomerulus ,medicine.drug_class ,Blotting, Western ,Kidney Glomerulus ,Immunology ,medicine.disease_cause ,Monoclonal antibody ,Autoimmune Diseases ,Autoimmunity ,Immunoglobulin kappa-Chains ,Glomerulonephritis ,Western blot ,Rats, Inbred BN ,medicine ,Animals ,Immunology and Allergy ,Autoantibodies ,Hybridomas ,biology ,medicine.diagnostic_test ,Antibodies, Monoclonal ,Idiotopes ,Molecular biology ,Antibodies, Anti-Idiotypic ,Rats ,Mercuric Chloride ,Monoclonal ,biology.protein ,Antibody - Abstract
Anti-idiotypic (Id) antibodies have been suggested to play a role in the self regulation process observed in Brown-Norway rats developing mercury-induced autoimmunity. However, the presence of such antibodies has not yet been directly demonstrated. For that purpose, spleen cells from a mercury-injected rat were fused and the resulting hybridomas tested for their anti-Id activity against monoclonal anti-glomerular basement membrane (GBM) antibodies produced in this model. A monoclonal antibody (mAb) was obtained that specifically reacted in an enzyme-linked immunosorbent assay with an anti-GBM mAb and to a much lesser extent with another one produced in the same fusion. In Western blot experiments this autoanti-Id mAb reacted under reducing conditions with the kappa L chains but not with the H chains of the two anti-GBM mAb. It did not react with the kappa L chains of eight other rat mAb. This mAb is therefore an autoanti-Id mAb that recognizes a V kappa-associated Id expressed on two anti-GBM mAb. These results demonstrate that anti-GBM antibodies and their corresponding autoanti-Id antibodies are simultaneously produced during this disease. Whether or not these autoanti-Id antibodies have a regulatory and/or a pathogenic role in this disease remains to be established.
- Published
- 1990
35. IgA Polyspecific autoantibodies in IgA nephropathy
- Author
-
Hechmi Louzir, P. Dosquet, Stratis Avrameas, E. Druet, P. Matsiota, and Philippe Druet
- Subjects
Adult ,Male ,Adolescent ,Renal glomerulus ,Immunology ,Nephropathy ,Antigen ,Antibody Specificity ,Immunopathology ,medicine ,Humans ,Immunology and Allergy ,Immunoadsorption ,Aged ,Autoantibodies ,biology ,Autoantibody ,Glomerulonephritis, IGA ,Glomerulonephritis ,Middle Aged ,medicine.disease ,Immunoglobulin A ,biology.protein ,Female ,Antibody ,Research Article - Abstract
The specificity of circulating and kidney-bound IgA during IgA nephropathy is still a matter of discussion. In the present study, high levels of IgA antibodies directed against a panel of self and non-self antigens were found in the serum from patients with IgA nephropathy and were eluted from four out of the seven kidney biopsies studied. After immunoadsorption of pooled selected serum samples on TNP and actin-coated columns, polyspecific IgA antibodies were eluted. This supports the hypothesis that IgA-bearing B cells clones most probably producing polyspecific antibodies are a major feature of human IgA nephropathy. These findings also suggest that it may be hazardous to draw conclusions from the finding of apparently monospecific IgA antibodies in this condition.
- Published
- 1990
36. Specificity and cross-reactive idiotypes of anti-glomerular basement membrane autoantibodies in HgCl2-induced autoimmune glomerulonephritis
- Author
-
François Hirsch, Chantal Mandet, Jean-Charles Guéry, E. Druet, Denis Glotz, Philippe Druet, and E. de Heer
- Subjects
medicine.drug_class ,Kidney Glomerulus ,Immunology ,Fluorescent Antibody Technique ,Cross Reactions ,Immunofluorescence ,Monoclonal antibody ,Autoantigens ,Basement Membrane ,Autoimmune Diseases ,Glomerulonephritis ,Immunoglobulin Idiotypes ,Antibody Specificity ,Rats, Inbred BN ,medicine ,Animals ,Immunology and Allergy ,Autoantibodies ,Basement membrane ,biology ,medicine.diagnostic_test ,Glomerular basement membrane ,Autoantibody ,Antibodies, Monoclonal ,medicine.disease ,Molecular biology ,Rats ,medicine.anatomical_structure ,Polyclonal antibodies ,Mercuric Chloride ,biology.protein ,Laminin ,Antibody - Abstract
Mercury-induced autoimmune glomerulonephritis in the Brown-Norway (BN) rat is characterized by the successive appearance of linear and granular glomerular IgG deposits. Anti-laminin autoantibodies represent the major part of the anti-glomerular basement membrane (GBM) antibodies produced in this model. Fusions were performed in this model and four anti-GBM monoclonal antibodies (mAb) were obtained. Three of them were laminin specific. Using rabbit anti-idiotype antibodies, cross-reactive idiotypes (CRId) were characterized on anti-laminin antibodies. They were expressed on the three anti-laminin mAb, on kidney-eluted and circulating anti-laminin antibodies. CRId-bearing immunoglobulins were detected transiently in the circulation and paralleled the anti-laminin antibody activity. By immunofluorescence studies on kidney cryostat sections two different CRId were defined. One was localized close to the antigen-combining site since it was not revealed on kidney-bound antibodies, in contrast with the second CRId. This latter CRId was also found deposited in a typical linear pattern in the early phase of the disease and in a granular pattern in the late phase, demonstrating that these CRId are components of immune deposits. Taken together, these results suggest that in this model of T-dependent polyclonal B cell activation, restricted sets of V genes encode for at least a part of the anti-GBM autoantibodies.
- Published
- 1990
37. Calcium channel blocker prevents T helper type 2 cell-mediated airway inflammation
- Author
-
Bruno Gomes, Catherine Leclerc, Pierre Paulet, Bernard Mariamé, Marilena Djata Cabral, Jean-Charles Guéry, Alexandra Gallard, Marc Moreau, Philippe Druet, Magali Savignac, Lucette Pelletier, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI)
- Subjects
MESH: Inflammation ,CD4-Positive T-Lymphocytes ,Intracellular Fluid ,MESH: Asthma ,medicine.medical_treatment ,MESH: Calcium Channel Blockers ,Critical Care and Intensive Care Medicine ,Lymphocyte Activation ,Severity of Illness Index ,Mice ,0302 clinical medicine ,MESH: Animals ,MESH: Administration, Intranasal ,Lung ,0303 health sciences ,Mice, Inbred BALB C ,biology ,MESH: Dendritic Cells ,MESH: Intracellular Fluid ,MESH: Enzyme-Linked Immunosorbent Assay ,MESH: CD4-Positive T-Lymphocytes ,respiratory system ,Calcium Channel Blockers ,3. Good health ,medicine.anatomical_structure ,Cytokine ,MESH: Calcium ,Female ,medicine.symptom ,Bronchoalveolar Lavage Fluid ,MESH: Injections, Intraperitoneal ,Injections, Intraperitoneal ,medicine.drug ,Pulmonary and Respiratory Medicine ,MESH: Mice, Transgenic ,Ovalbumin ,Nicardipine ,MESH: Mice, Inbred BALB C ,Inflammation ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,MESH: Nicardipine ,03 medical and health sciences ,Th2 Cells ,MESH: Th2 Cells ,Intensive care ,MESH: Severity of Illness Index ,MESH: Cell Proliferation ,medicine ,Animals ,MESH: Lung ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Lymphocyte Activation ,MESH: Mice ,B cell ,Interleukin 4 ,Administration, Intranasal ,030304 developmental biology ,Cell Proliferation ,MESH: Ovalbumin ,business.industry ,MESH: Bronchoalveolar Lavage Fluid ,T lymphocyte ,Dendritic Cells ,Asthma ,respiratory tract diseases ,Disease Models, Animal ,Immunology ,biology.protein ,Calcium ,MESH: Disease Models, Animal ,business ,MESH: Female ,030215 immunology - Abstract
RATIONALE: Ca(2+) signaling controls the production of T helper (Th) type 2 cytokines known to be deleterious in asthma. Recently, we showed that Ca(2+) signaling was dihydropyridine (DHP)-sensitive in Th2 lymphocytes and that the DHP derivate, nicardipine, used in the treatment of cardiovascular pathologies, prevents Th2-dependent B cell polyclonal activation. OBJECTIVES: We tested the effect of nicardipine in experimental allergic asthma. METHODS: BALB/c mice immunized with ovalbumin (OVA) in alum and challenged with intranasal OVA were treated with nicardipine once the Th2 response, or even airway inflammation, was induced. We also tested the effect of nicardipine in asthma induced by transferring OVA-specific Th2 cells in BALB/c mice exposed to intranasal OVA. We checked the impact of nicardipine on T-cell responses and airway inflammation. MEASUREMENTS AND MAIN RESULTS: Nicardipine inhibited in vitro Ca(2+) response in Th2 cells. In vivo, it impeded the development of Th2-mediated airway inflammation and reduced the capacity of lymphocytes from lung-draining lymph nodes to secrete Th2, but not Th1, cytokines. Nicardipine did not affect antigen presentation to CD4(+) T lymphocytes, nor the initial localization of Th2 cells into the lungs of mice exposed to intranasal OVA; however, it reduced the production of type 2 cytokines and the amplification of the Th2 response in mice with asthma. Conversely, nicardipine had no effect on Th1-mediated airway inflammation. CONCLUSIONS: Nicardipine improves experimental asthma by impairing Th2-dependent inflammation. This study could provide a rationale for developing drugs selectively targeting DHP receptors of Th2 lymphocytes, potentially beneficial in the treatment of asthma.
- Published
- 2007
38. The rat Toxo1 locus directs toxoplasmosis outcome and controls parasite proliferation and spreading by macrophage-dependent mechanisms
- Author
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Véronique Sergent, Thomas Faraut, Dominique Lagrange, Magali Mas, Marie-Hélène Bessières, Maryline Calise, Marie-France Cesbron-Delauw, Gilbert J. Fournié, Olivier Papapietro, Bernard Pipy, Abdelhadi Saoudi, Céline Colacios, Jean-François Subra, Cordelia Bisanz, Philippe Druet, Pierre Cavaillès, Sylvie Appolinaire, Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and ProdInra, Migration
- Subjects
Male ,Genetic Linkage ,[SDV]Life Sciences [q-bio] ,MESH: Genetic Markers ,Animals, Congenic ,Rats, Inbred BN ,TOXOPLASMOSIS ,MESH: Animals ,ComputingMilieux_MISCELLANEOUS ,Subclinical infection ,0303 health sciences ,Multidisciplinary ,MESH: Toxoplasmosis, Animal ,biology ,MESH: Toxoplasma ,MESH: Genetic Predisposition to Disease ,Chromosome Mapping ,MESH: Animals, Congenic ,Biological Sciences ,3. Good health ,[SDV] Life Sciences [q-bio] ,MESH: Rats, Inbred BN ,Female ,MESH: Rats, Inbred Lew ,Toxoplasma ,MESH: Macrophages, Peritoneal ,Injections, Intraperitoneal ,MESH: Injections, Intraperitoneal ,Genetic Markers ,MESH: Rats ,Congenic ,Locus (genetics) ,RATS ,03 medical and health sciences ,MESH: Cell Proliferation ,medicine ,Animals ,Genetic Predisposition to Disease ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Cell Proliferation ,030306 microbiology ,TOXO1 ,Toxoplasma gondii ,Fibroblasts ,medicine.disease ,biology.organism_classification ,Toxoplasmosis ,Forward genetics ,MESH: Male ,Chronic infection ,Toxoplasmosis, Animal ,Genetic marker ,Rats, Inbred Lew ,MESH: Fibroblasts ,Immunology ,Macrophages, Peritoneal ,RAT ,MESH: Microsatellite Repeats ,MESH: Chromosome Mapping ,MESH: Female ,MESH: Linkage (Genetics) ,Microsatellite Repeats - Abstract
Toxoplasmosis is a healthcare problem in pregnant women and immunocompromised patients. Like humans, rats usually develop a subclinical chronic infection. LEW rats exhibit total resistance toToxoplasma gondiiinfection, which is expressed in a dominant mode. A genome-wide search carried out in a cohort of F2progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 a major locus of control, which we calledToxo1. Using reciprocal BN and LEW lines congenic for chromosome 10 genomic regions from the other strain,Toxo1was found to govern the issue ofT. gondiiinfection whatever the remaining genome. Analyzes of rats characterized by genomic recombination withinToxo1, reduced the interval down to a 1.7-cM region syntenic to human 17p13.In vitrostudies showed that theToxo1-mediated refractoriness toT. gondiiinfection is associated with the ability of the macrophage to impede the proliferation of the parasite within the parasitophorous vacuole. In contrast, proliferation was observed in fibroblasts whatever the genomic origin ofToxo1. Furthermore,ex vivostudies indicate that macrophage controls parasitic infection spreading by aToxo1-mediated mechanism. This forward genetics approach should ultimately unravel a major pathway of innate resistance to toxoplasmosis and possibly to other apicomplexan parasitic diseases.
- Published
- 2006
39. Towards understanding the pathogenesis of SLE
- Author
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Philippe Druet and Gilbert J. Fournié
- Subjects
Transplantation ,Programmed cell death ,Systemic lupus erythematosus ,business.industry ,T cell ,urologic and male genital diseases ,Fas receptor ,medicine.disease ,Phenotype ,Pathogenesis ,medicine.anatomical_structure ,immune system diseases ,Nephrology ,Apoptosis ,Immunology ,Medicine ,skin and connective tissue diseases ,Cell activation ,business - Abstract
Tolerance to self antigens is based on the physical deletion of autoreactive B and T cell clones, or anergy (functional deletion) or regulation of autoreactive cells in the periphery, or a combination of these. The physical deletion of autoreactive clones proceeds through apoptosis, a physiological form of programmed cell death. Apoptosis is initiated by interaction between molecules present at the cell surface following some forms of cell activation; the Fas (or Apo-1 or CD95) and Fas-ligand molecules are the best known of these. It has recently been shown that the extensive lymphoproliferation and the lupus disease that are common features of the MRL-lpr/lpr (lpr for lymphoproliferation) and of the C3H-gld/gld (gld for generalized lymphoproliferative disease) mouse strains were due to mutations of the Fas (lpr phenotype) or of the Fas-l gene (gld phenotype) [1]. When a functional Fas gene was introduced into MRL-lpr/lpr mice, there was an important improvement of the syndrome demonstrating the direct involvement of the Fas defect in the occurrence of this form of lupus. Abnormalities reminiscent of those seen in MRL-lpr/lpr mice have recently been described in children with Fas gene mutations [2]. Also, introduction of the Bcl-2 gene (that prevents apoptosis) into normal B cells induces a lupus-like syndrome [3]. However, in other lupusprone mice as in most cases of human lupus no abnormality of Fas or Bcl-2 expression has been clearly identified.
- Published
- 1996
40. Studies of congenic lines in the Brown Norway rat model of Th2-mediated immunopathological disorders show that the aurothiopropanol sulfonate-induced immunological disorder (Aiid3) locus on chromosome 9 plays a major role compared to Aiid2 on chromosome 10
- Author
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Lucette Pelletier, Gilbert J. Fournié, Dominique Lagrange, Pierre Cavaillès, Jean-François Subra, Marie-Odile Christen, Céline Colacios, Philippe Druet, Dominique Gauguier, Maryline Calise, and Magali Mas
- Subjects
Genetic Markers ,Male ,Propanols ,Immunology ,Kidney Glomerulus ,Congenic ,Down-Regulation ,Locus (genetics) ,Chromosome 9 ,Quantitative trait locus ,Biology ,Th2 Cells ,Animals, Congenic ,Rats, Inbred BN ,Organometallic Compounds ,Immunology and Allergy ,Animals ,Sulfhydryl Compounds ,Allele ,Gene ,Crosses, Genetic ,Genetics ,Chromosome ,Chromosome Mapping ,Immunoglobulin E ,Rats ,Disease Models, Animal ,Phenotype ,Immune System Diseases ,Genetic marker ,Rats, Inbred Lew ,Immunoglobulin G ,Dimercaprol ,Female ,Gold ,Organogold Compounds - Abstract
Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F2 offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an ∼7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions.
- Published
- 2004
41. Dihydropyridine receptors are selective markers of Th2 cells and can be targeted to prevent Th2-dependent immunopathological disorders
- Author
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Jean-Charles Guéry, Bernard Mariamé, Abdelhadi Saoudi, Bruno Gomes, Alexandra Gallard, Stéphane Narbonnet, Marc Moreau, Gilbert J. Fournié, Catherine Leclerc, Philippe Druet, Magali Savignac, Lucette Pelletier, and Pierre Paulet
- Subjects
Male ,Encephalomyelitis, Autoimmune, Experimental ,Calcium Channels, L-Type ,Immunology ,Nicardipine ,chemistry.chemical_element ,Graft vs Host Disease ,Mice, Transgenic ,Calcium ,Pharmacology ,Autoimmune Diseases ,Myelin ,Mice ,Th2 Cells ,Metals, Heavy ,Rats, Inbred BN ,medicine ,Immunology and Allergy ,Animals ,Receptor ,Calcium signaling ,Mice, Inbred BALB C ,Voltage-dependent calcium channel ,Experimental autoimmune encephalomyelitis ,Dihydropyridine ,Cell Differentiation ,3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ,Th1 Cells ,medicine.disease ,Calcium Channel Blockers ,Rats ,medicine.anatomical_structure ,chemistry ,Rats, Inbred Lew ,Chronic Disease ,Interleukin-4 ,Biomarkers ,Injections, Intraperitoneal ,medicine.drug - Abstract
Th1 cells that produce IFN-γ are essential in the elimination of intracellular pathogens, and Th2 cells that synthetize IL-4 control the eradication of helminths. However, highly polarized Th1 or Th2 responses may be harmful and even lethal. Thus, the development of strategies to selectively down-modulate Th1 or Th2 responses is of therapeutic importance. Herein, we demonstrate that dihydropyridine receptors (DHPR) are expressed on Th2 and not on Th1 murine cells. By using selective agonists and antagonists of DHPR, we show that DHPR are involved in TCR-dependent calcium response in Th2 cells as well as in IL-4, IL-5, and IL-10 synthesis. Nicardipine, an inhibitor of DHPR, is beneficial in experimental models of Th2-dependent pathologies in rats. It strongly inhibits the Th2-mediated autoimmune glomerulonephritis induced by injecting Brown Norway (BN) rats with heavy metals. This drug also prevents the chronic graft vs host reaction induced by injecting CD4+ T cells from BN rats into (LEW × BN)F1 hybrids. By contrast, treatment with nicardipine has no effect on the Th1-dependent experimental autoimmune encephalomyelitis triggered in LEW rats immunized with myelin. These data indicate that 1) DHPR are a selective marker of Th2 cells, 2) these calcium channels contribute to calcium signaling in Th2 cells, and 3) blockers of these channels are beneficial in the treatment of Th2-mediated pathologies.
- Published
- 2004
42. Alloreactive CD4 T lymphocytes responsible for acute and chronic graft-versus-host disease are contained within the CD45RChigh but not the CD45RClow subset
- Author
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Anne Dejean, Philippe Druet, Talal Al-Saati, Isabelle Bernard, Emmanuel Xystrakis, and Abdelhadi Saoudi
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Adoptive cell transfer ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Stimulation ,Enzyme-Linked Immunosorbent Assay ,Biology ,Immune system ,Antigen ,T-Lymphocyte Subsets ,Rats, Inbred BN ,medicine ,Immunology and Allergy ,Animals ,Crosses, Genetic ,Autoantibodies ,Skin ,Autoantibody ,Immunoglobulin E ,medicine.disease ,Adoptive Transfer ,In vitro ,Rats ,body regions ,surgical procedures, operative ,Cytokine ,Graft-versus-host disease ,Liver ,Rats, Inbred Lew ,Acute Disease ,Chronic Disease ,Cytokines ,Leukocyte Common Antigens ,Immunologic Memory ,Cell Division - Abstract
Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation and occurs when donor T cells react with histo-incompatible recipient's antigens. In the present study, we analyzed the contribution of CD4 T cell subsets, defined according to their CD45RC expression level, in the development of acute and chronic GvHD. For this purpose, we used the model of GvHD induced in rats when parental lymphocytes are transferred to irradiated (LEWxBN) F1 hybrid recipients. We showed that parental CD45RC(high) (naive cells) CD4 T cells induced both acute and chronic GvHD while CD45RC(low) (memory cells) subset did not. In vitro, only CD45RC(high) CD4 T cells proliferated and produced cytokines in response to alloantigen stimulation. LEW and BN CD45RC(high) CD4 T cells produced different cytokine profiles in response to in vitro allostimulation, which could explain their ability to induce different forms of GvHD. Finally, we showed that memory CD45RC(low) CD4 T cells, known to contain regulatory T cells, were unable to prevent GvHD induction. Together these data show that memory CD45RC(low) CD4 T cells do not contain functional alloreactive T cells and suggest that selective transfusion of donor memory cells could greatly improve post-transplant immune reconstitution without risk of GvHD induction.
- Published
- 2004
43. Th2-type immunopathological manifestations induced by mercury chloride or gold salts in the rat: signal transduction pathways, cellular mechanisms and genetic control
- Author
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Abdelhadi Saoudi, Gilbert J. Fournié, Lucette Pelletier, and Philippe Druet
- Subjects
T cell ,Immunology ,Autoimmunity ,Immunoglobulin E ,medicine.disease_cause ,Th2 Cells ,Immunopathology ,Rats, Inbred BN ,Gene expression ,medicine ,Immunology and Allergy ,Animals ,Humans ,Regulation of gene expression ,biology ,Models, Immunological ,Gold Compounds ,Rats ,medicine.anatomical_structure ,Rats, Inbred Lew ,Mercuric Chloride ,Gold salts ,biology.protein ,Signal transduction ,medicine.drug ,Signal Transduction - Abstract
Heavy metals induce various immunopathological disorders including an increase in serum IgE concentration in predisposed humans. The effects of HgCl2 or gold salts differ depending on the strain of rats tested: they induce Th2-mediated immunopathology in Brown-Norway (BN) rats while HgCl2 triggers an immunosuppression in Lewis (LEW) rats. The disease is due to the emergence of self-MHC class II reactive Th2 cells in BN rats. Autoreactive T cells are also found in HgCl2-injected LEW rats but they produce TGFbeta and IL-10 and have immunoregulatory properties. Hg or Au act on the early steps of T cell activation resulting in IL-4 and IFNgamma gene expression with preferential IL-4 expression in BN rats. Analyzing the effects of HgCl2 on T cells led us to identify a new signaling pathway implicated in IL-4 production. An important feature of this model concerns genetics. Indeed Th2-dependent autoimmunity induced by metals occurs only in BN rats that are genetically committed to develop Th2 responses. Cellular features at play are discussed as well as the identification of loci that control both the Th1/Th2 balance and susceptibility to autoimmunity.
- Published
- 2003
44. Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells
- Author
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Pierre Chambon, Jérôme D. Coudert, Gilles Foucras, Jean-Charles Guéry, Philippe Druet, Arlette Maret, S. Dupont, Pierre Gourdy, Francis Bayard, Andrée Krust, and Lucile Garidou
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_specialty ,T cell ,Ovariectomy ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,Amino Acid Motifs ,Biology ,Interferon-gamma ,Mice ,Immune system ,Internal medicine ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Estrogen Receptor beta ,IL-2 receptor ,Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ,Estrogen receptor beta ,Bone Marrow Transplantation ,Mice, Knockout ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Estradiol ,ZAP70 ,GATA3 ,Estrogen Receptor alpha ,Th1 Cells ,Hematopoietic Stem Cells ,Cell biology ,Specific Pathogen-Free Organisms ,DNA-Binding Proteins ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,Receptors, Estrogen ,Radiation Chimera ,Gene Targeting ,Female ,Interleukin-4 ,Lymph Nodes ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists - Abstract
It is widely accepted that females have superior immune responses than males, but the ways by which sex hormones may enhance T cell responses are still poorly understood. In the present study, we analyzed the effect of estrogens on CD4 T cell activation and differentiation after immunization with exogenous antigens. We show that administration of low doses of 17beta-estradiol (E2) to castrated female mice results in a striking increase of antigen-specific CD4 T cell responses and in the selective development of IFN-gamma-producing cells. Quantitative assessment of the frequency of T cells bearing a public TCR beta chain CDR3 motif demonstrated that the clonal size of primary antigen-specific CD4 T cells was dramatically increased in immune lymph nodes from E2-treated mice. By using mice with disrupted estrogen receptor (ER) alpha or beta genes, we show that ERalpha, but not ERbeta, was necessary for the enhanced E2-driven Th1 cell responsiveness. Furthermore, ERalpha expression in hematopoietic cells was essential, since E2 effects on Th1 responses were only observed in mice reconstituted with bone marrow cells from ERalpha+/+, but not ERalpha-deficient mice. These results demonstrate that estrogen administration promotes strong antigen-specific Th1 cell responses in a mechanism that requires functional expression of ERalpha in hematopoietic cells.
- Published
- 2003
45. LF 15-0195 inhibits the development of rat central nervous system autoimmunity by inducing long-lasting tolerance in autoreactive CD4 T cells
- Author
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Valérie Duplan, Roland S. Liblau, Patrick Dutartre, Lennart T. Mars, Abdelhadi Saoudi, and Philippe Druet
- Subjects
CD4-Positive T-Lymphocytes ,Central Nervous System ,Male ,Adoptive cell transfer ,Encephalomyelitis, Autoimmune, Experimental ,Encephalomyelitis ,Injections, Subcutaneous ,Immunology ,Guinea Pigs ,Down-Regulation ,Epitopes, T-Lymphocyte ,medicine.disease_cause ,Lymphocyte Activation ,Autoantigens ,Guanidines ,Severity of Illness Index ,Epitope ,Drug Administration Schedule ,Autoimmunity ,Antibody Specificity ,medicine ,Immunology and Allergy ,Animals ,Autoantibodies ,Autoimmune disease ,biology ,Experimental autoimmune encephalomyelitis ,Immunization, Passive ,Myelin Basic Protein ,medicine.disease ,Adoptive Transfer ,In vitro ,Myelin basic protein ,Rats ,Self Tolerance ,Rats, Inbred Lew ,biology.protein ,Cytokines ,Lymph Nodes ,Immunosuppressive Agents - Abstract
Experimental autoimmune encephalomyelitis (EAE) is a T cell-dependent autoimmune disease induced in susceptible animals by a single immunization with myelin basic protein (MBP). LF 15-0195 is a novel immunosuppressor that has been shown to have a potent immunosuppressive effect in several pathological manifestations. The purpose of this study was to investigate the effect of this drug on the induction and progression of established rat EAE and to dissect the mechanisms involved. We show that LF 15-0195 administration at the time of MBP immunization reduces the incidence and severity of EAE in Lewis rats. This drug also inhibits ongoing and passively induced EAE, indicating that LF 15-0195 affects already differentiated pathogenic lymphocytes. Compared with lymph node cells from untreated rats, lymphocytes from MBP-immunized rats treated with LF 15-0195 proliferated equally well in response to MBP in vitro, while their ability to produce effector cytokines and to transfer EAE into syngeneic recipients was significantly reduced. This phenomenon is stable and long-lasting. Indeed, neither IL-12 nor repeated stimulation with naive APC and MBP in vitro rendered MBP-specific CD4 T cells from protected rats encephalitogenic. In conclusion, LF 15-0195 treatment suppresses EAE by interfering with both the differentiation and effector functions of autoantigen-specific CD4 T cells.
- Published
- 2003
46. Immunologically-mediated toxin-induced renal disease
- Author
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Philippe Druet, Magali Savignac, and Lucette Pelletier
- Subjects
Nephrology ,Kidney ,medicine.medical_specialty ,Toxin ,Effector ,Experimental autoimmune encephalomyelitis ,Disease ,Biology ,medicine.disease_cause ,medicine.disease ,Autoimmunity ,medicine.anatomical_structure ,Immune system ,Internal medicine ,Immunology ,medicine - Abstract
There is still a long way to go before all the mechanisms responsible for drug-induced immune kidney lesions will be explained. However, the notion that T-cell activation in addition to T-cell receptor-MHC peptide interactions also requires a tissue environment is an important concept for better understanding immunopathogenic mechanisms. For example, it is noteworthy that a toxic effect of the drugs on the kidney may initiate an immune response because they promote the presentation of haptenized determinants or even of self-peptides in inflammatory conditions. Th1 cells and probably Th2 cells may be pathogenic even if the effectors responsible for the lesions may be different. For example, in some patients, eosinophils, probably activated by Th2 cells could be pathogenic. Some drugs, such as hydralazine or heavy metals behave as T-cell polyclonal activators, which is sufficient for, or contributes to, the development of autoimmunity at least in some genetic backgrounds.
- Published
- 2003
47. Protein kinase C-mediated calcium entry dependent upon dihydropyridine sensitive channels: a T cell receptor-coupled signaling pathway involved in IL-4 synthesis
- Author
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Jeannie M.F. Ragab-Thomas, Jean-Charles Guéry, Philippe Druet, Abdallah Badou, Marc Moreau, Pierre Paulet, Magali Savignac, Lucette Pelletier, and Catherine Leclerc
- Subjects
Interleukin 2 ,Dihydropyridines ,Calcium Channels, L-Type ,T cell ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Protein tyrosine phosphatase ,In Vitro Techniques ,Biochemistry ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Th2 Cells ,Genetics ,medicine ,Humans ,Phosphorylation ,Molecular Biology ,Interleukin 4 ,Protein Kinase C ,biology ,T-cell receptor ,JAK-STAT signaling pathway ,Tyrosine phosphorylation ,Th1 Cells ,Cell biology ,medicine.anatomical_structure ,chemistry ,biology.protein ,Tyrosine ,Calcium ,Interleukin-4 ,Biotechnology ,medicine.drug - Abstract
SPECIFIC AIMCD4+T helper (Th) cells include effector Th1 cells, which produce interleukin 2 (IL-2) and interferon γ (IFN-γ), and IL-4-producing Th2 ceIls; these subsets have distinct functions and it has been suggested that low T cell receptor (TCR) –peptide interactions favor Th2 cell differentiation. Since signaling pathways involved in IL-4 production are poorly known, we investigated by which pathway IL-4 is produced after weak TCR engagement.PRINCIPAL FINDINGS1. IL-4 production on weak TCR engagement does not require a full pattern of tyrosine phosphorylationThe 2G12.1 T cell hybridoma produced a different set of cytokines depending on the strength of TCR engagement; when cells were stimulated on plates coated with 0.03 μg/ml anti-TCR mAb (defined as weak TCR stimulation), only IL-4 was produced, whereas these cells synthesized both IL-4 and IFN-γ when stimulated on plates coated with 1.6 μg/ml anti-TCR mAb (defined as strong TCR stimulation). We first studied the pattern of tyrosine phosphorylation ...
- Published
- 2001
48. Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals
- Author
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Magali Mas, Gilbert J. Fournié, Bastien Cautain, Jean-François Subra, Abdelhadi Saoudi, Maryline Calise, Philippe Druet, Magali Savignac, Lucette Pelletier, and Dominique Lagrange
- Subjects
CD4-Positive T-Lymphocytes ,Encephalomyelitis, Autoimmune, Experimental ,Cellular differentiation ,Health Status ,T-Lymphocytes ,Immunology ,Autoimmunity ,Biology ,medicine.disease_cause ,Autoimmune Diseases ,Xenobiotics ,Interferon-gamma ,Immune system ,Th2 Cells ,Adjuvants, Immunologic ,Metals, Heavy ,medicine ,Bystander effect ,Immunology and Allergy ,Animals ,Humans ,Autoimmune disease ,Experimental autoimmune encephalomyelitis ,Cell Differentiation ,Th1 Cells ,medicine.disease ,Immune System Diseases ,Mercuric Chloride ,Gold salts ,Leukocyte Common Antigens ,Gold ,Interleukin-4 ,Signal transduction ,medicine.drug ,Signal Transduction - Abstract
Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.
- Published
- 2001
49. The balance between CD45RChigh and CD45RClow CD4 T cells in rats is intrinsic to bone marrow-derived cells and is genetically controlled
- Author
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Bastien Cautain, Magali Mas, Gilbert J. Fournié, Abdelhadi Saoudi, Emmanuel Xystrakis, Jan Damoiseaux, Dominique Lagrange, Philippe Druet, Jean-François Subra, Harry van der Heijden, and Marie-Jose van de Gaar
- Subjects
CD4-Positive T-Lymphocytes ,Genetic Markers ,Male ,Aging ,Propanols ,medicine.medical_treatment ,T cell ,Injections, Subcutaneous ,Immunology ,Chromosome 9 ,Bone Marrow Cells ,Biology ,Major histocompatibility complex ,Centimorgan ,Immune system ,Quantitative Trait, Heritable ,T-Lymphocyte Subsets ,Rats, Inbred BN ,medicine ,Organometallic Compounds ,Immunology and Allergy ,Animals ,Humans ,Lymphocyte Count ,Sulfhydryl Compounds ,Cells, Cultured ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,Immunoglobulin E ,Molecular biology ,Hematopoiesis ,Rats ,body regions ,Haematopoiesis ,Cytokine ,medicine.anatomical_structure ,Rats, Inbred Lew ,biology.protein ,Cytokines ,Leukocyte Common Antigens ,Dimercaprol ,Female ,Bone marrow ,Gold ,Organogold Compounds - Abstract
The level of CD45RC expression differentiates rat CD4 T cells in two subpopulations, CD45RChigh and CD45RClow, that have different cytokine profiles and functions. Interestingly, Lewis (LEW) and Brown Norway (BN) rats, two strains that differ in their ability to mount type 1 and type 2 immune responses and in their susceptibility to autoimmune diseases, exhibit distinct CD45RChigh/CD45RClow CD4 T cell ratios. The CD45RChigh subpopulation predominates in LEW rats, and the CD45RClow subpopulation in BN rats. In this study, we found that the antiinflammatory cytokines, IL-4, IL-10, and IL-13, are exclusively produced by the CD45RClow CD4 T cells. Using bone marrow chimeras, we showed that the difference in the CD45RChigh/CD45RClow CD4 T cell ratio between naive LEW and BN rats is intrinsic to hemopoietic cells. Furthermore, a genome-wide search for loci controlling the balance between T cell subpopulations was conducted in a (LEW × BN) F2 intercross. Genome scanning identified one quantitative trait locus on chromosome 9 (∼17 centiMorgan (cM); log of the odds ratio (LOD) score 3.9). In addition, two regions on chromosomes 10 (∼28 cM; LOD score 3.1) and 20 (∼40 cM; LOD ratio score 3) that contain, respectively, a cytokine gene cluster and the MHC region were suggestive for linkage. Interestingly, overlapping regions on these chromosomes have been implicated in the susceptibility to various immune-mediated disorders. The identification and functional characterization of genes in these regions controlling the CD45RChigh/CD45RClow Th cell subpopulations may shed light on key regulatory mechanisms of pathogenic immune responses.
- Published
- 2001
50. Neonatal induction of tolerance to T(h)2-mediated autoimmunity in rats
- Author
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Laure Caccavelli, Joëlle Kuhn, Jacqueline Fillion, Anne-Christine Field, Philippe Druet, Chantal Mandet, and B. Bellon
- Subjects
medicine.medical_specialty ,Allergy ,Propanols ,Immunology ,Spleen ,Autoimmunity ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Immunoglobulin E ,Immune system ,Th2 Cells ,Laminin ,Internal medicine ,Rats, Inbred BN ,medicine ,Immune Tolerance ,Organometallic Compounds ,Immunology and Allergy ,Animals ,Sulfhydryl Compounds ,biology ,Peripheral tolerance ,General Medicine ,medicine.disease ,Adoptive Transfer ,Rats ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn ,Polyclonal antibodies ,Mercuric Chloride ,biology.protein ,Dimercaprol ,Organogold Compounds - Abstract
Brown-Norway (BN) rats are highly susceptible to drug-induced immune dysregulations and when injected with mercuric chloride (HgCl(2)) or sodium aurothiopropanolsulfonate (ATPS), they develop a syndrome characterized by a polyclonal B cell activation depending upon CD4(+) T(h)2 cells that recognize self-MHC class II molecules. Since peripheral tolerance of T(h)2 cells might be crucial in the prevention of immunological manifestations such as allergy, establishing conditions for inducing tolerance to HgCl(2)- or ATPS-mediated immune manifestations appeared to be of large interest. We report here that BN rats neonatally injected with HgCl(2): (i) do not develop the mercury disease, (ii) remain resistant to HgCl(2)-induced autoimmunity at 8 weeks of age and later, provided they are regularly exposed to HgCl(2), (iii) are still susceptible to ATPS-induced immune manifestations, and (iv) exhibit spleen cells that adoptively transfer tolerance to HgCl(2)-induced autoimmunity in naive, slightly irradiated, syngeneic recipients. These findings demonstrate that dominant specific tolerance can be neonatally induced using a chemical otherwise responsible for T(h)2-mediated autoimmunity.
- Published
- 2000
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