Tolerance to islet autoantigens in type 1 diabetes.
Tolerance to beta cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4(+) CD25(+) CD62L(+) T cell-mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of beta cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.
INSERM U 25, Hôpital Necker, 161 rue de Sèvres, Paris Cedex 15, 75743 France. bach@necker.fr
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Chatenoud
D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002986:Clinical Trials as Topic; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017635:Clonal Anergy; D017637:Clonal Deletion; D016207:Cytokines / Q000502:physiology; D003888:Desensitization, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016853:Muromonab-CD3 / Q000627:therapeutic use; D011236:Prediabetic State / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D001324:Autoantigens; D016207:Cytokines; D016853:Muromonab-CD3