Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells.
Crosspresentation of self-antigens by antigen-presenting cells is critical for the induction of peripheral tolerance. As apoptosis facilitates the entry of antigens into the crosspresentation pathway, we sought to prevent the development of autoimmune diabetes by inducing pancreatic beta cell apoptosis before disease onset. Accordingly, young nonobese diabetic (NOD) mice injected with a single low dose of streptozotocin (SZ), a drug cytotoxic for beta cells, exhibited impaired T cell responses to islet antigens and were protected from spontaneous diabetes. Furthermore, beta cell apoptosis was necessary for protection since SZ did not protect RIP-CrmA transgenic NOD mice in which beta cells expressed the caspase inhibitor CrmA. Our results support a model in which apoptosis of pancreatic beta cells induces the development of regulatory cells leading to the tolerization of self-reactive T cells and protection from diabetes.
Hugues
Stéphanie
S
Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, 660 Route des Lucioles, 06560 Valbonne, France.
Mougneau
Evelyne
E
Ferlin
Walter
W
Jeske
Dirk
D
Hofman
Paul
P
Homann
Dirk
D
Beaudoin
Lucie
L
Schrike
Corinne
C
Von Herrath
Matthias
M
Lehuen
Agnès
A
Glaichenhaus
Nicolas
N
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D015843:Serpins / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013311:Streptozocin / Q000008:administration & dosage / Q000494:pharmacology; D014764:Viral Proteins
D001324:Autoantigens; D015853:Cysteine Proteinase Inhibitors; D015843:Serpins; D014764:Viral Proteins; D013311:Streptozocin; C074641:interleukin-1beta-converting enzyme inhibitor