Tolerance to Islet Antigens and Prevention from Diabetes Induced by Limited Apoptosis of Pancreatic β 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 β cell apoptosis...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2002-02, Vol.16 (2), p.169-181
Main Authors: Hugues, Stéphanie, Mougneau, Evelyne, Ferlin, Walter, Jeske, Dirk, Hofman, Paul, Homann, Dirk, Beaudoin, Lucie, Schrike, Corinne, Von Herrath, Matthias, Lehuen, Agnès, Glaichenhaus, Nicolas
Format: Article
Language:English
Subjects:
Animals
Apoptosis - immunology
Autoantigens - immunology
CD4-Positive T-Lymphocytes - immunology
Cysteine Proteinase Inhibitors
Diabetes Mellitus, Experimental - immunology
Diabetes Mellitus, Experimental - prevention & control
Diabetes Mellitus, Type 1 - immunology
Diabetes Mellitus, Type 1 - prevention & control
Dose-Response Relationship, Drug
Female
Immune Tolerance - immunology
Islets of Langerhans - cytology
Islets of Langerhans - drug effects
Islets of Langerhans - immunology
Mice
Mice, Inbred NOD
Mice, Transgenic
Serpins - genetics
Signal Transduction - immunology
Streptozocin - administration & dosage
Streptozocin - pharmacology
Viral Proteins
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Summary: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 β cell apoptosis before disease onset. Accordingly, young nonobese diabetic (NOD) mice injected with a single low dose of streptozotocin (SZ), a drug cytotoxic for β cells, exhibited impaired T cell responses to islet antigens and were protected from spontaneous diabetes. Furthermore, β cell apoptosis was necessary for protection since SZ did not protect RIP-CrmA transgenic NOD mice in which β cells expressed the caspase inhibitor CrmA. Our results support a model in which apoptosis of pancreatic β cells induces the development of regulatory cells leading to the tolerization of self-reactive T cells and protection from diabetes.
ISSN:1074-7613
1097-4180
DOI:10.1016/S1074-7613(02)00273-X