Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells

Immunity. 2002 Feb;16(2):169-81. doi: 10.1016/s1074-7613(02)00273-x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Autoantigens
  • Cysteine Proteinase Inhibitors
  • Serpins
  • Viral Proteins
  • Streptozocin
  • interleukin-1beta-converting enzyme inhibitor