IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes

J Clin Invest. 1998 Sep 15;102(6):1249-57. doi: 10.1172/JCI2899.

Abstract

We have generated transgenic nonobese diabetic (NOD) mice expressing dominant negative mutant IFN-gamma receptors on pancreatic beta cells to investigate whether the direct effects of IFN-gamma on beta cells contribute to autoimmune diabetes. We have also quantitated by flow cytometry the rise in class I MHC on beta cells of NOD mice with increasing age and degree of islet inflammatory infiltrate. Class I MHC expression increases gradually with age in wild-type NOD mice; however, no such increase is observed in the transgenic beta cells. The transgenic mice develop diabetes at a similar rate to that of wild-type animals. This study dissociates class I MHC upregulation from progression to diabetes, shows that the rise in class I MHC is due to local IFN-gamma action, and eliminates beta cells as the targets of IFN-gamma in autoimmune diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Age Factors
  • Animals
  • Cyclophosphamide / pharmacology
  • Diabetes Mellitus, Type 1 / etiology*
  • Female
  • Genes, MHC Class I*
  • Histocompatibility Antigens Class I / biosynthesis*
  • Incidence
  • Interferon-gamma / pharmacology*
  • Islets of Langerhans / drug effects*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Receptors, Interferon / genetics
  • Sex Factors
  • Spleen / cytology
  • Spleen / immunology
  • Up-Regulation

Substances

  • Histocompatibility Antigens Class I
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma
  • Cyclophosphamide