Autoimmune diabetes in HLA-DR3/DQ8 transgenic mice expressing the co-stimulatory molecule B7-1 in the β cells of islets of Langerhans

Govindarajan Rajagopalan, Yogish C. Kudva, Lieping Chen, Li Wen, Chella S. David

Research output: Contribution to journalArticle

Abstract

The major predisposing genetic component in type 1 diabetes (T1D) maps to the MHC locus in both mice and humans. To better understand the HLA class II association with disease pathogenesis, we bred mice expressing HLA-DQ8 and -DR3, either alone or in combination, to transgenic mice expressing the co-stimulatory molecule B7-1 in the β cells of islets of Langerhans. Spontaneous diabetes occurred only in RIP-B7-1 transgenic mice expressing transgenic HLA-DR3 or -DQ8 molecules and the incidence of diabetes was comparable between the two (∼30% in either sex up to 50 weeks of age). Presence of DR3 and DQ8 together only marginally elevated the overall incidence of spontaneous disease (38%). Non-specific activation of T cells by superantigen and provision of concomitant co-stimulation through 4-1BB (CD137) by an agonistic antibody did not accelerate the incidence of diabetes over a short period of time. Neither the antibody-mediated depletion of CD25+ T cells nor sublethal, whole-body irradiation of young, naive HLA transgenic mice expressing RIP-B7-1 resulted in diabetes. However, administration of only two doses of the β cell toxin streptozotocin (STZ; 40 mg/kg) induced autoimmune diabetes in 85% of mice within 7 weeks after STZ treatment only when B7-1 was expressed on the pancreatic β cells. This effect was HLA dependent as none of the STZ-treated RIP-B7-1 transgenic mice lacking HLA class II developed diabetes. In conclusion, this study confirmed the diabetogenic potential of HLA-DQ8 and established the role of HLA-DR3 in the pathogenesis of T1D.

Original languageEnglish (US)
Pages (from-to)1035-1044
Number of pages10
JournalInternational Immunology
Volume15
Issue number9
DOIs
Publication statusPublished - Sep 1 2003
Externally publishedYes

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Keywords

  • Autoimmunity
  • Diabetes
  • HLA-DQ8
  • HLA-DR3
  • Transgenic/knockout

ASJC Scopus subject areas

  • Immunology

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