"Humanized" HLA transgenic NOD mice to identify pancreatic β cell autoantigens of potential clinical relevance to type 1 diabetes

David V. Serreze, Michele P. Marron, Teresa P. DiLorenzo

Research output: Chapter in Book/Report/Conference proceedingChapter

17 Scopus citations

Abstract

The mechanistic basis bywhich the H2g7 major histocompatibility complex (MHC) provides the primary risk factor for the development of T cell-mediated autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice involves contributions not only fromthe unusual Ag7 class II molecule, but also from the more common Kd and/or Db class I variants it encodes. Similarly, transgenic studies in NOD mice have confirmed the possibility first suggested in association studies that in the proper genetic context the common human HLA-A2.1 class I variant can mediate diabetogenic CD8 T cell responses. T1D continues to develop in a further refined NOD stock that expresses human HLA-A2.1, but no murine class I molecules (designated NOD.β2m-.HHD). Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an important antigenic target of diabetogenic CD8 cells in standard NOD mice. Three IGRP-derived peptides have also been identified that are presented by human HLA-A2.1 molecules to diabetogenic CD8 T cells in NOD.β2m-.HHD mice. At least one of these IGRP peptides (265-273) can also be the target of autoreactive CD8 T cells in HLA-A2.1-expressing human T1D patients. Studies are currently under way to determine whether HLA-A2.1-restricted IGRP peptides can be used in a tolerance-inducing protocol that inhibits T1D development in NOD. β2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans.

Original languageEnglish (US)
Title of host publicationHow Do We Best Employ Animal Models for Type 1 Diabetesand Multiple Sclerosis
PublisherBlackwell Publishing Inc.
Pages103-111
Number of pages9
ISBN (Print)1573316784, 9781573316781
DOIs
Publication statusPublished - Apr 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1103
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

    Fingerprint

Keywords

  • Autoimmunity
  • Diabetes
  • Humanized mice
  • T cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Serreze, DV, Marron, MP & DiLorenzo, TP 2007, "Humanized" HLA transgenic NOD mice to identify pancreatic β cell autoantigens of potential clinical relevance to type 1 diabetes. in How Do We Best Employ Animal Models for Type 1 Diabetesand Multiple Sclerosis. Annals of the New York Academy of Sciences, vol. 1103, Blackwell Publishing Inc., pp. 103-111. https://doi.org/10.1196/annals.1394.019