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 Cell Autoantigens of Potential Clinical Relevance to Type 1 Diabetes
a The Jackson Laboratory, Bar Harbor, Maine, USA b Department of Pediatrics, Division of Genetic and Translational Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA c Department of Microbiology and Immunology and Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York, USA
Key Words: autoimmunity • diabetes • humanized mice • T cells
Address for correspondence: Dr. David V. Serreze, The Jackson Laboratory, Bar Harbor, ME 04609, USA. Voice: 207-288-6403; fax: 207-288-6079. dave.serreze{at}jax.org
The mechanistic basis by which 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 from the 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.
 2m-.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.2m-.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. 2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans.
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