Faculty Research 1990 - 1999

Title

Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant.

Document Type

Article

Publication Date

1994

Keywords

Animal, Antigens-CD8: an, Autoimmune-Diseases: im, Base-Sequence, Diabetes-Mellitus-Experimental: im, Female, Histocompatibility-Antigens-Class-I: ge, im, Insulin, Male, Mice, Mice-Inbred-C57BL, Mice-Inbred-NOD, Molecular-Sequence-Data, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes: im

JAX Source

Diabetes 1994 Mar;43(3):505-9

Grant

DK46266/DK/NIDDK, DK27722/DK/NIDDK, DK36175/DK/NIDDK

Abstract

Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.

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