An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse

Parsing the Supporting Genetic Data

• MHC, major histocompatibility complex

Progenitors of the nonobese diabetic mouse strain (NOD/Shi) arose spontaneously in a colony at the Shionogi Research Laboratories in Aburahi, Japan in the 1970s. The strain has been used extensively in efforts to elucidate the pathogenesis of type 1 diabetes in humans. Both the mouse model and the human disease are characterized by the appearance of autoreactive T-cells targeting pancreatic islet antigens, the elaboration of anti-insulin autoantibodies, and the development of a β-cell–toxic inflammatory cellular infiltrate within the islets leading to insulin depletion and hyperglycemia. In both NOD mice and human type 1 diabetes, the breakdown of self-tolerance to β-cells is under polygenic control of major histocompatibility complex (MHC) class II alleles as well as non-MHC loci. An important difference between the mouse model and the human disease is that in NOD mice but not human type 1 diabetes, female subjects have a higher incidence of diabetes (75–100% by 30 weeks) than males (30–60%) (1). Because the development of diabetes in NOD mice depends on interacting genetic and environmental factors comparable with those interacting in human type 1 diabetes, genes that modify the NOD phenotype deserve close attention. The article by McDuffie et al. (2 in this issue identifies such a candidate molecule.

Previous studies elucidating the critical steps in the development of autoimmune β-cell destruction in NOD mice have suggested several points of pathogenic relevance. β-Cell destruction in NOD mice is dependent on the production and unrestrained activation of autoreactive T-cells. Antibody-mediated elimination of T-cells and interventions that promote T-cell tolerance, such as the production of regulatory T-cells, effectively inhibit development of diabetes in …