An update on the use of NOD mice to study autoimmune (Type 1) diabetes.

The widely used nonobese diabetic (NOD) mouse model of autoimmune (Type 1) diabetes mellitus shares multiple characteristics with the human disease, and studies employing this model continue to yield clinically relevant and important information. Here, we review some of the recent key findings obtained from NOD mouse investigations that have both advanced our understanding of disease pathogenesis and suggested new therapeutic targets and approaches. Areas discussed include antigen discovery, identification of genes and pathways contributing to disease susceptibility, development of strategies to image islet inflammation and the testing of therapeutics. We also review recent technical advances that, combined with an improved understanding of the NOD mouse model's limitations, should work to ensure its popularity, utility and relevance in the years ahead.

Rapid identification of MHC class I-restricted antigens relevant to autoimmune diabetes using retrogenic T cells.

The method described herein provides a novel strategy for the rapid identification of CD8(+) T cell epitopes relevant to type 1 diabetes in the context of the nonobese diabetic (NOD) mouse model of disease. Obtaining the large number of antigen-sensitive monospecific T cells required for conventional antigen discovery methods has historically been problematic due to (1) difficulties in culturing autoreactive CD8(+) T cells from NOD mice and (2) the large time and resource investments required for the generation of transgenic NOD mice. We circumvented these problems by exploiting the rapid generation time of retrogenic (Rg) mice, relative to transgenic mice, as a novel source of sensitive monospecific CD8(+) T cells, using the diabetogenic AI4 T cell receptor on NOD.SCID and NOD.Rag1(-/-) backgrounds as a model. Rg AI4 T cells are diabetogenic in vivo, demonstrating for the first time that Rg mice are a means for assessing the pathogenic potential of CD8(+) T cell receptor specificities. In order to obtain a sufficient number of Rg CD8(+) T cells for antigen screens, we optimized a method for their in vitro culture that resulted in a approximately 500 fold expansion. We demonstrate the high sensitivity and specificity of expanded Rg AI4 T cells in the contexts of (1) specific peptide challenge, (2) islet cytotoxicity, and (3) their ability to resolve previously defined mimotope candidates from a positional scanning peptide library. Our method is the first to combine the speed of Rg technology with an optimized in vitro Rg T cell expansion protocol to enable the rapid discovery of T cell antigens.

Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.

Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant C57BL/6/scid mice. Our results suggest that the NOD genetic background may predispose them to diabetic complications, including insulin resistance in the absence of high circulating glucose levels and without autoimmune destruction of their beta cells. Several of these genes lie within known type 1 and 2 diabetes loci. These data suggest that the NOD mouse may be a good candidate to study an interface between type 1 and type 2 diabetes.