The NOD Mouse A Model For Insulin Dependent Diabetes Mellitus

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Nonobese diabetic (NOD) designates an inbred, genetically well characterized mouse strain. Like the DP-BB/Wor rat (unit 15.3), NOD mice spontaneously develop autoimmune T cell-mediated insulin-dependent diabetes mellitus (IDDM). However, the two models are sharply contrasted in that NOD mice, unlike BB rats, do not exhibit T lymphocytopenia, but rather the inverse (Serreze and Leiter, 1995). NOD mice are very easy to breed and are available from suppliers in the United States, Europe, and Japan. In addition to the extensive genetic characterization of the NOD genome, the availability of monoclonal antibodies to murine leukocyte antigens as well as the availability of a variety of congenic and transgenic stocks of NOD mice makes these mice especially useful for the immunologic dissection of autoimmune IDDM. Diabetogenesis in NOD mice is the consequence of heritable immunodeficiencies under complex polygenic control. The penetrance of these susceptibility-contributing polygenes is strongly influenced by the physical environment, particularly the diet and exposure to microbial pathogens. One of the intriguing features of NOD mice is that stimulation of the NOD immune system by environmental pathogens actually leads to development of a more normal immune system and IDDM resistance. Thus, NOD mice must be raised under stringent specific-pathogen-free (SPF) conditions for expression of the diabetes phenotype. This unit will define a protocol required for maintaining NOD mice under conditions permissive to full expression of their autoimmune potential (see Basic Protocol 1). Methods are also described for diagnosing IDDM on the basis of glycosuria and glycosemia (see Basic Protocol 2) as well as for the semiquantitation of insulitis, a valuable subphenotype diagnostic of prediabetes in these mice (see Alternate Protocol), including a procedure for aldehyde fuchsin staining to identify P granules in p islet cells for diagnostic purposes. An adoptive-transfer method is also included (see Basic Protocol 3) in which leukocytes, purified T cells, or T cell infiltrates obtained from the insulitic pancreas tissue of NOD mice are injected into prediabetic NOD or diabetes-resistant F1 mice, which then develop disease in an accelerated fashion. Basic Protocol 3 also includes alternative steps in which bone-marrow cells from NOD mice are transferred to syngeneic, irradiated NOD mice, allowing for recon-sistution with a diabetogenic immune system. This method can also be used to reconstitute NOD/LtSz-scid/scid mice with NOD bone-marrow cells. Steps for isolating pancreatic islet cells, which can then be used for a variety of purposes (e.g., as a source of islet antigens to establish and maintain autoreactive T cell lines) are included (see Support Protocol). Finally, steps are outlined that can be used to introduce transgenes into NOD mice (see Basic Protocol 4). Basic Protocol 4 also discusses important considerations for introduction of targeted mutations produced in embryonic stem cells derived from other inbred strains, or introduction of other genes from non-diabetes-prone strains.

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