MULTIFACTORIAL CONTROL OF AUTOIMMUNE INSULIN-DEPENDENT DIABETES IN NOD MICE - LESSONS FOR IBD

Development of autoimmune insulin-dependent diabetes mellitus in nonob ese diabetic (NOD) mice is an example of a complex multifactorial dise ase with strong genetic and environmental components. As such, this mo del may provide insight not only into mouse models of inflammatory bow el disease, but also may provide insight into how the environment may interact with the genome to initiate pathogenesis in humans. NOD mice are characterized by accumulation of unusually high percentages of T l ymphocytes in lymphoid organs. Pancreatic beta cell destruction in NOD mice is T lymphocyte-mediated. Complex interactions between the inher ently diabetogenic major histocompatibility complex (MHC) haplotype of this strain and non-MHC-associated insulin-dependent diabetes suscept ibility genes (Idd) are required for cytopathic activation of the leuk ocytic infiltrates in the pancreas (insulitis). Penetrance of the diab etogenic Idd genes is strongly influenced by both dietary and microbio logical factors in the environment. Genetic susceptibility is transmit ted by hemopoietic stem cells, and specific defects in T immunoregulat ion have been traced to defects in the development and function of mar row-derived antigen presenting cells. The spontaneous development of d iabetes in NOD mice is different from experimentally induced forms of diabetes in mice in several important respects. In addition to the pat hognomic development of pancreatic insulitis, the generalized loss of immunoregulatory control of autoreactive T lymphocytes in NOD mice is reflected by development of leukocytic infiltrates into a plethora of organ systems including the submandibular salivary glands, thyroid gla nds, kidneys and, occasionally, the colon.