EXCESSIVE PRODUCTION OF NITRIC-OXIDE BY MACROPHAGES FROM DP-BB RATS IS SECONDARY TO THE T-LYMPHOPENIC STATE OF THESE ANIMALS

Activated macrophages are the first mononuclear cells to migrate to th e pancreas of DP-BB rats at the initiation of insulitis. These cells p roduce an excess of NO, which has been implicated as a mediator of bot h p-cen damage and inhibition of T-cell proliferation in this rat stra in. Genetic studies have shown that the impaired proliferative respons e of T-cells segregates with one of the diabetes-susceptibility genes of the DP-BB rat, lyp, which is responsible for a peripheral T-lymphop enia. This observation suggests that the dysregulated expression of in ducible NO synthase (iNOS) is under the control of lyp itself or a gen e in linkage disequilibrium with lyp. Using two models of hemopoietic chimeras-DP-BB rats reconstituted with isocongenic T-cells and irradia ted (WF x DP-BB)F1 animals reconstituted with bone marrow of both pare ntal strains-we demonstrated that the production of NO by DP-BB macrop hages is normal when these cells originate from a non-T-lymphopenic en vironment. Consequently, these macrophages no longer inhibit the stimu lation of DNA synthesis in activated T-cells. Macrophages of young WF rats were found to produce high levels of NO, which inhibited T-cell p roliferation in vitro. This observation strongly suggests that upregul ation of NO synthesis in DP-BB macrophages represents the abnormal per sistence of a phenomenon restricted to the first few weeks of life in non-diabetes-prone rats. Taken together, these results demonstrate tha t the elevated production of NO by DP-BB macrophages results from the lyp mutation and represents a crucial mechanism through which T-lympho penia contributes to the development of diabetes.