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 the pancreas of DP-BB rats at the initiation of insulitis. These cells produce an excess of NO, which has been implicated as a mediator of both beta-cell damage and inhibition of T-cell proliferation in this rat strain. Genetic studies have shown that the impaired proliferative response of T-cells segregates with one of the diabetes-susceptibility genes of the DP-BB rat, lyp, which is responsible for a peripheral T-lymphopenia. This observation suggests that the dysregulated expression of inducible NO synthase (iNOS) is under the control of lyp itself or a gene in linkage disequilibrium with lyp. Using two models of hemopoietic chimeras--DP-BB rats reconstituted with isocongenic T-cells and irradiated (WF x DP-BB)F1 animals reconstituted with bone marrow of both parental strains--we demonstrated that the production of NO by DP-BB macrophages is normal when these cells originate from a non-T-lymphopenic environment. Consequently, these macrophages no longer inhibit the stimulation of DNA synthesis in activated T-cells. Macrophages of young WF rats were found to produce high levels of NO, which inhibited T-cell proliferation in vitro. This observation strongly suggests that upregulation of NO synthesis in DP-BB macrophages represents the abnormal persistence of a phenomenon restricted to the first few weeks of life in non-diabetes-prone rats. Taken together, these results demonstrate that the elevated production of NO by DP-BB macrophages results from the lyp mutation and represents a crucial mechanism through which T-lymphopenia contributes to the development of diabetes.
Lau
A
A
Department of Immunology, University of Toronto, Ontario, Canada.
Ramanathan
S
S
Poussier
P
P
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011913:Rats, Inbred BB; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology
D009569:Nitric Oxide; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat