PARADOXICAL ANTIDIABETOGENIC EFFECT OF GAMMA-INTERFERON IN DP-BB RATS

Previous studies have shown that anti-gamma-interferon (IFN-gamma) ant ibody reduces the frequency of autoimmune IDDM in the DP-BB rat. We te sted the effects of systemically administered recombinant rat IFN-gamm a in both DP-BB and DR-BB rats. Unexpectedly, IFN-gamma markedly reduc ed the incidence of IDDM as compared with control rats when administer ed six times per week at a dosage of 280,000 U between ages 30-35 to 1 05 days or ages 60-64 to 105 days. A lower dosage (28,000 U on alterna te days) was also protective when administered to DP-BB rats between b irth and age 60 days. However, long-lasting protection against IDDM de velopment over the 1-year study period was achieved only by the highes t dosage of IFN-gamma administered from age 30 to 105 days. Ex vivo pr oduction of tumor necrosis factor-alpha from splenic lymphoid cells (S LCs) and peritoneal macrophages of the rats treated with IFN-gamma was comparable with that of controls; however, SLCs from the IFN-gamma-tr eated animals secreted lower amounts of IFN-gamma after stimulation wi th concanavalin A. IFN-gamma treatment also markedly reduced the frequ ency of phenotypically activated SLC-expressing class II antigens and interleukin-2 receptor. Finally, in agreement with the observed antidi abetogenic effects, exogenously administered IFN-gamma induced neither insulitis nor IDDM development in DR-BB rats, a subline of DP-BB rats in which autoimmune diabetes rarely occurs spontaneously but can be i nduced by administration of polyinosinic-polycytidilic acid.