Endocrine Abstracts

We have shown that Type I IFN paradoxically inhibits autoimmune diabetes in the NOD mouse and BB rat. We assessed the structure function relationship and potential mechanism of this interferon action by determining: (1) the diabetes sparing effect of several type 1 IFNs: recombinant human IFN-A/D bgl 11 (rIFN-alpha), rIFN-alphaB/D, rIFN-alpha-consensus (CIFN), IFN-taumod1 in NOD mice (2) the effect of IFN-tau administration in IL-4 KO and IFN-gamma KO NOD mice (3) the effect of IFN-tau administration on NOD spleen cell expression of CD152 (CD40-ligand) and class 11 MHC (Ia^k) (4) the effect of various type 1 IFNs on LPS induced spleen cell production of nitric oxide in vitro. Both rIFN-alpha and IFN-tau (2×10⁵ units IP TIW) potently inhibited the development of diabetes (P<0.01) while rIFN-alphaB/D and CIFN did not. IFN-tau (2×10⁵ units IP TIW) inhibited the development of diabetes in IL-4 KO NOD mice while had no effect on IFN-gamma KO mice. IFN-tau (2×10⁵ units IP TIW) administration decreased the expression of class 11 MHC expression on B cells and CD40L expression on T cells by 45 and 60% respectively. rIFN-alpha and rIFN-alphaB/D inhibited LPS stimulated NO by 84 and 74% respectively (P<0.01) while IFN-tau and CIFN had no effect. In conclusion, these data support the contention that IFN-gamma reduction has a role in mediating the diabetes sparing effect of type 1 IFN. Further, only some Type I IFNs have this inhibitory effect on the autoimmune diabetic process in mice. The inhibition of class 11 MHC binding and CD40–CD40 ligand interactions by IFN-tau may play a mediate the diabetes sparing effect. Although some type 1 IFNs inhibit the production of NO, this action may not be an important mediator for any or all type 1 IFNs since NO inhibition did not correlate with diabetes sparing activity.