PROTECTION OF NIT-1 PANCREATIC BETA-CELLS FROM IMMUNE ATTACK BY INHIBITION OF NF-KAPPA-B

We have recently observed that inhibition of NF-kappa B in NIT-1 insul inoma cells protects them from tumour necrosis factor (TNF)-induced ce ll death in vitro, possibly because expression of interleukin-1 (IL-1) beta-converting enzyme (ICE), a member of the cysteine protease pathwa y of cell death, is decreased. In the current study we have examined t he effect of the same inhibitor of NF-kappa B on class I major histoco mpatibility complex (MHC) protein expression in NIT-1 cells and shown that inhibition of NF-kappa B activation decreased basal and TNF-induc ed class I MHC levels. Although inducible nitric oxide synthase (iNOS) may also be inhibited by inhibition of NF-kappa B, this could not be demonstrated in NIT-1/Delta sp cells because wild-type NIT-1 cells exp ress very little iNOS. When NIT-1/Delta sp12 cells, expressing high le vels of the NF-kappa B inhibitor, are transplanted into immunodeficien t NOD/scid mice, tumorigenesis and death by hypoglycemia proceed simil arly to untransfected NIT-1 cells. Untransfected NIT-1 cells were kill ed by co-transfer of splenic T cells from diabetic but not non-diabeti c NOD mice. NIT-1/Delta sp12 cells were protected from killing in vivo by T cells from diabetic mice, in that tumours developed in four out of five mice and the kinetics of tumour development were not significa ntly delayed. NIT-1/Delta sp12 cells were not protected from killing b y T cells from mice previously primed with NIT-1 cells. In conclusion, inhibition of NF-kappa B is likely to suppress several different path ways of immune-mediated cell death in beta-cells and protects NIT-1 ce lls from immune attack by diabetogenic T cells in vivo. Inhibition of NF-kappa B is a potentially effective strategy for protection of pancr eatic beta-cells in autoimmune diabetes. (C) 1997 Academic Press Limit ed.