CYTOTOXIC EFFECT OF IFN-GAMMA PLUS TNF-ALPHA ON HUMAN ISLET CELLS

We have previously reported that the combination of IFN-γ plus TNF-α is able to induce the de novo expression of HLA class II on human β cells. In the present study, we have investigated the effect of these cytokines, alone or in combination, on the function and viability of human islet cells in vitro. Three hour insulin release was markedly reduced in human islet monolayer cultures after 4 days' exposure to 1000 U/ml of the combination TNF-α plus IFN-γ (36.7 ± 7.7, % of the control ± SEM) or to TNF-α alone (49.5 ± 7% of the control) while IFN-γ had little effect. On direct inspection cell damage was clearly detected only in the cultures treated with TNF-α plus IFN-γ in which staining by indirect immunofluorescence (IFL) for insulin revealed that the number of β cells was also significantly reduced, thus suggesting a real cytotoxic effect of this cytokine combination. This effect was not β cell specific since glucagon release and the number of α cells were also reduced in the cultures exposed to IFN-γ plus TNF-α. 51Cr release experiments supported the cytoxicity of these cytokines to normal islet cells. There was a time course relationship between class II induction (2 days) and the cytotoxic effect of IFN-γ plus TNF-α (4 days) on the same islet cells. In conclusion, these results indicate that the combination of IFN-γ and TNF-α exerts a cytotoxic effect on human islet cells in vitro. © 1991.