PREVENTION OF AUTOIMMUNE DIABETES-MELLITUS IN NOD MICE BY TRANSGENIC EXPRESSION OF SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTOR P55

The non-obese diabetic (NOD) mouse represents a relevant animal model of autoimmunity for insulin-dependent diabetes mellitus. The pathogeni c role of tumor necrosis factor (TNF) in insulitis and beta cell destr uction observed in these mice remains controversial, since injections of TNF or of anti-TNF antibodies have been reported to exert protectio n or acceleration of diabetes, depending on the timing of administrati on. In this study, we demonstrate that, in contrast to the non-transge nic littermates, NOD mice with permanent neutralization of TNF by high blood levels of soluble TNF receptor p55-human FcIgG3-fusion molecule s resulting from the expression of a transgene are protected from spon taneous diabetes. They are also protected from accelerated forms of di sease caused by transfer of NOD spleen cells or cyclophosphamide injec tions. This protection is associated with a marked decrease in the sev erity and incidence of insulitis and in the expression of the adhesion molecules MAdCAM-1 and ICAM-1 on the venules of pancreatic islets. Th ese data suggest a central role for TNF-alpha in the mediation of insu litis and of the subsequent destruction of insulin-secreting beta-cell s observed in NOD mice. They may be relevant to cell-mediated autoimmu ne diseases in general, in which treatment with soluble TNF receptors might be beneficial.