THE B-SUBUNIT OF CHOLERA-TOXIN INDUCES IMMUNOREGULATORY CELLS AND PREVENTS DIABETES IN THE NOD MOUSE

The B-subunit of the cholera toxin molecule (CT-B) has T-cell immunomo dulatory properties, Because the pathogenesis of diabetes in the nonob ese diabetic (MOD) mouse model of IDDM is thought to be a T-cell-media ted process due to an imbalance of immunoregulatory and anti-islet eff ector cells, we examined the effect of CT-B administration on the deve lopment of diabetes in the NOD mouse and assessed whether this potenti al diabetes-sparing effect of CT-B is mediated by changes in immunoreg ulatory and/or anti-islet cytotoxic effector cell activity. The admini stration of either intravenous or intraperitoneal CT-B decreased the d evelopment of diabetes with no apparent drug toxicity, At 6 months of age, only 18% of CT-B vs. 75% of saline-treated animals had diabetes, Histopathological examination revealed less islet atrophy in CT-B-trea ted animals, The in vitro proliferative responses of mononuclear splen ocytes and thymocytes to concanavalin A and lipolysaccharide and the p roportion of B-cells and T-cell subsets were not altered by CT-B treat ment, CT-B administration did not inhibit the primary immunization of mice to tetanus toroid, The development of diabetes in irradiated MOD mice was slower in the animals injected with spleen cells (SC) from CT -B-treated than from saline-treated NOD mice, suggesting that CT-B dec reases anti-islet effector cell activity. The injection of SC horn CT- B-treated mice inhibited the adoptive transfer of diabetes by SC fi om diabetic mice into irradiated NOD mice, documenting that, CT-B admini stration induces regulatory cell activity, in conclusion, CT-B adminis tration prevents the development of diabetes in NOD mice by inhibiting the immune destruction of islets, This islet-sparing activity appears mediated, at least in pare, by the induction of regulatory cells and, in turn, suppression of anti-islet effector cells, which is not assoc iated with generalised immunosuppression or T- or B-cell depletion.