TREATMENT WITH AN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN PROLONGS MOUSE ISLET ALLOGRAFT SURVIVAL

An interleukin-1 receptor antagonist protein was evaluated with regard to its efficacy in allogeneic and xenogeneic islet transplantation. A lloxan-induced diabetic C57BL/6 (H-2b) mice were transplanted under th e kidney capsule with 500 C57BL/Ks (H-2d) mouse islets. Alzet(R) osmot ic pumps, which release their content over an 11- to 13-day period, we re implanted subcutaneously for continuous infusion of interleukin-1 r eceptor antagonist protein (1.0, 5.0, 8.0 mg . kg-1 . day-1) or phosph ate-buffered saline. Blood glucose determinations were performed every second or third day; at death, the islet-bearing kidneys were morphol ogically evaluated. Mice treated initially with the higher interleukin -1 receptor antagonist protein concentrations were followed for an add itional period after cessation of the drug release to evaluate whether a transitory interleukin-1 receptor antagonist protein treatment woul d induce tolerance to the graft. All phosphate-buffered saline-treated mice were hyperglycemic 11 days after islet allotransplantation. Most of their grafts were heavily infiltrated with mononuclear cells. In t he various interleukin-1 receptor antagonist protein-treated groups, 6 0-80% of the mice were normoglycemic after 11 days. Moreover, light mi croscopic examinations showed that most mice treated with interleukin- 1 receptor antagonist protein had normal islet grafts or grafts infilt rated with only a few mononuclear cells. After interruption of interle ukin-1 receptor antagonist protein infusion (8.0 mg . kg-1 . day-1), a ll animals developed hyperglycemia with 2-9 days. In xenogeneic experi ments, 500-750 fetal porcine islet-like cell clusters were transplante d under the kidney capsule of normoglycemic C57BL/6 mice. These animal s were treated either with interleukin-1 receptor antagonist protein ( 8.0 mg . kg-1 . day-1) or phosphate-buffered saline. Examination of gr aft morphology on day 11 showed similarly rejected grafts in both grou ps. In conclusion, these data suggest that interleukin-1 receptor anta gonist protein protects islet allograft, but not xenograft, against ac ute rejection. Interleukin-1 receptor antagonist protein may become us eful as an adjuvant immunosuppressive drug after human islet transplan tation.