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. Alloxan-induced diabetic C57BL/6 (H-2 b ) mice were transplanted under the kidney capsule with 500 C57BL/Ks (H-2 d ) mouse islets. Alzet osmotic pumps, which release their content over an 11- to 13-day period, were implanted subcutaneously for continuous infusion of interleukin-1 receptor antagonist protein (1.0, 5.0, 8.0 mg · kg −1 · day −1 ) or phosphate-buffered saline. Blood glucose determinations were performed every second or third day; at death, the islet-bearing kidneys were morphologically evaluated. Mice treated initially with the higher interleukin-1 receptor antagonist protein concentrations were followed for an additional period after cessation of the drug release to evaluate whether a transitory interleukin-1 receptor antagonist protein treatment would 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 the various interleukin-1 receptor antagonist protein–treated groups, 60–80% of the mice were normoglycemic after 11 days. Moreover, light microscopic examinations showed that most mice treated with interleukin-1 receptor antagonist protein had normal islet grafts or grafts infiltrated with only a few mononuclear cells. After interruption of interleukin-1 receptor antagonist protein infusion (8.0 mg · kg −1 · day −1 ), all animals developed hyperglycemia within 2–9 days. In xenogeneic experiments, 500–750 fetal porcine islet-like cell clusters were transplanted under the kidney capsule of normoglycemic C57BL/6 mice. These animals were treated either with interleukin-1 receptor antagonist protein (8.0 mg · kg −1 · day −1 ) or phosphate-buffered saline. Examination of graft morphology on day 11 showed similarly rejected grafts in both groups. In conclusion, these data suggest that interleukin-1 receptor antagonist protein protects islet allograft, but not xenograft, against acute rejection. Interleukin-1 receptor antagonist protein may become useful as an adjuvant immunosuppressive drug after human islet transplantation.