THE INHIBITOR CYTOKINE INTERLEUKIN-1 RECEPTOR ANTAGONIST SYNERGISTICALLY AUGMENTS CYCLOSPORINE IMMUNOSUPPRESSION IN A RAT CARDIAC ALLOGRAFTMODEL

Interleukin-1 receptor antagonist (IL-1ra) competes with IL-1 for bind ing of the IL-I receptor, but does not elicit a cellular immune respon se. This study was designed to evaluate the effectiveness of IL-1ra in the immune and inflammatory responses to rat heart allografts. Experi mental design was as follows: Group I HTx was syngeneic, BN to BN. The remaining groups were DA (RT 1(a)) to BN (RT 1(n)) allogeneic HTx. Gr oup II was transplanted without immunosuppression. Group III received a low-dose IL-1ra regimen via osmotic pump into the peritoneum. Group IV recipients were similarly treated with a higher dose IL-1ra regimen . Group V rats received subtherapeutic cyclosporine (CsA) therapy whil e Group VI was treated with both CsA and low-dose IL-1ra. Group I rats survived indefinitely. Group II rats rejected their grafts at 5.33 +/ - 1.37 days. Group III grafts survived for 7.16 +/- 0.48 days, and Gro up IV grafts for 8.16 +/- 0.75 days, both significantly longer than in Group II (P < 0.01). Group V animals treated with low-dose CsA had gr aft survival of 7.7 +/- 1.6 days, but combined therapy with CsA and IL -1ra in Group VI yielded significantly prolonged graft survival of 17. 2 +/- 1.3 days (P < 0.0001). Histologic examination in treated recipie nts revealed delayed appearance of mononuclear cell infiltration. IL-1 ra-treated recipients all demonstrated significantly reduced numbers o f graft-infiltrating leukocytes; all phenotype subsets were equally af fected. This study demonstrates the effectiveness of IL-1ra, in combin ation with low-dose CsA, in reducing the inflammatory response and rej ection in the transplant setting. (C) 1995 Academic Press, Inc.