The inhibitor cytokine interleukin-1 receptor antagonist synergistically augments cyclosporine immunosuppression in a rat cardiac allograft model.
Interleukin-1 receptor antagonist (IL-1ra) competes with IL-1 for binding of the IL-1 receptor, but does not elicit a cellular immune response. This study was designed to evaluate the effectiveness of IL-1ra in the immune and inflammatory responses to rat heart allografts. Experimental design was as follows: Group I HTx was syngeneic, BN to BN. The remaining groups were DA (RT 1a) to BN (RT 1n) allogeneic HTx. Group 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 while 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 Group 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 graft 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 recipients revealed delayed appearance of mononuclear cell infiltration. IL-1ra-treated recipients all demonstrated significantly reduced numbers of graft-infiltrating leukocytes; all phenotype subsets were equally affected. This study demonstrates the effectiveness of IL-1ra, in combination with low-dose CsA, in reducing the inflammatory response and rejection in the transplant setting.
Shiraishi
M
M
Department of Surgery, Cedars Sinai, UCLA School of Medicine 90024-6904, USA.
Csete
M
M
Yasunaga
C
C
McDiarmid
S V
SV
Vannice
J L
JL
Busuttil
R W
RW
Shaked
A
A
D000818:Animals; D001769:Blood / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D006085:Graft Survival / Q000187:drug effects; D006207:Half-Life; D016027:Heart Transplantation; D007165:Immunosuppression Therapy; D053590:Interleukin 1 Receptor Antagonist Protein; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D012795:Sialoglycoproteins / Q000097:blood / Q000494:pharmacology*; D014184:Transplantation, Homologous
D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D016572:Cyclosporine