title: Synergistic mechanisms by which sirolimus and cyclosporin inhibit rat heart and kidney allograft rejection.
abstract: The studies presented herein examined the mechanism(s) whereby sirolimus (SRL) and cyclosporin (CsA) act synergistically to block allograft rejection. Combination index (CI = 1 reflects additive, CI > 1 antagonistic, and CI < 1 synergistic, effects) analysis documented potent synergism between SRL and CsA to block allograft rejection. Combinations of the two drugs produced synergistic prolongation of heart (CI = 0.001-0.2) or kidney (CI = 0.03-0.5) allograft survival at SRL/CsA ratios ranging from 1:12.5 to 1:200. Pharmacokinetic analysis of the individual drugs showed that CsA does not affect the blood levels of SRL, and SRL mildly increases the levels of CsA in SRL/CsA-treated rats. Quantitative polymerase chain reaction analysis was used to document that both subtherapeutic (1.0 mg/kg) and therapeutic (2.0 or 4.0 mg/kg) CsA doses inhibited the expression of interferon-gamma (IFN-gamma) (P < 0.03) and IL-2 (P < 0.003) mRNA produced by T helper (Th) 1 cells, as well as IL-10 (P < 0.001), but not IL-4 (NS) mRNA produced by Th2 cells. Contrariwise, all tested SRL doses (0.02, 0.04 or 0.08 mg/kg) did not affect cytokine mRNA expression. However, heart allografts from rat recipients treated with synergistic SRL/CsA doses displayed reduced levels of IFN-gamma (P < 0.01), IL-2 (P < 0.001) and IL-10 (P < 0.001) mRNA. Thus, because subtherapeutic doses of CsA reduce Th1/Th2 activity, thereby facilitating the inhibition of signal transduction by low does of SRL, the two agents act synergistically to inhibit allograft rejection.
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston, 77030, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: K L
authors.initials: KL
authors.lastname: Napoli
authors.forename: R
authors.initials: R
authors.lastname: Ghobrial
authors.forename: M E
authors.initials: ME
authors.lastname: Wang
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D011090:Polyenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D020123:Sirolimus; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D011090:Polyenes; D012333:RNA, Messenger; D016572:Cyclosporine; D020123:Sirolimus