title: Synergistic interaction of 3 M KCl-extracted donor antigens (e-HAg) with cyclosporine or cyclosporine/sirolimus for prolongation of rat heart allograft survival.
abstract: Extracted donor histocompatibility antigens (e-HAg) may potentiate the effects of drugs to protect organ allografts from rejection. We examined the capacity of e-HAg when combined with cyclosporine (CsA) alone, sirolimus (rapamycin, RAPA) alone, or CsA/RAPA combinations to prolong heart allograft survival in rats. Wistar-Furth (WF; RT1u) rats that received CsA (10 mg/kg/day) by oral gavage for 3 (days 0, 1 and 2) or 7 (days 0, 1, 2, 3, 4, 5 and 6) consecutive days displayed modest prolongation of Brown Norway (BN; RT1n) heart allograft survival from a mean survival time of 7.2 +/- 0.8 days in untreated controls to 12.2 +/- 1.1 days and 18.6 +/- 2.7 days, respectively (p < 0.01). Although administration on the day of transplantation (day 0) of a single intravenous (i.v.) dose of BN e-HAg (5 mg/kg) failed to affect allograft survival, both three (days 0, 1 and 2) and five (days 0, 1, 2, 3 and 4) injections significantly potentiated the effect of a 3-day course of oral CsA (18.6 +/- 1.3 days (p < 0.01) and 20.0 +/- 1.4 days (p < 0.01), respectively) and of a 7-day course of oral CsA (25.3 +/- 4.4 days (p < 0.05) and 33.5 +/- 9.3 days (p < 0.01), respectively). Median-effect analysis confirmed a synergistic interaction between CsA (0.5 mg/kg x 7 days, i.v.) and e-HAg with combination index (CI) values less than 0.7 (CI = 1 shows additive interactions, CI < 1 synergistic, and CI > 1 antagonistic, interactions). In contrast, e-HAg failed to affect the immunosuppressive effect of RAPA. However, e-HAg (5.0 mg/kg x 3 days) significantly potentiated the effects of a 7-day or 14-day course of RAPA (0.01 mg/kg)/CsA (0.5 mg/kg) combination therapy, namely from 26.0 +/- 4.8 days with a 7-day treatment of CsA/RAPA alone to 32.6 +/- 3.6 days (p < 0.01) and from 28.2 +/- 2.7 days with a 14-day course of CsA/RAPA alone to 42.0 +/- 4.9 days (p < 0.05), respectively (CI = 0.2-0.5). Thus, e-HAg potentiates the immunosuppressive effects of CsA alone and of the CsA/RAPA combination, but not of sirolimus alone.
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston 77030, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hamashima
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D004338:Drug Combinations; D006085:Graft Survival; D016027:Heart Transplantation; D006649:Histocompatibility Antigens / Q000494:pharmacology*; D008297:Male; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D020123:Sirolimus; D014184:Transplantation, Homologous
chemical_list: D003524:Cyclosporins; D004338:Drug Combinations; D006649:Histocompatibility Antigens; D011090:Polyenes; D020123:Sirolimus