Synergistic interaction of 3 M KCl-extracted donor antigens (e-HAg) with cyclosporine or cyclosporine/sirolimus for prolongation of rat heart allograft survival Journal Article


Authors: Hamashima, T.; Stepkowski, S. M.; Chou, T. C.; Kahan, B. D.
Article 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 × 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 × 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. © 1995.
Keywords: controlled study; transplantation, homologous; drug potentiation; nonhuman; animals; animal tissue; animal experiment; drug effect; survival time; rat; immunomodulation; rats; graft rejection; graft survival; rats, sprague-dawley; drug combinations; rapamycin; sirolimus; cyclosporin; intravenous drug administration; oral drug administration; histocompatibility antigens; heart transplantation; histocompatibility antigen; cyclosporins; male; priority journal; article; polyenes; rats, inbred bn; rats, inbred wf
Journal Title: Transplant Immunology
Volume: 3
Issue: 4
ISSN: 0966-3274
Publisher: Elsevier BV  
Date Published: 1995-12-01
Start Page: 335
End Page: 341
Language: English
DOI: 10.1016/0966-3274(95)80020-4
PUBMED: 8665153
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 28 August 2018 -- Source: Scopus
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MSK Authors
  1. Ting-Chao Chou
    272 Chou