Hamashima T, Stepkowski S M, Chou T C, Kahan B D
Department of Surgery, University of Texas Medical School at Houston 77030, USA.
Transpl Immunol. 1995 Dec;3(4):335-41. doi: 10.1016/0966-3274(95)80020-4.
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.
提取的供体组织相容性抗原（e-HAg）可能会增强药物保护器官异体移植免受排斥的效果。我们研究了e-HAg与单独使用环孢素（CsA）、单独使用西罗莫司（雷帕霉素，RAPA）或CsA/RAPA联合使用时，延长大鼠心脏异体移植存活时间的能力。通过口服灌胃连续3天（第0、1和2天）或7天（第0、1、2、3、4、5和6天）给予环孢素（10mg/kg/天）的Wistar-Furth（WF；RT1u）大鼠，其Brown Norway（BN；RT1n）心脏异体移植的存活时间有适度延长，从未经治疗的对照组的平均存活时间7.2±0.8天分别延长至12.2±1.1天和18.6±2.7天（p<0.01）。尽管在移植当天（第0天）单次静脉注射（i.v.）剂量的BN e-HAg（5mg/kg）未能影响异体移植存活时间，但三次（第0、1和2天）和五次（第0、1、2、3和4天）注射均显著增强了口服CsA 3天疗程（分别为18.6±1.3天（p<0.01）和20.0±1.4天（p<0.01））以及口服CsA 7天疗程（分别为25.3±4.4天（p<0.05）和33.5±9.3天（p<0.01））的效果。中位效应分析证实CsA（0.5mg/kg×7天，静脉注射）与e-HAg之间存在协同相互作用，联合指数（CI）值小于0.7（CI = 1表示相加相互作用，CI < 1表示协同作用，CI > 1表示拮抗作用）。相比之下，e-HAg未能影响RAPA的免疫抑制作用。然而，e-HAg（5.0mg/kg×3天）显著增强了RAPA（0.01mg/kg）/CsA（0.5mg/kg）联合治疗7天或14天疗程的效果，即单独使用CsA/RAPA治疗7天时的26.0±4.8天延长至32.6±3.6天（p<0.01），单独使用CsA/RAPA治疗14天时的28.2±2.7天延长至42.0±4.9天（p<0.05），联合指数（CI） = 0.2 - 0.5。因此，e-HAg增强了单独使用CsA以及CsA/RAPA联合使用的免疫抑制作用，但未增强单独使用西罗莫司的免疫抑制作用。
