van den Helder T B, Benhaim P, Anthony J P, McCalmont T H, Mathes S J
Division of Plastic and Reconstructive Surgery, University of California, San Francisco 94143-0932.
Transplantation. 1994 Feb;57(3):427-33. doi: 10.1097/00007890-199402150-00020.
The requirement for effective, minimally toxic immunosuppression remains a major obstacle to performing human composite tissue allotransplantation. The skin component of composite tissue (e.g., limb) allografts is especially antigenic, necessitating toxic immunosuppressant doses to prevent or reverse acute rejection. In previous experiments, RS-61443, an experimental mycophenolic acid ester that inhibits lymphocyte proliferation with minimal toxicity, prevented acute limb allograft rejection in rats for more than 8 months when started on the day of transplantation. In this study, the ability of RS-61443 to reverse established acute rejection was tested in a rat model of hindlimb allotransplantation. Brown-Norway donors and Fischer 344 recipients provided a MHC mismatch for orthotopic midfemur limb transplants that were performed with microsurgical repair of femoral vessels and sciatic nerve. Three groups were studied: untreated allografts (n = 6); allografts receiving RS-61443 at 30 mg/kg/day, started on postoperative day 7 (n = 11); and allografts receiving RS-61443 at 30 mg/kg/day, started on postoperative day 9 (n = 9). Skin and soft tissues were biopsied periodically to assess rejection. Untreated allografts had complete acute rejection within 12-13 days. Animals in both the 7- and 9-day groups developed moderate to severe rejection clinically and histologically before initiation of immunosuppressive therapy. In both groups, RS-61443 was able to reverse rejection completely in all animals from which biopsies were obtained at the time of death at 9-16 weeks after transplantation (P < 0.007). RS-61443 was highly effective as a primary immunosuppressant for reversing established acute rejection in rat hindlimb allografts.
有效且毒性最小的免疫抑制的需求仍然是进行人类复合组织同种异体移植的主要障碍。复合组织（如肢体）同种异体移植物的皮肤成分具有特别强的抗原性，需要使用毒性较大的免疫抑制剂剂量来预防或逆转急性排斥反应。在先前的实验中，RS - 61443是一种实验性的霉酚酸酯，它以最小的毒性抑制淋巴细胞增殖，在移植当天开始使用时，可在大鼠中预防急性肢体同种异体移植排斥反应超过8个月。在本研究中，在大鼠后肢同种异体移植模型中测试了RS - 61443逆转已建立的急性排斥反应的能力。棕色挪威大鼠供体和Fischer 344受体为原位股骨中段肢体移植提供了主要组织相容性复合体（MHC）不匹配，移植时对股血管和坐骨神经进行了显微外科修复。研究了三组：未治疗的同种异体移植物（n = 6）；术后第7天开始接受30 mg/kg/天RS - 61443治疗的同种异体移植物（n = 11）；术后第9天开始接受30 mg/kg/天RS - 61443治疗的同种异体移植物（n = 9）。定期对皮肤和软组织进行活检以评估排斥反应。未治疗的同种异体移植物在12 - 13天内发生完全急性排斥反应。在免疫抑制治疗开始前，7天组和9天组的动物在临床和组织学上均出现了中度至重度排斥反应。在两组中，RS - 61443能够在移植后9 - 16周死亡时从所有获取活检组织的动物中完全逆转排斥反应（P < 0.007）。RS - 61443作为一种主要的免疫抑制剂，在逆转大鼠后肢同种异体移植物已建立的急性排斥反应方面非常有效。
