Jonker Margreet, Ringers Jan, Ossevoort Miriam A, Slingerland Wim, van den Hout Yvon, Haanstra Krista, Wubben Jacqueline, Kuhn Eva, Friend Peter, Calne Roy
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Transplantation. 2002 Mar 27;73(6):874-80. doi: 10.1097/00007890-200203270-00008.
Tolerance to organ allografts in primates including man has been elusive, although in rodents and pigs tolerance can be achieved to organ allografts with relatively short courses of immunosuppressive treatment. In all varieties of graft acceptance that do not require full-dose maintenance immunosuppression, immunological engagement of donor and recipient and an early unstable period have been observed. On the basis of the hypothesis that elimination of aggressive T cell function should tip the balance in favor of an operationally tolerant state, experiments have been performed in monkeys allowing recipient-donor interaction before T-cell ablation and a short course of immunosuppression.
Rhesus monkeys received an allogeneic kidney graft from a MHC-mismatched donor. The animals either received anti-CD3 immunotoxin (FN18-CRM9) alone, started 2 days after transplantation, or in combination with a short course of cyclosporine (CsA) and/or rapamycin (RAPA), started at 5 days after transplantation. Kidney function was followed by monitoring serum creatinine levels and regular biopsies. Humoral and cellular antidonor immunity was tested in vitro before and at several time points after transplantation.
Graft survival of monkeys that received CsA alone (mean survival time (MST)=29.3) was significantly prolonged compared with the controls (MST=6). FN18-CRM9 treatment alone also resulted in prolonged graft survival (MST=29.4). The combined treatment of FN18-CRM9 and CsA and/or RAPA resulted in prolonged graft survival after all immunosuppression was stopped (MST=207.8).
It seems feasible to postpone immunosuppression posttransplantation and yet prevent allograft rejection without the need of permanent immunosuppression.
尽管在啮齿动物和猪中，通过相对较短疗程的免疫抑制治疗可以实现对器官同种异体移植的耐受，但包括人类在内的灵长类动物对器官同种异体移植的耐受一直难以实现。在所有不需要全剂量维持免疫抑制的移植接受类型中，都观察到了供体和受体的免疫相互作用以及早期不稳定期。基于消除攻击性T细胞功能应使平衡向有利于操作性耐受状态倾斜的假设，已在猴子身上进行了实验，允许在T细胞消融和短期免疫抑制之前进行受体-供体相互作用。
恒河猴接受来自MHC不匹配供体的同种异体肾移植。动物在移植后2天单独接受抗CD3免疫毒素（FN18-CRM9），或在移植后5天与短期环孢素（CsA）和/或雷帕霉素（RAPA）联合使用。通过监测血清肌酐水平和定期活检来跟踪肾功能。在移植前和移植后的几个时间点在体外测试体液和细胞抗供体免疫。
单独接受CsA的猴子的移植物存活时间（平均存活时间（MST）=29.3）与对照组（MST=6）相比显著延长。单独使用FN18-CRM9治疗也导致移植物存活时间延长（MST=29.4）。在停止所有免疫抑制后，FN18-CRM9与CsA和/或RAPA的联合治疗导致移植物存活时间延长（MST=207.8）。
移植后推迟免疫抑制并在不需要永久免疫抑制的情况下预防同种异体移植排斥似乎是可行的。
