Haanstra Krista G, Ringers Jan, Sick Ella A, Ramdien-Murli Seema, Kuhn Eva-Maria, Boon Louis, Jonker Margreet
Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Transplantation. 2003 Mar 15;75(5):637-43. doi: 10.1097/01.TP.0000054835.58014.C2.
Costimulation blockade has been proposed to induce allograft tolerance. We combined an antagonist anti-CD40 monoclonal antibody (mAb) with an antagonist anti-CD86 mAb in a rhesus monkey kidney allograft model. We chose this combination because it leaves CD80-CD152 signaling unimpaired, allowing for the down-regulatory effect of CD152 signaling to take place through this pathway.
Rhesus monkeys underwent transplantation with a major histocompatibility complex-mismatched kidney. One group of animals received anti-CD40 alone, and a second group received the combination of anti-CD40 and anti-CD86, twice weekly for 56 days.
Three animals with low levels of anti-CD40 rejected the transplanted kidney while still receiving treatment. Three animals with high levels of anti-CD40 rejected at days 91, 134, and 217 with signs of chronic rejection. Animals treated with the combination of anti-CD40 and anti-CD86 mAbs rejected their kidneys at days 61, 75, and 78, shortly after cessation of treatment. Two animals were killed on days 71 and 116 with a blocked ureter. These animals developed virtually no signs of tubulitis or infiltration during treatment and no donor-specific alloantibodies.
Both treatment protocols prevented rejection for the duration of the treatment in most animals. Blocking costimulation by anti-CD40 or by anti-CD40 plus anti-CD86 may be an effective method to prevent graft rejection and may obviate the need for other immunosuppressive drugs, especially in the immediate posttransplantation period.
共刺激阻断已被提出用于诱导同种异体移植耐受。我们在恒河猴肾移植模型中将一种抗CD40单克隆抗体（mAb）拮抗剂与一种抗CD86 mAb拮抗剂联合使用。我们选择这种联合方式是因为它不会损害CD80 - CD152信号传导，从而使CD152信号传导的下调作用能够通过该途径发生。
恒河猴接受了主要组织相容性复合体不匹配的肾脏移植。一组动物单独接受抗CD40治疗，另一组接受抗CD40和抗CD86的联合治疗，每周两次，持续56天。
3只抗CD40水平较低的动物在仍接受治疗时排斥了移植的肾脏。3只抗CD40水平较高的动物在第91天、134天和217天出现慢性排斥迹象时发生排斥反应。接受抗CD40和抗CD86 mAb联合治疗的动物在治疗停止后不久，于第61天、75天和78天排斥了它们的肾脏。2只动物在第71天和116天因输尿管阻塞而被处死。这些动物在治疗期间几乎没有出现肾小管炎或浸润的迹象，也没有产生供体特异性同种抗体。
两种治疗方案在大多数动物的治疗期间都预防了排斥反应。通过抗CD40或抗CD40加抗CD86阻断共刺激可能是预防移植排斥的有效方法，并且可能无需使用其他免疫抑制药物，尤其是在移植后的即刻阶段。
