Qi Z, Riesbeck K, Ostraat O, Tufveson G, Ekberg H
Department of Experimental Research, Lund University, University Hospital, Malmö, Sweden.
Transpl Immunol. 1997 Sep;5(3):204-11. doi: 10.1016/s0966-3274(97)80039-1.
Repeated administration of monoclonal antibodies (mAb) directed against the CD4 lymphocyte receptor may induce specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression. We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb (OX-38) on allograft survival in high- and low-responder rat strain combinations. Isogenic strains of DA (RT1av1), PVG (RT1c), AUG (RT1c), and WF (RT1u) rats were used. Recipients in antibody treated groups were given one dose of 5 mg/kg OX-38 mAb on the day of transplant, a dose which was shown to effectively deplete (or block) circulating CD4+ T cells. Other groups were treated for 10 days with cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first compound able to fully eliminate the effect of CsA in the rat cardiac allograft model. The DA strain was identified as a low-responder to the allogeneic haplotype RT1c (PVG or AUG), but not to RT1u (WF), and developed true tolerance following RT1c grafting and OX-38 or low-dose CsA (5 mg/kg) induction, as verified by the response to retransplantation of a graft from the same donor strain or a third-party challenge. PVG recipients of DA grafts were characterized by high response and only modest (OX-38; median 9.5 days) or moderate (CsA; 23.5 days) prolongation of graft survival. Contrasting graft survival results were obtained in the low-responder combination, either very early rejection (at 10 days) or permanent graft survival (> 100 days). Linomide challenge affected CsA treatment in the high-responder combination but not tolerance induction in the low-responder combination, or the effect of OX-38. It was concluded that in rat heart transplantation a single-dose anti-CD4 mAb therapy may induce permanent donor-specific unresponsiveness in a low-responder strain combination, and that anti-CD4 mAb seems to be unique among immunosuppressive agents while being resistent to challenge by Linomide.
反复给予针对CD4淋巴细胞受体的单克隆抗体（mAb），在不进行额外免疫抑制的情况下，可诱导大鼠对完全MHC不匹配的心脏同种异体移植物产生特异性、持久的无反应性。我们评估了单剂量鼠抗大鼠耗竭性抗CD4 mAb（OX-38）对高反应性和低反应性大鼠品系组合中同种异体移植物存活的影响。使用了DA（RT1av1）、PVG（RT1c）、AUG（RT1c）和WF（RT1u）大鼠的同基因品系。抗体治疗组的受体在移植当天给予一剂5 mg/kg的OX-38 mAb，该剂量已被证明可有效耗竭（或阻断）循环中的CD4+ T细胞。其他组用环孢素A（CsA）和/或新型免疫调节剂利诺米德治疗10天，利诺米德是第一种能够在大鼠心脏同种异体移植模型中完全消除CsA作用的化合物。DA品系被确定为对同种异体单倍型RT1c（PVG或AUG）反应低，但对RT1u（WF）反应不低，并且在RT1c移植以及OX-38或低剂量CsA（5 mg/kg）诱导后产生了真正的耐受性，这通过对来自同一供体品系的移植物再移植或第三方攻击的反应得到证实。DA移植物的PVG受体表现出高反应性，移植物存活仅适度延长（OX-38；中位数9.5天）或中度延长（CsA；23.5天）。在低反应性组合中获得了相反的移植物存活结果，即要么非常早期排斥（在10天），要么永久移植物存活（> 100天）。利诺米德攻击影响了高反应性组合中的CsA治疗，但不影响低反应性组合中的耐受性诱导或OX-38的作用。得出的结论是，在大鼠心脏移植中，单剂量抗CD4 mAb疗法可能在低反应性品系组合中诱导永久性供体特异性无反应性，并且抗CD4 mAb在免疫抑制剂中似乎是独特的，同时对利诺米德的攻击具有抗性。
