Chavin K D, Qin L, Woodward J E, Lin J, Bromberg J S
Department of Surgery, Medical University of South Carolina, Charleston 29425.
Transplantation. 1994 Mar 15;57(5):736-40. doi: 10.1097/00007890-199403150-00017.
CsA, FK506, and rapamycin prolong allograft survival; however, each has significant associated side effects at therapeutic doses. Anti-CD2 mAbs also prolong survival but without toxicity. We tested whether alpha CD2 mAbs in combination with subtherapeutic immunosuppression could prolong allograft survival in a synergistic fashion. C57BL/6 (H-2b) mouse hearts were transplanted to CBA (H-2k) mice in a heterotopic, non-vascularized cardiac allograft model. Recipients received immunosuppressants intraperitoneally for 14 days and/or alpha CD2 mAb intravenously for 2 days starting at the time of grafting. Survival was determined by electrocardiogram monitoring. Anti-CD2 alone prolonged survival to 22.4 +/- 1.0 days versus 13.4 +/- 0.5 days for untreated controls (P < 0.05), while low dose FK506 minimally prolonged survival to 16.7 +/- 0.7 days (P < 0.057). However, FK506 plus alpha CD2 resulted in synergistic prolongation of graft survival to 28.0 +/- 2.1 days. Several doses of CsA and rapamycin in combination with alpha CD2 did not prolong survival over alpha CD2 administered alone. A 60-day course of low dose FK506 plus alpha CD2 resulted in indefinite graft survival (> 165 days). These animals were tolerant since they accepted a second donor-specific graft. CTL and MLR activity in long-term recipients were normal to both donor-specific and third party alloantigen. The combination of alpha CD2 with low dose FK506 is synergistic in prolonging cardiac allograft survival, while combinations with CsA and rapamycin are not. Continuous administration of low dose FK506 plus alpha CD2 results in a state of tolerance. This suggests that FK506 acts at a different locus in allograft immunity compared with the other immunosuppressants and this may be related to the alternative CD2 T cell activation pathway.
环孢素A（CsA）、他克莫司（FK506）和雷帕霉素可延长同种异体移植物的存活时间；然而，在治疗剂量下，每种药物都有显著的相关副作用。抗CD2单克隆抗体（mAbs）也可延长存活时间，但无毒性。我们测试了α-CD2 mAbs与亚治疗剂量免疫抑制联合使用是否能以协同方式延长同种异体移植物的存活时间。在异位、非血管化心脏同种异体移植模型中，将C57BL/6（H-2b）小鼠的心脏移植到CBA（H-2k）小鼠体内。从移植时开始，受体腹腔内接受免疫抑制剂治疗14天和/或静脉内接受α-CD2 mAb治疗2天。通过心电图监测确定存活情况。单独使用抗CD2可将存活时间延长至22.4±1.0天，而未治疗的对照组为13.4±0.5天（P<0.05），而低剂量FK506仅将存活时间延长至16.7±0.7天（P<0.057）。然而，FK506加α-CD2可使移植物存活时间协同延长至28.0±2.1天。几种剂量的CsA和雷帕霉素与α-CD2联合使用并未比单独使用α-CD2更能延长存活时间。低剂量FK506加α-CD2的60天疗程可使移植物无限期存活（>165天）。这些动物具有耐受性，因为它们接受了第二个供体特异性移植物。长期受体中针对供体特异性和第三方同种异体抗原的细胞毒性T淋巴细胞（CTL）和混合淋巴细胞反应（MLR）活性正常。α-CD2与低剂量FK506联合使用在延长心脏同种异体移植物存活时间方面具有协同作用，而与CsA和雷帕霉素联合使用则不然。持续给予低剂量FK506加α-CD2会导致耐受状态。这表明FK506在同种异体移植免疫中的作用位点与其他免疫抑制剂不同，这可能与替代性CD2 T细胞激活途径有关。
