Seydel K, Shizuru J, Grossman D, Wu A, Alters S, Fathman C G
Department of Medicine, Stanford University School of Medicine, California 94305-5111.
Diabetes. 1991 Nov;40(11):1430-4. doi: 10.2337/diab.40.11.1430.
We studied the effects of anti-CD4 treatment of diabetic ACI rats on the induction of tolerance to allogeneic (Lewis) islet allografts. When given as a 4-day treatment regimen, OX38, a mouse anti-rat CD4 antibody, caused depletion of greater than 80% of CD4+ cells from the peripheral blood of treated rats. After induction of diabetes (a single high-dose bolus of streptozocin) and 3 days after the initiation of anti-CD4 immunotherapy, recipient ACI rats were transplanted with fully allogeneic (Lewis) islets of Langerhans via the portal circulation. These transplanted islets were capable of returning the anti-CD4-treated ACI recipients to normoglycemia, which was maintained indefinitely in the absence of further immunosuppression. In contrast, treatment of recipient rats with OX8, an anti-CD8 monoclonal antibody (MoAb), induced only a slight prolongation of graft survival (less than or equal to 30 days). Further characterization of the cellular requirements for the induction of long-term transplantation survival revealed that successful pretransplantation anti-CD4 therapy could be ablated by the coincident treatment of recipient rats with depleting levels of anti-CD8 MoAb. These data point to the necessity of a regulator CD8+ cell in the induction of anti-CD4-mediated transplantation survival in this rat model of islet transplantation.
我们研究了抗CD4治疗对糖尿病ACI大鼠诱导同种异体（Lewis）胰岛移植耐受的影响。当采用为期4天的治疗方案时，小鼠抗大鼠CD4抗体OX38可使接受治疗大鼠外周血中80%以上的CD4+细胞耗竭。在诱导糖尿病（单次大剂量注射链脲佐菌素）并开始抗CD4免疫治疗3天后，通过门静脉循环将完全同种异体（Lewis）的胰岛移植给受体ACI大鼠。这些移植的胰岛能够使接受抗CD4治疗的ACI受体恢复正常血糖，在没有进一步免疫抑制的情况下，血糖水平可无限期维持。相比之下，用抗CD8单克隆抗体（MoAb）OX8治疗受体大鼠，仅使移植物存活期稍有延长（小于或等于30天）。对诱导长期移植存活的细胞需求进行的进一步研究表明，受体大鼠同时接受耗竭水平的抗CD8 MoAb治疗可消除移植前成功的抗CD4治疗效果。这些数据表明，在该胰岛移植大鼠模型中，调节性CD8+细胞对于诱导抗CD4介导的移植存活是必需的。
