Scully R, Qin S, Cobbold S, Waldmann H
Department of Pathology, University of Cambridge.
Eur J Immunol. 1994 Oct;24(10):2383-92. doi: 10.1002/eji.1830241019.
CBA/Ca mice may be made tolerant to minor histoincompatible B10.BR skin grafts by treatment with a short course of non-depleting anti-mouse CD4 and CD8 monoclonal antibodies (mAb), during the transplantation period. We wished to determine when, in relation to antibody therapy, the T cells became tolerant. This was investigated by a series of adoptive transfer experiments in which mAb-treated cells were removed from therapeutic antibody at defined times after skin grafting, and exposed to fresh antigen in the absence of further mAb treatment. We show here that T cells do not become fully tolerant until 5 weeks after skin grafting. If antibody therapy is continued for the full 5 weeks, T cell tolerance can still be established, suggesting that antibody therapy does not prevent lymphocytes from registering the presence of antigen. Once the tolerant state is established, it is difficult to break that tolerance by lymphocyte infusions from normal donors. This "resistance" is mediated by T cells of the tolerant host. We show that the maintenance of both tolerance and "resistance" requires a continuous supply of antigen. When tolerant cells were "parked" in T cell-depleted mice, tolerance and "resistance" were eventually lost by 6 months. In contrast, "parked" cells exposed to fresh antigen at any time up to 4 months remained tolerant and "resistant" indefinitely. Finally, we wished to establish whether "resistance" was peculiar to this form of peripheral tolerance, or whether it might also be present in tolerance considered to be classically central. We observed resistance to be greater in the mAb-treated peripherally tolerant group, but noted that some of the centrally tolerant animals also exhibited a level of resistance above that of T cell-ablated controls. This suggests that a tolerance mechanism whose role is only minor in central tolerance may have a major role in antibody-mediated peripheral tolerance.
在移植期间，通过短期使用非清除性抗小鼠CD4和CD8单克隆抗体（mAb）治疗，CBA/Ca小鼠可以对轻微组织不相容的B10.BR皮肤移植物产生耐受。我们希望确定与抗体治疗相关的T细胞何时产生耐受。通过一系列过继转移实验对此进行了研究，在这些实验中，在皮肤移植后的特定时间将经mAb处理的细胞从治疗性抗体中移除，并在没有进一步mAb治疗的情况下暴露于新鲜抗原。我们在此表明，T细胞直到皮肤移植后5周才完全产生耐受。如果抗体治疗持续整整5周，T细胞耐受仍可建立，这表明抗体治疗不会阻止淋巴细胞识别抗原的存在。一旦建立了耐受状态，通过输注正常供体的淋巴细胞很难打破这种耐受。这种“抗性”由耐受宿主的T细胞介导。我们表明，耐受和“抗性”的维持都需要持续供应抗原。当将耐受细胞“寄养”在T细胞耗竭的小鼠中时，耐受和“抗性”最终在6个月时丧失。相比之下，在长达4个月的任何时间暴露于新鲜抗原的“寄养”细胞仍无限期地保持耐受和“抗性”。最后，我们希望确定“抗性”是否是这种外周耐受形式所特有的，或者它是否也可能存在于被认为是经典中枢耐受的情况中。我们观察到在经mAb处理的外周耐受组中抗性更大，但注意到一些中枢耐受的动物也表现出高于T细胞消融对照组的抗性水平。这表明一种在中枢耐受中作用较小的耐受机制可能在抗体介导的外周耐受中起主要作用。
