Marshall S E, Cobbold S P, Davies J D, Martin G M, Phillips J M, Waldmann H
Department of Pathology, University of Cambridge, United Kingdom.
Transplantation. 1996 Dec 15;62(11):1614-21. doi: 10.1097/00007890-199612150-00015.
The induction of tolerance in a primed immune system would be valuable therapeutically, but has been difficult to achieve. Mice primed to multiple minor histoincompatible antigens (minors) are able to rapidly reject secondary grafts using either their CD4+ or CD8+ T-cell subpopulations. Short courses of treatment with nonlytic anti-CD4 and anti-CD8 antibodies targeted at both T-cell subsets can induce long-term peripheral T-cell tolerance in primed mice. We examine the mechanisms by which peripheral tolerance is maintained, and show that tolerant mice harbor CD4+ T cells capable of specifically suppressing rejection mediated by either subset of primed T cells. Remarkably, elimination of CD4+ T cells from tolerant mice resulted in graft rejection, suggesting that graft-reactive CD8+ T cells had not been eliminated, but had been under continuous regulation by "tolerant" CD4+ T cells. This result demonstrates that it may be possible to establish therapeutic operational tolerance without permanently inactivating all antigen-reactive cells.
在已致敏的免疫系统中诱导免疫耐受具有重要的治疗价值，但一直难以实现。对多种次要组织相容性抗原（次要抗原）致敏的小鼠能够利用其CD4+或CD8+ T细胞亚群迅速排斥二次移植的组织。针对这两个T细胞亚群的非溶细胞性抗CD4和抗CD8抗体的短期治疗疗程可在致敏小鼠中诱导长期外周T细胞耐受。我们研究了维持外周耐受的机制，并表明耐受小鼠体内存在能够特异性抑制由致敏T细胞任一亚群介导的排斥反应的CD4+ T细胞。值得注意的是，从耐受小鼠中清除CD4+ T细胞会导致移植组织被排斥，这表明移植反应性CD8+ T细胞并未被清除，而是一直受到“耐受”CD4+ T细胞的持续调节。这一结果表明，有可能在不使所有抗原反应性细胞永久失活的情况下建立治疗性操作耐受。
