Kingsley Cherry I, Karim Mahzuz, Bushell Andrew R, Wood Kathryn J
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
J Immunol. 2002 Feb 1;168(3):1080-6. doi: 10.4049/jimmunol.168.3.1080.
Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of allogeneic skin grafts mediated by CD45RB(high)CD4+ T cells. In this study, we wished to determine whether donor-specific regulatory cells can be generated during the induction phase of unresponsiveness, i.e., before transplantation. We provide evidence that pretreatment with anti-CD4 Ab plus a donor-specific transfusion generates donor-specific regulatory CD25+CD4+ T cells that can suppress rejection of skin grafts mediated by naive CD45RB(high)CD4+ T cells. Regulatory cells were contained only in the CD25+ fraction, as equivalent numbers of CD25-CD4+ T cells were unable to regulate rejection. This pretreatment strategy led to increased expression of CD122 by the CD25+CD4+ T cells. Blockade of both the IL-10 and CTLA-4 pathways abrogated immunoregulation mediated by CD25+ T cells, suggesting that IL-10 and CTLA-4 are required for the functional activity of this population of immunoregulatory T cells. In clinical transplantation, the generation of regulatory T cells that could provide dynamic control of rejection responses is a possible route to permanent graft survival without the need for long-term immunosuppression.
在体内可诱导对供体同种异体抗原产生特异性和选择性免疫无反应性。我们之前已经表明，对供体同种异体抗原表现出长期操作性耐受的小鼠的CD25⁺CD4⁺ T细胞可调节由CD45RB(高)CD4⁺ T细胞介导的同种异体皮肤移植排斥反应。在本研究中，我们希望确定在无反应性诱导阶段，即在移植前，是否能够产生供体特异性调节细胞。我们提供的证据表明，用抗CD4抗体加供体特异性输血进行预处理可产生供体特异性调节性CD25⁺CD4⁺ T细胞，其可抑制由幼稚CD45RB(高)CD4⁺ T细胞介导的皮肤移植排斥反应。调节细胞仅存在于CD25⁺组分中，因为等量的CD25⁻CD4⁺ T细胞无法调节排斥反应。这种预处理策略导致CD25⁺CD4⁺ T细胞的CD122表达增加。阻断IL-10和CTLA-4途径可消除由CD25⁺ T细胞介导的免疫调节，这表明IL-10和CTLA-4是这群免疫调节性T细胞功能活性所必需的。在临床移植中，产生能够动态控制排斥反应的调节性T细胞是实现永久移植存活而无需长期免疫抑制的一条可能途径。
