细胞共刺激阻断诱导的移植耐受已在啮齿动物模型中实现，但这些策略在非人灵长类动物和临床移植中无法有效转化。一个可能导致这种差异的干扰因素是移植物所承受的更大的缺血性炎症。在小鼠中，冷缺血储存（CIS）时间延长的心脏移植物在移植之前会增加缺血再灌注损伤，这会在移植后几个小时内增加内源性记忆CD8 T细胞的浸润和激活，从而介导急性移植物炎症和细胞毒性淋巴分子-4免疫球蛋白耐药性排斥。本研究测试了在这种高缺血移植物中抑制记忆CD8 T细胞激活的策略，以实现长期存活。A/J（H-2a）心脏经过0.5或8小时的CIS移植到C57BL/6（H-2b）受体中，并进行围手术期细胞共刺激阻断治疗。在移植后60天，用抗CD25单克隆抗体（mAb）或白喉毒素去除了高缺血移植物接受者的调节性T细胞（Treg）。围手术期（在0和+1天）的抗淋巴细胞功能相关抗原-1 mAb和抗CD154 mAb可使超过60％的CIS最小移植物在100天以上存活，但只有20％的CIS延长移植物在移植后80天以上存活，而拒绝反应伴随着高滴度的特异性供体抗体。围手术期的抗淋巴细胞功能相关抗原-1、抗肿瘤坏死因子-α和抗CD154 mAb以及在第14和16天加用额外的抗CD154 mAb消除了这种特异性供体抗体，并促进了60％的高缺血移植物的Treg介导耐受和存活超过100天的存活，但所有移植物在移植后120天内均失败。这些研究表明，通过Treg介导的耐受来诱导长时间的高缺血移植物存活的策略并不能持续无限期。版权所有©2023 Wolters Kluwer Health，Inc.。保留所有权利。

Costimulatory blockade-induced allograft tolerance has been achieved in rodent models, but these strategies do not translate well to nonhuman primate and clinical transplants. One confounder that may underlie this discrepancy is the greater ischemic inflammation imposed on the transplants. In mice, cardiac allografts subjected to prolonged cold ischemic storage (CIS) before transplant have increased ischemia-reperfusion injury, which amplifies infiltrating endogenous memory CD8 T-cell activation within hours after transplantation to mediate acute graft inflammation and cytotoxic lymphocyte-associated molecule-4 immunoglobulin-resistant rejection. This study tested strategies inhibiting memory CD8 T-cell activation within such high ischemic allografts to achieve long-term survival.A/J (H-2a) hearts subjected to 0.5 or 8 h of CIS were transplanted to C57BL/6 (H-2b) recipients and treatment with peritransplant costimulatory blockade. At 60 d posttransplant, regulatory T cells (Treg) were depleted in recipients of high ischemic allografts with anti-CD25 monoclonal antibody (mAb) or diphtheria toxin.Whereas peritransplant (days 0 and +1) anti-lymphocyte function-associated antigen-1 mAb and anti-CD154 mAb prolonged survival of >60% allografts subjected to minimal CIS for >100 d, only 20% of allografts subjected to prolonged CIS survived beyond day 80 posttransplant and rejection was accompanied by high titers of donor-specific antibody. Peritransplant anti-lymphocyte function-associated antigen-1, anti-tumor necrosis factor-α, and anti-CD154 mAb plus additional anti-CD154 mAb on days 14 and 16 obviated this donor-specific antibody and promoted Treg-mediated tolerance and survival of 60% of high ischemic allografts beyond day 100 posttransplant, but all allografts failed by day 120.These studies indicate a strategy inducing prolonged high ischemic allograft survival through Treg-mediated tolerance that is not sustained indefinitely.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.