Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3 iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4 Foxp3 iTreg following transplantation, treatment with anti-CD40 or deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3 iTreg and found that blockade of CD11b in recipients resulted in increased donor-reactive Foxp3 iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1β from CD11b and CD11c dendritic cells, and blockade of IL-1β synergized with CD40 deficiency to promote Foxp3 iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1β-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3 iTreg during transplantation.

中文翻译：

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通过阻断 CD154 与 CD40 差异诱导供体反应性 Foxp3+ 调节性 T 细胞


最近发表的小鼠模型研究和非人类灵长类肾移植研究的荟萃分析表明，在动物模型和多个器官中，抗 CD154 试剂比 CD40 阻滞剂具有显着的生存优势。在这里，我们试图比较用抗 CD154 和抗 CD40 单克隆抗体 (mAb) 治疗的小鼠中供体反应性叉头盒 P3+ 诱导的调节性 T 细胞 (Foxp3 iTreg) 的诱导情况。结果表明，虽然抗 CD154 mAb 治疗导致移植后供体反应性 CD4 Foxp3 iTreg 的频率显着增加，但抗 CD40 或缺陷治疗未能重现这一结果。因为我们最近发现 CD11b 在同种免疫期间是 CD154 的替代受体，所以我们探讨了 CD154:CD11b 相互作用在 Foxp3 iTreg 生成中的作用，并发现与 CD40 缺陷相比，受体中 CD11b 的阻断导致供体反应性 Foxp3 iTreg 增加独自的。从机制上讲，CD154:CD11b 抑制可减少 CD11b 和 CD11c 树突状细胞中的白介素 (IL)-1β，并且阻断 IL-1β 与 CD40 缺陷协同促进 Foxp3 iTreg 诱导并延长同种异体移植物存活。综上所述，这些数据为所观察到的抗 CD40 阻滞剂与抗 CD154 mAb 相比的劣势提供了机制基础，并阐明了 IL-1β 依赖性机制，通过该机制 CD154:CD11b 相互作用可阻止供体反应性 Foxp3 iTreg 的产生。移植。