Antagonism of the CD154/CD40 pathway is a highly effective means of inducing long‐term graft survival in preclinical models. Using a fully allogeneic murine transplant model, we found that CD154 blockade was more effective in prolonging graft survival than was CD40 blockade, raising the possibility that CD154 binds a second receptor. To test this, we queried the impact of CD154 antagonism in the absence of CD40. Data indicated that anti‐CD154 functioned to reduce graft‐infiltrating CD8⁺ T cells in both WT and CD40^−/− hosts. Because it has recently been reported that CD154 can ligate CD11b, we addressed the impact of blocking CD154‐CD11b interactions during transplantation. We utilized a specific peptide antagonist that prevents CD154 binding of CD11b but has no effect on CD154‐CD40 interactions. CD154:CD11b antagonism significantly increased the efficacy of anti‐CD40 in prolonging allograft survival as compared to anti‐CD40 plus control peptide. Mechanistically, CD154:CD11b antagonism functioned to reduce the frequency of graft‐infiltrating CD8⁺ T cells and innate immune cells. These data therefore demonstrate that blocking CD154 interactions with both CD40 and CD11b is required for optimal inhibition of alloimmunity and provide an explanation for why CD40 blockers may be less efficacious than anti‐CD154 reagents for the inhibition of allograft rejection.

中文翻译：

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CD11b 是同种免疫期间 CD154 的新型替代受体。


CD154/CD40 通路的拮抗作用是在临床前模型中诱导长期移植物存活的高效方法。使用完全同种异体小鼠移植模型，我们发现 CD154 阻断比 CD40 阻断更有效地延长移植物存活，这提高了 CD154 结合第二种受体的可能性。为了测试这一点，我们询问了在没有 CD40 的情况下 CD154 拮抗作用的影响。数据表明，抗 CD154 可以减少 WT 和 CD40 ^−/−宿主中的移植物浸润 CD8 ⁺ T 细胞。由于最近有报道称 CD154 可以连接 CD11b，因此我们解决了移植过程中阻断 CD154-CD11b 相互作用的影响。我们使用了一种特定的肽拮抗剂，可以阻止 CD154 与 CD11b 结合，但对 CD154-CD40 相互作用没有影响。与抗 CD40 加对照肽相比，CD154:CD11b 拮抗作用显着增加了抗 CD40 在延长同种异体移植物存活方面的功效。从机制上讲，CD154:CD11b 拮抗作用可降低移植物浸润 CD8 ⁺ T 细胞和先天免疫细胞的频率。因此，这些数据表明，阻断 CD154 与 CD40 和 CD11b 的相互作用是同种免疫的最佳抑制所必需的，并解释了为什么 CD40 阻断剂在抑制同种异体移植排斥方面可能不如抗 CD154 试剂有效。