CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity

摘要/摘要 几十年来，阻断移植后CD40-CD154的相互作用被证明是一种高度的 抑制同种异体反应性T细胞反应和诱导移植物长期存活的有效手段，以及 在某些条件下，小鼠和非人类灵长类动物模型中的移植耐受。然而， 这一治疗策略对移植结果产生变革性影响的潜力尚未得到证实 意识到了。具体地说，与抗CD154单抗可能导致血栓栓塞症相关的问题 通过Fc依赖的机制结合和交联血小板上的CD154阻碍了临床翻译 CD154阻滞剂，并鼓动将CD40作为替代疗法的治疗靶点。而这些 抗CD40试剂当然具有显著延长同种异体移植物存活的能力，但还没有实现 抗CD154单抗诱导耐受效果显著。这些观察结果提高了 封锁CD154和封锁CD40的可能性实际上并不是机械上等价的。就像这些 抗CD40试剂正在通过移植临床翻译的管道，这是 迫切需要确定阻断CD40的观察到的劣势是否有生物学解释 与阻断CD154相比，以便随后设计出克服它的方法。在这里，我们展示了令人信服的 新的初步数据显示，CD11b是同种免疫过程中CD154的第二个受体， 通过它的信号被抗CD154试剂阻断，但不能被抗CD40试剂阻断。使用特定的 多肽拮抗剂，我们发现CD154：CD11b相互作用在同种异体移植物内局部发挥作用，以增强 供者反应性CD8+T细胞浸润，加速同种异体排斥反应。然而，通过这些机制 CD154：CD11b相互作用促进T细胞向同种异体移植物迁移尚不清楚。此外，对Foxp3+的诱导 ITreg在抗CD154诱导的移植耐受中起关键作用，但我们新的初步数据显示 ITreg不是通过CD40阻断或在CD40/-受体中诱导的。因此，我们还将审问 阻断新的CD154：CD11b相互作用诱导Foxp3+iTreg和促进免疫耐受 同种异体豁免。拟议的实验结果将阐明CD154依赖的新方面 不被抗CD40单抗阻断的同种异体免疫，从而填补了我们对基本 同种异体移植排斥反应的机制。拟议的实验也具有高度的临床相关性，因为 抗CD40单抗通过临床翻译管道，了解CD154：CD11b的影响 相互作用(在CD40封锁设置中畅通无阻地进行)至关重要，以便 设计创新的策略来阻止这些相互作用，从而优化CD40阻滞剂的使用，以促进 临床上的移植耐受。

Abstract/ Summary For decades, blockade of CD40-CD154 interactions following transplantation has been shown to be a highly effective means of inhibiting alloreactive T cell responses and inducing long-term survival of allografts, and under some conditions, transplantation tolerance in both murine and non-human primate models. However, the potential of this therapeutic strategy to have a transformative impact on transplantation outcomes has yet to be realized. Specifically, problems associated with the fact that anti-CD154 mAbs may cause thromboembolism by binding and cross-linking CD154 on platelets via Fc-dependent mechanisms stymied the clinical translation of CD154 blockers, and instigated the therapeutic targeting of CD40 as an alternative therapy. While these anti-CD40 reagents certainly possess the ability to significantly prolong allograft survival, none has achieved the remarkable tolerance-inducing results observed with anti-CD154 mAbs. These observations raise the possibility that blockade of CD154 vs. blockade of CD40 are actually not mechanistically equivalent. As these anti-CD40 reagents make their way through the pipeline for clinical translation in transplantation, it is imperative to determine if there is a biological explanation underlying the observed inferiority of blocking CD40 as compared to blocking CD154, in order to then devise ways to overcome it. Here, we present compelling new preliminary data revealing that CD11b is a second receptor for CD154 during alloimmunity, signaling through which is blocked by anti-CD154 reagents but not anti-CD40 reagents. Using a specific peptide antagonist, we find that CD154:CD11b interactions function locally within the allograft to enhance donor-reactive CD8+ T cell infiltration and accelerate allograft rejection. However, the mechanisms by which CD154:CD11b interactions promote T cell migration into allografts are unknown. Moreover, induction of Foxp3+ iTreg is a critical effect in anti-CD154-elicted transplantation tolerance, but our new preliminary data show iTreg are not induced via CD40 blockade or in CD40-/- recipients. Thus, we will also interrogate the role of blocking novel CD154:CD11b interactions in inducing Foxp3+ iTreg and promoting tolerance during alloimmunity. Results from the proposed experiments will illuminate novel CD154-dependent aspects of alloimmunity that are not blocked by anti-CD40 mAbs, thus filling a gap in our understanding of fundamental mechanisms of allograft rejection. The proposed experiments are also highly clinically relevant, because as anti-CD40 mAbs move through the pipeline for clinical translation, understanding the impact of CD154:CD11b interactions (that proceed unimpeded in the setting of CD40 blockade) is of the utmost importance in order to devise innovative strategies to block these interactions and thus optimize the use of CD40 blockers to facilitate transplantation tolerance in the clinic.