CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity

CD11b：同种免疫期间 CD154 的新型替代受体

• 批准号: 10666184
• 负责人: Mandy L Ford
• 金额: $ 4.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666184
• 关键词: Address; Adhesions; Affinity; Allografting; Alternative Therapies; Anti-CD40; Antibodies; Binding; Binding Sites; Biological; Biological Assay; Blood Platelets; CD8-Positive T-Lymphocytes; Chemotactic Factors; Clinic; Clinical; Clinical Research; Communication; Data; Event; Experimental Models; FOXP3 gene; Frequencies; Generations; Hemostatic Agents; Human; ITGAM gene; Immunosuppression; Inferior; Infiltration; Inflammation; Leukocytes; Mediating; Mediator of activation protein; Methods; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Nature; Outcome; Paper; Pathway interactions; Peptides; Phase; Primates; Reagent; Reporting; Residual state; Role; Safety; Signal Transduction; Solid; Source; Surface Plasmon Resonance; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Thromboembolism; Transplant Recipients; Transplantation; Transplantation Tolerance; Tumor-infiltrating immune cells; allograft rejection; antagonist; cell motility; clinical development; clinical translation; clinically relevant; crosslink; early phase clinical trial; experimental study; in vivo; innovation; isoimmunity; migration; monocyte; nonhuman primate; novel; pre-clinical; preclinical study; prevent; receptor; therapeutic target; trafficking

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.

摘要/概要 几十年来，移植后阻断CD40-CD154相互作用已被证明是一种高度有效的方法。 抑制同种异体反应性T细胞应答和诱导同种异体移植物长期存活的有效手段，和 在某些条件下，在鼠和非人灵长类动物模型中的移植耐受性。但 这种治疗策略对移植结果产生变革性影响的潜力还有待进一步研究。 实现了具体而言，与抗CD154单克隆抗体可能导致血栓栓塞的事实相关的问题 通过Fc依赖性机制结合和交联血小板上的CD154， CD 154阻滞剂的研究，并激发了CD 40作为替代疗法的治疗靶向。虽然这些 抗CD40试剂确实具有显著延长同种异体移植物存活的能力，但没有一种试剂能够达到这一目的。 用抗CD154 mAb观察到的显著的耐受诱导结果。这些观察提出了 阻断CD 154与阻断CD 40实际上在机制上不等同的可能性。因为这些 抗CD40试剂通过管道进入移植临床转化， 必须确定是否存在观察到的阻断CD40的劣效性的生物学解释 与阻断CD 154相比，以便设计克服它的方法。在这里，我们提出了令人信服的 新的初步数据显示，CD11b是同种免疫过程中CD154的第二受体， 通过其的信号传导被抗CD154试剂阻断，但不被抗CD40试剂阻断。使用特定 肽拮抗剂，我们发现CD154：CD11b相互作用在同种异体移植物中局部发挥作用， 供者反应性CD8 + T细胞浸润并加速同种异体移植排斥反应。然而， CD154：CD11b相互作用促进T细胞迁移到同种异体移植物中尚不清楚。此外，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不通过CD40阻断或在CD40-/-受体中诱导。因此，我们也将询问 阻断新型CD154：CD11b相互作用诱导Foxp3 + iTreg并促进免疫耐受 同种免疫来自所提出的实验的结果将阐明新的CD154依赖性方面， 不被抗CD40单克隆抗体阻断的同种免疫，从而填补了我们对基础免疫的理解上的空白。 同种异体移植排斥反应的机制。所提出的实验也是高度临床相关的，因为 抗CD40单克隆抗体通过临床转化管道，了解CD154：CD11b的影响 相互作用（在CD40阻断的情况下不受阻碍地进行）是最重要的， 设计创新的策略来阻断这些相互作用，从而优化CD40阻断剂的使用， 临床上的移植耐受性。