CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity

CD11b：同种免疫期间 CD154 的新型替代受体

基本信息

批准号：
10356115
负责人：
Mandy L Ford
金额：
$ 39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10356115
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

项目摘要

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/摘要几十年来，移植后CD40-CD154相互作用的阻断已被证明是高度有效抑制同种异体T细胞反应并诱导同种异体移植的长期存活的有效手段，在某些条件下，鼠和非人类灵长类动物模型中的移植耐受性。但是，这种治疗策略对移植结果产生变革性影响的潜力尚未实现。具体而言，与抗CD154 mAb可能引起血栓栓塞有关的事实相关的问题通过FC依赖机制在血小板上结合和交联CD154，阻碍了临床翻译 CD154阻滞剂，并促进了CD40作为替代疗法的治疗靶向。而这些抗CD40试剂当然具有显着延长同种异体移植生存的能力，没有实现用抗CD154 mAb观察到的显着耐受性诱导结果。这些观察提出了 CD154与CD40封锁的封锁实际上在机械上相当的可能性。这样抗CD40试剂通过管道进行移植的临床翻译，这是必须确定观察到的封闭CD40的自卑感是否存在生物学解释与阻止CD154相比，为了设计克服它的方法。在这里，我们提出了引人注目的新的初步数据揭示了CD11b是同种免疫期间CD154的第二个受体，通过抗CD154试剂阻断的信号传导，而不是抗CD40试剂。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起作用以增强供体反应性CD8+ T细胞浸润和加速同种异体移植排斥。但是， CD154：CD11b相互作用促进T细胞迁移到同种异体移植中是未知的。此外，诱导foxp3+ ITREG是抗CD154避免的移植耐受性的关键作用，但我们的新初步数据显示 ITREG不会通过CD40封锁或CD40 - / - 受体诱导。因此，我们还将审问阻止新颖的CD154：CD11b相互作用在诱导Foxp3+ ITREG中的相互作用并促进公差同种免疫。提出的实验的结果将阐明新颖的CD154依赖性方面不会被抗CD40 mAB阻止的同种异体免疫力，从而填补了我们对基本的理解的空白同种异移植排斥的机制。拟议的实验在临床上也非常相关，因为抗CD40 mAb在管道中移动进行临床翻译，了解CD154：CD11b的影响相互作用（在CD40封锁的情况下不受阻碍的进行）至关重要制定创新策略来阻止这些相互作用，从而优化使用CD40阻滞剂以促进诊所的移植耐受性。