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：
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
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/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

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/总结几十年来，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 细胞反应并诱导同种异体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均具有移植耐受性。然而，这种治疗策略对移植结果产生变革性影响的潜力尚未确定意识到了。具体来说，与抗 CD154 mAb 可能导致血栓栓塞这一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 阻碍了临床转化 CD154 阻滞剂的研究，并促使将 CD40 作为替代疗法。虽然这些抗CD40试剂当然具有显着延长同种异体移植物存活的能力，但目前还没有实现使用抗 CD154 mAb 观察到显着的耐受诱导结果。这些观察结果提出了 CD154 的阻断与 CD40 的阻断实际上在机制上并不等效。正如这些抗CD40试剂正在进入移植临床转化的管道，必须确定所观察到的阻断 CD40 的劣势是否存在生物学解释与阻断 CD154 相比，以便随后想出克服它的方法。在这里，我们向您展示引人注目的新的初步数据表明 CD11b 是同种免疫期间 CD154 的第二个受体，抗 CD154 试剂可阻断该信号传导，但抗 CD40 试剂不会阻断该信号传导。使用特定的肽拮抗剂，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，以增强供体反应性 CD8+ T 细胞浸润并加速同种异体移植排斥。然而，其机制 CD154:CD11b 相互作用促进 T 细胞迁移到同种异体移植物中的作用尚不清楚。此外，Foxp3+的诱导 iTreg 在抗 CD154 引发的移植耐受中发挥着关键作用，但我们的新初步数据显示 iTreg 不是通过 CD40 阻断或在 CD40-/- 受体中诱导的。因此，我们还将质疑阻断新型 CD154:CD11b 相互作用诱导 Foxp3+ iTreg 并促进耐受同种免疫。拟议实验的结果将阐明 CD154 依赖性的新方面抗CD40单克隆抗体不能阻断同种免疫，从而填补了我们对基本免疫的理解空白同种异体移植排斥的机制。所提出的实验也具有高度的临床相关性，因为抗 CD40 单克隆抗体通过临床转化渠道，了解 CD154:CD11b 的影响相互作用（在 CD40 封锁的情况下不受阻碍地进行）对于设计创新策略来阻断这些相互作用，从而优化 CD40 阻断剂的使用，以促进临床上的移植耐受性。