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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：
10728916
负责人：
Mandy L Ford
金额：
$ 7.17万
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/10728916
关键词：
Acceleration 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 Infiltration Inflammation Leukocytes Mediating Mediator 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 infiltration T cell response T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Therapeutic Thromboembolism Transplant Recipients Transplantation Transplantation Tolerance 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.

抽象/总结