Role of PD-L2 in Antigen-Specific B Cell Responses in Transplantation

PD-L2 在移植中抗原特异性 B 细胞反应中的作用

• 批准号: 9806674
• 负责人: Scott M Krummey
• 金额: $ 9.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806674
• 关键词: Ablation; Adoptive Cell Transfers; Allogenic; Antibodies; Antibody Formation; Antigens; Apoptosis; Attenuated; Award; B Cell Proliferation; B-Lymphocyte Subsets; B-Lymphocytes; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Blocking Antibodies; Blood; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Surface Receptors; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical; Data; Epitopes; Funding; Generations; Goals; Graft Rejection; Graft Survival; Histocompatibility; Human; Immune response; Immunoglobulin G; Immunologics; Immunologist; Immunosuppression; In Vitro; Injury; Kidney Transplantation; Laboratories; Lead; Ligands; MHC Class II Genes; Mediating; Memory; Memory B-Lymphocyte; Mentors; Mentorship; Methods; Monitor; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Organ Transplantation; Outcome; PDCD1LG1 gene; Pathway interactions; Patients; Peripheral; Phase; Plasma Cells; Plasmablast; Play; Population; Prevention strategy; Proliferating; Public Health; Reagent; Research; Resistance; Resources; Risk; Role; SLEB2 gene; Signal Transduction; Solid; Structure of germinal center of lymph node; Survival Rate; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Training; Translating; Transplant Recipients; Transplantation; Treatment Efficacy; Work; adaptive immune response; adaptive immunity; career; clinical biomarkers; curative treatments; differentiated B cell; end-stage organ failure; experience; immune checkpoint blockade; improved; improved outcome; in vitro Assay; kidney allograft; member; novel strategies; novel therapeutics; post-transplant; pre-clinical research; prevent; programs; receptor; response; selective expression; therapeutic target; treatment strategy

Project Summary/Abstract Transplantation is curative treatment for end-stage organ failure. Antibodies that are directed against donor HLA, termed donor specific antibodies (DSA), are associated with rejection and are increasingly recognized as a barrier to improving long-term transplant outcomes. DSA are serially monitored in transplant patients using advanced methods, but treatment strategies are resource intensive and have limited efficacy. Memory B cells that differentiate following allogeneic sensitization form a cellular reservoir that differentiates into antibody secreting plasma cells in the presence of antigen. Despite their role in contributing to DSA formation, the memory B cell compartment is not assessed clinically and there are no effective therapeutic strategies that inhibit it. Recent work has established the importance of the PD-1 pathway in restraining adaptive immunity, but the role of PD-L2 on B cells is not well understood. In this proposal, we have developed a cutting-edge approach to study murine allogeneic B cells through all stages of differentiation from naïve to memory. Using an approach of selective PD-L2 ablation on B cells, we will assess the requirements for germinal center dependent and independent formation of allogeneic memory. In the mentored K99 Phase in Aim 1, we will assess the role of PD-L2 on the differentiation of secondary germinal centers and plasmablasts following restimulation. In Aim 2, we will investigate the effect of B cell expressed PD-L2 on PD-1+ CD4+ T follicular populations using MHC Class II tetramers to identify allogeneic CD4+ T cells. Finally, in Aim 3, during the independent R00 phase, I will investigate activated B cell subsets in the blood of renal transplant patients who form DSA following transplantation. We will examine the possibility that the proliferating activated B cell subsets can be used as a biomarker of DSA formation and rejection in conjunction with the degree of known epitope mismatches at MHC Class II loci. Finally, we will assess the ability of PD-L2 blockade with a monoclonal antibody to inhibit B cell proliferation and antibody production in vitro. The proposed work is aligned with the NIAID strategic priority of identifying therapeutic targets for the enhancement of translational efforts to extend renal allograft survival through preclinical research. These findings will lead to new understanding of the key factors that determine the potency of memory B cells and the cellular processes that lead to DSA formation. Through this work we hope to identify new therapeutic checkpoints that can be exploited to inhibit memory B cell formation and prevent DSA formation and antibody mediated rejection. I am applying for this K99/R00 as a clinical histocompatibility fellow with extensive experience as a T cell immunologist. This application will support extensive advanced training as a B cell immunologist. My long-term career goal is to become an HLA laboratory director with an independently funded basic science laboratory.

项目总结/摘要 移植是终末期器官衰竭的治愈性治疗。针对供体的抗体 HLA，称为供体特异性抗体（DSA），与排斥反应相关，并且越来越多地被认为是 这是改善长期移植结果的障碍。DSA在移植患者中进行连续监测， 虽然有先进的方法，但治疗战略需要大量资源，而且疗效有限。记忆B细胞 在同种异体致敏后分化形成细胞库，分化为抗体 在抗原存在下分泌浆细胞。尽管它们在促进每日生活津贴的形成方面发挥了作用， 记忆B细胞区室没有在临床上进行评估，也没有有效的治疗策略， 最近的工作已经确定了PD-1通路在抑制适应性免疫中的重要性， 但PD-L2对B细胞的作用还不清楚。在这个提案中，我们开发了一种尖端的 通过从幼稚到记忆的所有分化阶段研究鼠同种异体B细胞的方法。使用 一种选择性PD-L2消融B细胞的方法，我们将评估对老年中心的要求 同种异体记忆的依赖性和独立性形成。在目标1的K99辅导阶段，我们将 评估PD-L2对继发性生殖中心和浆母细胞分化的作用， 再刺激目的二：研究表达PD-L2的B细胞对PD-1+ CD 4 + T细胞滤泡性T细胞的影响。 使用MHC II类四聚体鉴定同种异体CD 4 + T细胞。最后，在目标3中， 在独立的R 00阶段，我将研究肾移植患者血液中活化的B细胞亚群， 形成DSA。我们将研究增殖活化的B细胞 亚群可用作DSA形成和排斥反应的生物标志物， 表位错配的MHC II类基因座。最后，我们将评估PD-L2阻断的能力， 单克隆抗体抑制体外B细胞增殖和抗体产生。拟议的工作是 与NIAID的战略重点一致，即确定增强翻译的治疗靶点， 通过临床前研究努力延长肾移植存活率。这些发现将导致新的 了解决定记忆B细胞效力的关键因素以及决定记忆B细胞效力的细胞过程 导致DSA形成。通过这项工作，我们希望确定新的治疗检查点， 用于抑制记忆B细胞形成和防止DSA形成和抗体介导的排斥。我是 作为临床组织相容性研究员申请K99/R 00，具有丰富的T细胞经验 免疫学家该应用程序将支持作为B细胞免疫学家的广泛高级培训。我的长期 职业目标是成为HLA实验室主任，拥有独立资助的基础科学实验室。