Mechanisms of Selective CD28 Blockade on T Follicular Helper Cell Responses During Transplantation

移植过程中选择性 CD28 阻断滤泡辅助 T 细胞反应的机制

• 批准号: 9760429
• 负责人: Glenn Michael La Muraglia II
• 金额: $ 3.88万
• 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: 2019-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760429
• 关键词: Acute; Address; Allogenic; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Attenuated; B-Lymphocytes; Basic Science; Binding; Biological Process; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; CD86 gene; CTLA4 gene; CTLA4-Ig; Calcineurin; Cell Lineage; Cells; Chronic; Clinical; Clinical Research; Data; Development; End stage renal failure; Exhibits; Failure; Generations; Goals; Graft Survival; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Incidence; Injury; Interleukin-2; Intervention; Kidney Transplantation; Knock-out; Lead; Ligand Binding; Ligands; Ligation; Mediating; Mission; Modality; Modeling; Mus; Organ Transplantation; Outcome; PDCD1LG1 gene; Pathway interactions; Patients; Pharmacology; Phase; Play; Provider; Public Health; Publishing; Quality of life; Regulatory T-Lymphocyte; Research; Research Project Grants; Role; Scientist; Series; Signal Transduction; Skin Transplantation; Solid; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Training; Transgenic Organisms; Transplantation; Transplantation Immunology; United States National Institutes of Health; base; career; clinical translation; effector T cell; experimental study; immunoregulation; improved; in vivo; inhibitor/antagonist; insight; interest; kidney allograft; kidney dysfunction; knockout gene; novel; novel therapeutics; post-transplant; preservation; prevent; receptor; recombinase-mediated cassette exchange; response; transplant model

Abstract Kidney transplantation is the treatment modality of choice for the majority of patients suffering from end stage renal disease, with widely accepted benefits in patient survival and quality of life. Mounting evidence suggests that donor-specific antibodies (DSAs) are a major barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade therapy with CTLA-4Ig has shown promise as a potential therapeutic strategy to control DSAs, showing reductions in the incidence of DSA titers in the post-transplant phase compared to traditional calcenurin targeted immunosuppression. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. CTLA-4Ig inhibits T cell activation by binding the ligands CD80 and CD86 to prevent their engagement with the T cell co-stimulator CD28. Undesirably, this mechanism of action also indiscriminately blocks CD80 and CD86 ligation of the co- inhibitor CTLA-4, depriving T cells of important inhibitory signals and interactions. Our group has demonstrated that use of selective CD28 domain antibody (dAb) that directly antagonizes CD28 affords improved graft survival and suppression of Tfh cell-mediated DSA responses compared to CTLA-4Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting a potential role for CTLA-4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, within this proposal we aim to determine the requirement of coinhibitory signaling through CTLA-4 and PD-L1 in the improved suppression of Tfh-mediated responses following transplantation exhibited by selective CD28 blockade. In vivo experiments will be performed investigating the effect of pharmacological blockade of CTLA-4 and PD-L1 in conjunction with CD28 dAb treatment to observe any changes in the efficacy of graft survival and Tfh cell-mediated allo-immune responses. Further in vivo experiments utilizing the inducible conditional gene knockout Cre-Lox system will then be performed to determine the intrinsic or extrinsic role of CTLA-4 and or PD-L1 in the enhancement of selective CD28 blockade. The proposed research project will serve as a framework for the applicant’s training goals of integrating basic science research in transplantation immunology into a career as an academic scientist whose research interest will focus on developing new strategies of immunosuppression for the induction of graft-specific tolerance. These studies will address the treatment of end stage kidney disease with renal transplantation using a novel immunomodulatory strategy to better suppress T cell dependent and Tfh driven donor-specific antibody responses.

抽象的 肾脏移植是大多数患有终阶段患者的首选治疗方式 肾脏疾病，在患者生存和生活质量方面受到广泛接受的益处。越来越多的证据表明 该供体特异性抗体（DSA）是肾脏后长期结局改善的主要障碍 移植。 CTLA-4IG的COTIMIMATION BLOCKADE BLOCKADE THERAPY已显示出有望作为一种潜在疗法 控制DSA的策略，显示移植阶段DSA滴度事件的减少 与传统的钙嘌呤靶向免疫抑制相比。 T卵泡辅助器（TFH）细胞，CD4+ T的子集 最佳抗体产生所需的细胞依赖于CD28共刺激途径。 CTLA-4IG抑制 T细胞通过结合配体CD80和CD86的激活以防止其与T细胞共刺激剂的互动 CD28。不可思议的是，这种作用机理也不加区别地阻止了CD80和CD86共同的连接 抑制剂CTLA-4，剥夺了T细胞重要的抑制信号和相互作用。我们的小组已经证明了 使用直接拮抗CD28的选择性CD28域抗体（DAB）提供了改善的移植物存活率 与CTLA-4ig相比，TFH细胞介导的DSA反应的抑制。有趣的是，供体反应性TFH 细胞对CTLA4表达的更新不同，这表明CTLA-4在介导 用抗CD28 DAB观察到的优质抑制作用。因此，在此提案中，我们旨在确定 通过CTLA-4和PD-L1进行共抑制信号的需求，以改善TFH介导的抑制作用 通过选择性CD28封锁暴露的移植后反应。将进行体内实验 研究CTLA-4和PD-L1的药物阻断与CD28 DAB的影响 可以观察到移植物存活效率和TFH细胞介导的异源免疫反应的任何变化。 进一步利用诱导条件基因敲除cre-lox系统的体内实验将是 进行确定CTLA-4和或PD-L1在选择性增强中的内在或外在作用 CD28封锁。 拟议的研究项目将成为申请人培训目标的框架 移植免疫学的科学研究成为学术科学家的职业生涯 将着重于制定新的免疫抑制策略，以诱导移植物特异性耐受性。这些 研究将使用一种新颖 免疫调节策略以更好地抑制T细胞依赖性和TFH驱动的供体特异性抗体 回答。