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.

摘要 肾移植是大多数终末期肾病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具有广泛接受的获益。越来越多的证据表明 供体特异性抗体（DSA）是改善肾脏移植后长期结局的主要障碍， 移植CTLA-4 Ig的共刺激阻断疗法已显示出作为潜在治疗剂的前景 控制DSA的策略，显示移植后阶段DSA滴度的发生率降低 与传统的钙调磷酸酶靶向免疫抑制相比。滤泡辅助性T细胞（Tfh），CD 4 + T细胞亚群 最佳抗体产生所需的细胞依赖于CD 28共刺激途径。CTLA-4 Ig抑制 通过结合配体CD 80和CD 86以防止它们与T细胞共刺激分子接合来活化T细胞 CD28。不希望的是，这种作用机制也不加区别地阻断了共刺激分子的CD 80和CD 86连接。 抑制剂CTLA-4，剥夺T细胞的重要抑制信号和相互作用。我们的团队已经证明了 直接拮抗CD 28的选择性CD 28域抗体（dAb）的使用提供了改善的移植物存活 以及与CTLA-4 Ig相比Tfh细胞介导的DSA应答的抑制。有趣的是，供体反应性Tfh 细胞差异上调CTLA-4表达，提示CTLA-4在介导细胞凋亡中的潜在作用。 观察到抗CD 28 dAb的上级抑制作用。因此，在本提案中，我们的目标是确定 通过CTLA-4和PD-L1的共抑制信号传导在改善Tfh介导的Tfh抑制中的需求 选择性CD 28阻断表现出移植后的反应。将进行体内实验 研究CTLA-4和PD-L1与CD 28 dAb联合药理学阻断的效果 治疗以观察移植物存活和Tfh细胞介导的同种免疫应答的功效的任何变化。 然后将进行利用诱导型条件基因敲除Cre-Lox系统的进一步体内实验。 进行测定以确定CTLA-4和/或PD-L1在选择性免疫增强中的内在或外在作用。 CD 28阻断。 拟议的研究项目将作为申请人的培训目标的框架， 移植免疫学的科学研究转变为学术科学家的职业生涯， 将致力于开发新的免疫抑制策略，以诱导移植物特异性耐受。这些 研究将使用一种新的方法， 更好地抑制T细胞依赖性和Tfh驱动供体特异性抗体的免疫调节策略 应答