Role of TIGIT Signaling in Transplantation

TIGIT 信号传导在移植中的作用

基本信息

批准号：
10228813
负责人：
Mandy L Ford
金额：
$ 67.17万
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：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228813
关键词：
Acute Agonist Allografting Binding CD28 gene CD8-Positive T-Lymphocytes CD80 gene CD8B1 gene CTLA4 blockade CTLA4 gene Calcineurin inhibitor Cells Chimeric Proteins Clinical Clinical Trials Data Exhibits FOXP3 gene Family Glean Goals Graft Survival Human Immunity Immunosuppression Immunotherapeutic agent In Vitro Incidence Kidney Transplantation Knock-out Ligands Mediating Memory Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Paper Pathway interactions Patient-Focused Outcomes Patients Play Population Publishing Regimen Regulatory T-Lymphocyte Resistance Risk Role Seminal Serum Signal Transduction System T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic immunosuppression Toxic effect Transplant Recipients Transplantation Tumor Immunity base clinically relevant conditional knockout curative treatments cytokine end-stage organ failure experimental study improved insight isoimmunity mortality risk mouse model new therapeutic target novel novel therapeutics patient population prevent response side effect

项目摘要

Summary. Transplantation is a curative treatment for end-stage organ failure, but rates of significant morbidity and graft loss due to immunosuppression-induced toxicities remain unacceptably high. Belatacept, a CTLA-4Ig fusion protein and the first new therapy for immunosuppression in transplantation in over 20 years, offers a significant benefit to renal transplant recipients in that it carries a 43% reduced risk of death or graft loss after 7 years as compared to calcineurin inhibitor-based regimens. However, belatacept confers a significantly increased risk of acute rejection as compared to calcineurin inhibitors. The two main cellular subsets that have been implicated in belatacept-resistant rejection are 1) Foxp3+ Treg and 2) CD8+ memory T cells. First, numerous studies have shown that because belatacept/CTLA-4Ig binds to the CD80/86 ligands for CTLA-4, the CTLA-4-mediated suppressive function of Treg is compromised under these conditions. Second, a separate body of work has shown that distinct CD8+ memory T cell populations exhibit reduced requirements for CD28 costimulation. Studies in mouse, NHP, and humans have identified CD8+ alloreactive memory T cells as forming a barrier to graft acceptance during transplantation. As such, identifying alternate pathways that 1) augment Treg suppressive function in the context of CTLA-4 blockade and 2) control memory CD8+ T cell populations during rejection or tolerance are clinically relevant questions in transplantation. Our preliminary data show that that while agonism of TIGIT alone had no effect on graft survival, agonism of TIGIT mitigated the costimulation blockade-resistant rejection observed in the setting of treatment with CTLA-4Ig, resulting in prolonged allograft survival. However, the mechanisms underlying these observations are not understood. What is the impact of TIGIT agonism on Tregs in the context of CTLA-4Ig? What are the cellular and molecular pathways downstream of TIGIT agonism on Tregs? Is there a cell-intrinsic role for TIGIT agonism on memory CD8+ T cells in the context of CTLA-4Ig? How does TIGIT agonism of Foxp3+ Treg impact memory CD8+ T cells? What is the impact of belatacept treatment of human T cells isolated from transplant recipients on these pathways? In this proposal, we will parse apart the effect of TIGIT agonism on Foxp3+ Treg (which could secondarily impact graft-reactive CD8+ T cell responses) and a cell-intrinsic effect on CD8+ memory T cells using conditional knockouts of TIGIT on either Foxp3+ Treg or memory CD8+ T cells. This proposal will answer these fundamental questions, thereby filling a gap in our current understanding of the role of TIGIT coinhibition in T cell alloimmunity during transplantation. Finally, we propose to directly test the clinical relevance of these findings and hypotheses by interrogating the impact of TIGIT agonism on both Foxp3+ Treg and CD8+ effector/memory T cells isolated from belatacept-treated human renal transplant recipients. Understanding the mechanisms by which TIGIT signaling overcomes belatacept-resistant rejection will provide important information to optimize the use of belatacept for use in clinical transplantation.

概括。移植是治疗终阶段器官衰竭的治疗方法，但发病率明显免疫抑制引起的毒性导致的移植物损失仍然不可接受。 Belatacept，CTLA-4IG 融合蛋白和20多年来接受移植中免疫抑制的新疗法，提供肾移植接受者的重大好处是，它降低了43％的死亡风险或7次后移植的风险与基于钙调神经蛋白抑制剂的方案相比。但是，belatacept大量赋予了一个与钙调蛋白抑制剂相比，急性排斥的风险增加。具有的两个主要细胞子集与Belatacept抗拒的拒绝相关的是1）Foxp3+ Treg和2）CD8+记忆T细胞。第一的，许多研究表明，由于Belatacept/CTLA-4Ig与CTLA-4的CD80/86配体结合，，在这些条件下，Treg的CTLA-4介导的抑制功能受到损害。第二，a 单独的工作表明，不同的CD8+记忆T细胞群体表现出减少的需求用于CD28共刺激。小鼠，NHP和人类的研究已经鉴定出CD8+同种异体记忆T细胞作为在移植过程中形成接枝接受的障碍。因此，确定1）的替代途径在CTLA-4封锁和2）控制内存CD8+ T单元格的背景下增强Treg抑制功能拒绝或容忍期间的种群是移植中临床上相关的问题。我们的初步数据表明，虽然仅提吉特的激动剂对移植物的生存没有影响，但提示的激动在用CTLA-4IG治疗中观察到的抗封锁抗拒拒绝的拒绝，导致长时间的同种异移植生存。但是，尚不了解这些观察结果的机制。在CTLA-4IG的背景下，Tigit激动剂对Tregs有什么影响？细胞和分子是什么 tigit激动剂在tregs上的途径？在记忆中，是否有细胞中心作用 CD8+ T细胞在CTLA-4Ig的背景下？ Foxp3+ Treg的Tigit激动作用如何影响记忆CD8+ T 细胞？ Belatacept治疗从移植受者分离的人类T细胞对这些的影响是什么途径？在此提案中，我们将分析Tigit激动剂对Foxp3+ Treg的影响（可能其次，影响移植物反应的CD8+ T细胞反应）和对CD8+记忆T细胞的细胞中性效应使用在Foxp3+ Treg或内存CD8+ T细胞上进行Tigit的条件敲除。该建议将回答这些基本问题，从而填补了我们当前对Tigit共抑制作用的理解的空白在移植过程中T细胞同种免疫。最后，我们建议直接测试这些临床相关性通过询问Tigit激动剂对Foxp3+ Treg和CD8+的影响，发现和假设效应子/记忆T细胞从Belatacept处理的人肾移植受者中分离出来。了解 Tigit信号克服BELATACEPT抗拒排斥的机制将提供重要的信息以优化使用Belatacept用于临床移植的信息。