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。移植是终末期器官衰竭的一种治疗方法，但发病率很高由于免疫抑制引起的毒性导致的移植物损失仍然高得令人无法接受。贝拉西普，一种 CTLA-4Ig 融合蛋白和 20 多年来第一个用于移植免疫抑制的新疗法，提供了对肾移植受者有显着的好处，因为 7 年后死亡或移植物丢失的风险降低了 43% 与基于钙调神经磷酸酶抑制剂的治疗方案相比，需要花费数年的时间。然而，贝拉西普具有显着的与钙调神经磷酸酶抑制剂相比，急性排斥反应的风险增加。两个主要的细胞亚群与贝拉西普耐药性排斥有关的细胞包括 1) Foxp3+ Treg 和 2) CD8+ 记忆 T 细胞。第一的，大量研究表明，由于belatacept/CTLA-4Ig 与 CTLA-4 的 CD80/86 配体结合， CTLA-4 介导的 Treg 抑制功能在这些条件下受到损害。第二，一个单独的工作表明，不同的 CD8+ 记忆 T 细胞群表现出较低的需求用于 CD28 共刺激。对小鼠、NHP 和人类的研究已鉴定出 CD8+ 同种异体反应性记忆 T 细胞在移植过程中形成移植物接受的障碍。因此，确定替代途径：1) 在 CTLA-4 阻断的背景下增强 Treg 抑制功能和 2) 控制记忆 CD8+ T 细胞排斥或耐受期间的群体是移植中的临床相关问题。我们的初步数据显示，虽然单独使用 TIGIT 的激动作用对移植物存活没有影响，但 TIGIT 的激动作用会减轻在 CTLA-4Ig 治疗中观察到的共刺激阻滞抵抗排斥反应，导致延长同种异体移植物的存活率。然而，这些观察结果背后的机制尚不清楚。在 CTLA-4Ig 的背景下，TIGIT 激动剂对 Tregs 有什么影响？什么是细胞和分子 Tregs 上 TIGIT 激动的下游途径？ TIGIT 激动剂对记忆是否具有细胞内在作用 CTLA-4Ig 背景下的 CD8+ T 细胞？ Foxp3+ Treg 的 TIGIT 激动如何影响记忆 CD8+ T 细胞？ Belatacept 治疗从移植受者分离的人类 T 细胞对这些有什么影响？途径？在本提案中，我们将解析 TIGIT 激动对 Foxp3+ Treg 的影响（这可能其次影响移植物反应性 CD8+ T 细胞反应）以及对 CD8+ 记忆 T 细胞的细胞内在效应使用条件性敲除 Foxp3+ Treg 或记忆 CD8+ T 细胞上的 TIGIT。该提案将回答这些基本问题，从而填补了我们目前对 TIGIT 共抑制作用理解的空白移植过程中T细胞同种免疫。最后，我们建议直接测试这些的临床相关性通过询问 TIGIT 激动剂对 Foxp3+ Treg 和 CD8+ 的影响得出的发现和假设从贝拉西普治疗的人肾移植受者中分离出效应/记忆 T 细胞。了解 TIGIT 信号传导克服贝拉西普耐药排斥的机制将提供重要的优化贝拉西普在临床移植中的使用的信息。