Defining the T Cell Mediators of Clinical Response in Chronic GVHD

项目1：确定慢性移植物抗宿主病临床反应的T细胞介质 摘要： 慢性移植物抗宿主病(CGVHD)是术后并发症和晚期死亡的主要原因。 造血干细胞移植。而多种先天性和获得性免疫细胞群 有助于其病理生理，供者T细胞在所有阶段协调cGVHD，无论是通过他们的直接 或者通过它们对其他细胞群体的影响。然而，尽管有关于 小鼠cGVHD的控制机制及几种新的临床研究进展 治疗方面，完全应答率(CR)仍然很低：大多数患者只表现出部分缓解 对治疗有反应，许多人患有治疗难治的cGVHD。此外，严重缺乏 关于决定接受cGVHD治疗的个别患者的临床反应的信息。使 我们对人类慢性移植物抗宿主病发病机制的认识取得突破，并优先考虑下一代 在治疗学中，我们必须(1)准确地定义活跃在患者体内的免疫途径，最终 发展cGVHD和(2)确定cGVHD治疗方案成功和失败的机制 在个体病人的层面上。为了实现这些目标，本项目将完成以下具体工作 目标。在目标1中，我们将在+100天确定cGVHD的风险分配免疫配置文件。在目标2中，我们将 确定慢性移植物抗宿主病患者治疗反应与耐药免疫模式的演变。在……里面 目的3基于已完成的轨迹分析，我们将研究Tregs基因修饰的影响。 对低剂量IL-2有反应者与无反应者，以创建优化的细胞治疗以控制 CGVHD。通过实现这些目标，该项目有望识别出能够预测 CGVHD，以及与cGVHD治疗反应或抵抗相关的那些，从而为 成功预防和治疗这种疾病的新时代。

Project 1: Defining the T Cell Mediators of Clinical Response in Chronic GVHD Abstract: Chronic graft versus host disease (cGVHD) represents the major cause of morbidity and late mortality after hematopoietic stem cell transplantation (HCT). While multiple innate and adaptive immune cell populations contribute to its’ pathophysiology, donor T cells orchestrate cGVHD at all stages, either through their direct effects, or through their influence on other cell populations. However, despite detailed information about the mechanisms controlling cGVHD derived from mouse models, and the development of several new clinical therapeutics, the rates of complete response (CR) remain low: most patients demonstrate only a partial response to therapy, and many have therapy-refractory cGVHD. Moreover, there is a critical lack of information about what determines clinical response in individual patients treated for cGVHD. To make breakthroughs in our understanding of the pathogenesis of human cGVHD and to prioritize the next generation of therapeutics, we must (1) Accurately define the immune pathways that are active in patients who ultimately develop cGVHD and (2) Determine the mechanisms of both success and failure of cGVHD treatment regimens at the level of the individual patient. To accomplish these goals, this Project will complete the following Specific Aims. In Aim 1, we will identify Risk Assignment immune profiles for cGVHD at Day +100. In Aim 2, we will determine the evolution of treatment-responsive versus -resistant immune profiles in patients with cGVHD. In Aim 3 we will investigate the impact of gene modification of Tregs based on completed trajectory analyses from responders versus non-responders to low-dose IL-2, in order to create an optimized cellular therapeutic to control cGVHD. By accomplishing these Aims, this Project promises to identify the molecular networks that predict cGVHD, and those associated with response or resistance to cGVHD therapies, thereby paving the way for a new era of successful prevention and treatment strategies for this disease.