Mechanisms of GVHD

描述（由申请人提供）： 造血干细胞移植（HSCT）的全部潜力尚未实现，因为移植相关的并发症。这些并发症中最突出的是急性移植物抗宿主病（GVHD）。 虽然移植物可能包括重要的抗肿瘤作用，但直接的器官毒性和免疫重建的延迟导致大量的发病率和死亡率。该项目的总体目标是获得对GVHD病理生理学的新见解，并促进新疗法的开发，以控制GVHD，同时维持移植物V白血病（GVL）。虽然人们普遍认为淋巴细胞的运输、粘附和迁移对于GVHD和GVL的发展至关重要，但这一领域在临床移植中很少受到关注。该项目旨在提供一个平台，用于测试预防GVHD的新预防策略，同时提供严格定义的GVHD和非GVHD患者队列。这将使免疫重建、嵌合、淋巴细胞粘附/迁移和次要组织相容性抗原（mHA）识别的实验室数据与患者结局准确相关。具体而言，该项目将研究：1）预防来自相关和非相关供体的异基因HSCT中急性GVHD的策略。西罗莫司和他克莫司联合应用在URD移植中的协同作用研究以及CD 8 T细胞耗竭的评价将为该项目提供临床平台。2)趋化因子在GVH反应的启动和维持中的作用。趋化因子是器官特异性白细胞迁移和运输的关键介质，但对HSCT中这些重要分子几乎一无所知。了解它们的作用可能有助于开发具有临床价值的特异性趋化因子抑制剂。3)识别与GVHD发展相关的新型mHA的策略。在组织相容性移植中，GVHD是针对mHA的，但这些抗原很少被鉴定。血清学方法的发展，以确定mHA承诺允许更精确的供体选择，预测GVHD的风险，并可能识别GVL的具体目标。 预计临床项目和实验室研究之间的协同关系将提供可用于临床试验和开发GVHD控制新方法的见解。

DESCRIPTION (provided by applicant): The full potential of hematopoietic stem cell transplantation (HSCT) has not been realized because of transplant related complications. Prominent among these complications is acute graft-v-host disease (GVHD). While the graft may include important anti-tumor effects, the direct organ toxicity and delay of immunologic reconstitution results in substantial morbidity and mortality. The overall goal of this project is to acquire new insights into the pathophysiology of GVHD and to foster the development of new therapies to control GVHD while maintaining graft-v-leukemia (GVL). While it is accepted that the trafficking, adhesion, and migration of lymphocytes is critical for the development of GVHD and GVL, this area has received little attention in clinical transplantation. The project is intended to provide a platform for the testing of new prophylactic strategies to prevent GVHD, while providing a stringently defined cohort of patients with and without GVHD. This will allow accurate correlation of laboratory data on immune reconstitution, chimerism, lymphocyte adhesion/migration, and minor histocompatibility antigens (mHA) recognition with patient outcomes. Specifically, the project will study: 1) strategies to prevent acute GVHD in allogeneic HSCT from related and unrelated donors. Studies of the synergistic combination of sirolimus and tacrolimus in URD transplantation, and the evaluation of CD8 T cell depletion will provide the clinical platform for the project. 2) The role of chemokines in the initiation and maintenance of the GVH reaction. Chemokines are critical mediators of organ specific leukocyte migration and trafficking, but almost nothing is known about these important molecules in HSCT. Understanding their role may allow the development of specific chemokine inhibitors with clinical value. 3) Strategies to identify novel mHA pertinent to the development of GVHD. In histocompatible transplantation GVHD is directed against mHA, but few of these antigens have been identified. The development of a serologic method to identify mHA promises to allow more precise donor selection, prediction of GVHD risk, and potentially the identification of specific targets for GVL. It is anticipated that the synergistic relationship between the clinical project and the laboratory investigations will provide insights that can be evaluated for clinical testing and the development of new approaches to GVHD control.