MODULATING GVH/GVL POST-BMT USING TK EXPRESSING T CELLS

描述：(申请人摘要)成功的同种异体骨髓 移植(BMT)取决于建立持久的供体。 植入、移植物抗白血病效应的保留和 移植物抗宿主病(GVHD)毒性的改善。供者T细胞 在促进异体移植和调解GVL方面发挥关键作用 但也会引发移植物抗宿主病，这是异基因移植的主要并发症 北京时间。当前的GVHD预防策略，如体外T细胞耗尽 捐献的骨髓移植在预防移植物抗宿主病方面是有效的，但 移植物排斥反应和疾病复发增加的意外影响 损害免疫重建。作为一种替代策略，申请者有 研究了一种允许选择性体内操作的方法 供体T细胞在宿主内的特定时间点。他培育了一只小鼠 使用供体转基因小鼠的模型，其T细胞已被设计为表达 胸苷激酶(TK)基因。利用这些小鼠作为同种异体基因的供体 骨髓移植实验允许选择性地消除T细胞 通过给药抗病毒药物更昔洛韦来限定间隔。 因此，捐赠者T细胞在预防复发、促进 植入和引起移植物抗宿主病的风险可以动态评估。他 基因修饰供体可成功调节GVHD的假说 T细胞使有益的GVL和促进移植物的作用相关联 保留GVHD或独立于GVHD，同时保留与GVH相关的附属主机 组织损伤减轻。本申请的具体目的是：1) 确定是否选择性消除成熟供体TK T细胞 移植后能够在不影响GVL反应性的情况下缓解GVHD， 2)确定供者T细胞的激活状态如何在 移植影响GVL的反应性，3)以确定如何消除 宿主反应性供者T细胞影响对第三方的残余免疫应答 和病毒感染，以及4)确定如何消除TK转基因 供者T细胞移植后对GVH/GVL反应性的影响 有条件的收件人。这个项目的总体目标是有选择地 调节T细胞功能和体内存活，以增加 异基因骨髓移植治疗指数。

DESCRIPTION: (Applicant's Abstract) Successful allogeneic bone marrow transplantation (BMT) is contingent upon the establishment of durable donor engraftment, the retention of the graft-versus-leukemia effect and the amelioration of toxicity from graft-versus-host disease (GVHD). Donor T cells play a pivotal role in facilitating allo engraftment and mediating the GVL effect but also initiate GVHD, which is the major complication of allogeneic BMT. Current GVHD prevention strategies such as ex vivo T cell depletion of the donor marrow graft have been effective at preventing GVHD but have had the unintended effects of increasing graft rejection and disease relapse as well as impairing immune reconstitution. As an alternative strategy, the applicant has examined an approach that allows for the selective in vivo manipulation of donor T cells at defined time points in the host. He has developed a murine model using donor transgenic mice whose T cells have been engineered to express the thymidine kinase (TK) gene. Use of these mice as donors in allogeneic marrow transplant experiments permits the selective elimination of T cells at defined intervals by administration of the antiviral agent ganciclovir. Consequently, the role of donor T cells in preventing relapse, facilitating engraftment, and causing GVHD can be assessed in a dynamic fashion. He hypothesizes that GVHD can be successfully modulated using gene modified donor T cells such that the beneficial GVL and graft promoting effects associated with or independent of GVHD are retained while collateral GVH-related host tissue damage is mitigated. The specific aims of this application are: 1) to determine whether the selective elimination of mature donor TK+ T cells post-transplant is able to mitigate GVHD without compromising GVL reactivity, 2) to define how the activation status of the donor T cell prior to transplantation affects GVL reactivity, 3) to determine how the elimination of host-reactive donor T cells affects the residual immune response to third party and viral infection, and 4) to determine how the elimination of TK+ transgenic donor T cells post-transplant affects GVH/GVL reactivity in suboptimally conditionally recipients. The overall goal of this project is to selectively modulate T-cell function and survival in vivo in order to augment the therapeutic index of allogeneic BMT.