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 骨髓移植（BMT）取决于持久供体的建立 移植物抗白血病效应的保留以及 改善移植物抗宿主病（GVHD）的毒性。供体T细胞 在促进同种异体移植和介导GVL中起关键作用 但也引发GVHD，这是同种异体移植的主要并发症， BMT。目前的GVHD预防策略，如体外T细胞耗竭， 供体骨髓移植在预防GVHD方面是有效的， 增加移植物排斥和疾病复发的非预期效应以及 损害免疫重建。作为替代策略，申请人已 研究了一种方法，允许选择性地在体内操纵 供体T细胞在宿主中的限定时间点。他培育了一种 使用供体转基因小鼠的模型，其T细胞已被工程化以表达 胸苷激酶（TK）基因。这些小鼠作为供体在同种异体移植中的用途 骨髓移植实验允许选择性消除T细胞， 通过给予抗病毒剂更昔洛韦确定间隔。 因此，供体T细胞在预防复发、促进免疫应答和免疫应答方面的作用是不确定的。 移植，并引起GVHD可以以动态的方式进行评估。他 假设使用基因修饰的供体可以成功地调节GVHD， T细胞，使得有益的GVL和移植物促进作用相关 与GVHD相关或不相关的宿主被保留，而与GVHD相关的旁系宿主 减轻了组织损伤。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 移植后能够减轻GVHD而不损害GVL反应性， 2)以确定供体T细胞的活化状态如何在移植前 移植影响GVL反应性，3）确定如何消除GVL反应性， 宿主反应性供体T细胞影响对第三方的残余免疫应答 和病毒感染，以及4）以确定如何消除TK+转基因 移植后供体T细胞影响GVH/GVL反应性， 有条件的接受者。该项目的总体目标是有选择地 调节体内T细胞功能和存活， 异基因骨髓移植的治疗指数。

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.