Augmentation of GVL Reactivity Without GVHD

移植物抗白血病(GVL)效应是有效采用的最有力的证明之一。 异基因骨髓移植后的免疫治疗。不幸的是，GVL的反应性通常 与移植物抗宿主病(GVHD)共表达，移植物抗宿主病(GVHD)是该疗法的主要并发症。对于 在过去的五年里，我们研究了一种临床上可行的方法，即胸苷激酶基因修饰。 同种异体反应性供者T细胞在骨髓移植后早期被选择性地消除，以调节供者T细胞的存活。vbl.使用 这一策略在小鼠骨髓移植模型中，我们已经能够证明在 其中GVHD可以在不损失GVL效应的情况下显著减少。我们还观察到GVHD 导致自我耐受性丧失，导致自身免疫的发展，这可归因于 骨髓移植后缺乏CD4+CD25+调节性T细胞(Tregs)。这些研究使我们假设 同种异体反应性供者T细胞与Tregs之间的相互作用在GVL和Tregs的生物学中起主导作用 异基因骨髓移植受者的GVH反应和分离它们的努力。为此， 这一竞争性更新的目标是检查同种异体反应的时间动力学和组织迁移 供体T细胞和调节性T细胞在GVL和GVH反应演变过程中影响能力 解离GVL/GVH反应性。赠款的具体目的是：(1)确定GVL的时间动力学 和GVH反应性，(2)表征调节性T细胞在调节GVHD严重程度中的作用，以及 (3)确定Tregs和同种异体反应性供者T细胞之间的相互作用如何影响 分离GVL和GVH反应性。这些研究将利用新的、临床相关的小鼠 模型来解决这些问题。总体目标是这项提案将提供重要的临床前 这些数据将进一步加深我们对Tregs如何调节GVL和GVH反应性的理解，并将作为 为将这一总体策略应用于临床奠定了基础。 该项目与公共卫生的相关性源于这样一个事实，即GVHD是 异基因干细胞移植。更好地理解如何在工作期间减少这种并发症 同时，保留移植的有益效果将导致新的治疗方法和 为患者提供更好的结果。

The graft versus leukemia (GVL) effect is one of the most potent demonstrations of effective adoptive immunotherapy after allogeneic bone marrow transplantation (BMT). Unfortunately, GVL reactivity is often coexpressed with graft versus host disease (GVHD) which is the major complication of this therapy. For the past five years, we have examined a clinically feasible approach whereby thymidine kinase gene-modified alloreactive donor T cells are selectively eliminated early post-BMT to modulate donor T cell survival. Using this strategy in a murine BMT model, we have been able to show that there is a therapeutic window during which GVHD can be significantly reduced without loss of the GVL effect. We have also observed that GVHD results in a loss of self tolerance leading to the development of autoimmunity and that this is attributable to the absence of CD4+ CD25+ regulatory T cells (Tregs) post-BMT. These studies lead us to hypothesize that the interaction between alloreactive donor T cells and Tregs plays a dominant role in the biology of GVL and GVH responses and efforts to separate them in allogeneic marrow transplant recipients. To that end, the goal of this competing renewal is to examine how the temporal kinetics and tissue migration of alloreactive donor T cells and regulatory T cells during the evolution of GVL and GVH responses affect the ability to dissociate GVL/GVH reactivity. The specfic aims of the grant are: (1) to define the temporal kinetics of GVL and GVH reactivity, (2) to characterize the role of regulatory T cells in modulating the severity of GVHD, and (3) to determine how the interaction between Tregs and alloreactive donor T cells affects the ability to separate GVL and GVH reactivity. These studies will take advantage of novel, clinically relevant murine models to address these questions. The overall goal is that this proposal will provide important preclinical data that will further our understanding of how Tregs modulate GVL and GVH reactivity and will serve as a foundation for the application of this overall strategy into the clinic. The relevance of this project to public health derives from the fact that GVHD is the major complication of allogeneic stem cell transplantation. Better understanding of how to reduce this complication while at the same time preserving the beneficial effects that result from the transplant will lead to new therapies and better outcomes for patients.