Augmentation of GVL Reactivity Without GVHD

移植物抗白血病（GVL）效应是有效过继免疫治疗的最有力的证据之一。 异基因骨髓移植（BMT）后的免疫治疗。不幸的是，GVL反应性通常 与移植物抗宿主病（GVHD）共表达，GVHD是该疗法的主要并发症。为 在过去的五年里，我们已经研究了一种临床可行的方法， 同种异体反应性供体T细胞在BMT后早期被选择性消除以调节供体T细胞存活。使用 在小鼠BMT模型中，我们已经能够证明， 所述GVHD可以显著降低而不损失GVL效应。我们还观察到GVHD 导致自身耐受性丧失，导致自身免疫性的发展，这可归因于 BMT后不存在CD 4 + CD 25+调节性T细胞（TcB）。这些研究让我们假设， 同种异体反应性供体T细胞和TCLs之间的相互作用在GVL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， 这种竞争性更新的目标是研究同种异体反应性的时间动力学和组织迁移如何影响免疫应答。 在GVL和GVH应答的演变过程中，供体T细胞和调节性T细胞影响了 解离GVL/GVH反应性。该基金的具体目标是：（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严重性中的作用，和 (3)以确定T细胞与同种异体反应性供体T细胞之间的相互作用如何影响 单独的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，该提案将提供重要的临床前 这些数据将进一步加深我们对TGF 1 α如何调节GVL和GVH反应性的理解，并将作为一种新的研究方法。 为将这一整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GVHD是移植物抗宿主病的主要并发症这一事实。 异基因干细胞移植更好地了解如何减少这种并发症，而在 同时，保留移植产生的有益效果将导致新的治疗方法， 为患者带来更好的结果。

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.