SEPARATION OF GVH AND GVL IN MOUSE MODELS

在小鼠模型中进行的研究已经导致了临床策略的开发，该临床策略形成了这些交互式RO1中包括的临床试验的基础。在小鼠模型中，我们已经观察到，当在初始骨髓移植后几周给予延迟的供体白细胞输注时，用非清髓性预处理方案产生的混合异基因嵌合体可以转化为完全供体嵌合体。令人惊讶的是，这种“淋巴造血移植物抗宿主反应”与临床上明显的移植物抗宿主病（GVHD）无关。本项目的总体目标是开发白血病模型，其中混合嵌合体随后延迟供体白细胞输注用于实现GVL效应而不发生GVHD，并确定GVL的机制。将利用表达各种类型的MHC分子的髓样和淋巴样白血病。在这些模型中，我们将评估GVL反应在混合嵌合体中比在完全同种异体嵌合体中更有效的假设，因为靶同种抗原直接呈递宿主骨髓源性抗原呈递细胞（APC）的功效。此外，我们将评估GVL效应也可能通过间接效应机制发生的可能性，间接效应机制是由肿瘤不共享的宿主同种异体抗原呈递引起的。我们将确定哪些类型的组织相容性抗原，这些GVL反应是直接通过比较的能力，实现淋巴造血GVHR，包括GVL，没有GVHD，在各种组织相容性的设置。此外，我们将确定供体T细胞亚群在实现GVL和GVHD分离中的作用。这些研究可能会导致在使用混合嵌合体的方法，以实现最佳的GVL效果，同时最大限度地减少GVHD的进一步完善。这些改进将应用于项目1的临床试验。

Studies performed in the mouse model have led to the development of the clinical strategy that forms the basis of the clinical trial included in these interactive RO1'S. In the mouse model, we have observed that mixed allogeneic chimeras produced with a non-myeloablative conditioning regimen can be converted to fully donor chimeras when delayed donor leukocyte infusions are administered several weeks following the initial bone marrow transplant. Surprisingly, this "lymphohematopoietic graft- versus-host reaction" is not associated with clinically evident graft- versus-host disease (GVHD). The overall goal of this project is to develop leukemia models in which mixed chimerism followed by delayed donor leukocyte infusions is used to achieve GVL effects without GVHD, and to determine the mechanisms of GVL. Both myeloid and lymphoid leukemias expressing various classes of MHC molecules will be utilized. In these models, we will evaluate the hypothesis that GVL responses are more potent in mixed chimeras than in fully allogeneic chimeras because of the efficacy of direct presentation of target alloantigens on host marrow-derived antigen-presenting cells (APC). In addition, we will evaluate the possibility that GVL effects can also occur through indirect effector mechanisms that result from presentation of host alloantigens not shared by the tumor. We will determine which type(s) of histocompatibility antigens these GVL responses are directed by comparing the ability to achieve lymphohematopoietic GVHR, including GVL, without GVHD, in the setting of various histo histocompatibilities. Furthermore, we will determine the role of donor T cell subsets in achieving the separation of GVL and GVHD in each combination. These studies are likely to lead to further refinements in the use of the mixed chimerism approach to achieve optimal GVL effects while minimizing GVHD. These improvements will be applied to the clinical trial in Project 1.