SEPARATION OF GVH AND GVL IN MOUSE MODELS

在小鼠模型中进行的研究导致了临床策略的发展，该策略构成了这些交互式ro1中包括的临床试验的基础。在小鼠模型中，我们观察到，在初始骨髓移植后几周延迟输注供体白细胞，用非清髓调节方案产生的混合异体嵌合体可以转化为完全的供体嵌合体。令人惊讶的是，这种“淋巴造血移植物抗宿主反应”与临床明显的移植物抗宿主病（GVHD）无关。本项目的总体目标是建立混合嵌合后延迟供体白细胞输注的白血病模型，在没有GVHD的情况下实现GVL效应，并确定GVL的机制。骨髓性和淋巴性白血病表达各种类型的MHC分子将被利用。在这些模型中，我们将评估混合嵌合体中GVL反应比完全同种异体嵌合体更有效的假设，因为目标异体抗原在宿主骨髓源性抗原呈递细胞（APC）上直接呈递的有效性。此外，我们将评估GVL效应也可以通过间接效应机制发生的可能性，这种机制是由肿瘤不共享的宿主异体抗原呈递引起的。我们将通过比较在不同组织相容性下实现淋巴造血GVHR（包括GVL，不包括GVHD）的能力来确定哪些类型的组织相容性抗原是这些GVL反应的导向。此外，我们将确定供体T细胞亚群在每种组合中实现GVL和GVHD分离的作用。这些研究可能会导致进一步改进混合嵌合方法的使用，以实现最佳的GVL效果，同时最大限度地减少GVHD。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.