SEPARATION OF GVH AND GVL IN MOUSE MODELS

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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.