The potential of the graft versus leukemia (GVL) effect to cure leukemia is illustrated by the success of adoptive immunotherapy with donor leukocyte infusions (DLI) to treat patients who have relapsed with CML after an allogeneic bone marrow transplant. Understanding the immunologic mechanisms underlying this could lead to a significant advancement in the treatment of leukemia in both children and adults through adoptive immunotherapy. The following hypothesis will be tested in the proposed research project: The therapeutic effect of DLI is mediated by a distinguishable population of donor-derived, MHC- restricted T cells responding to both allogeneic and leukemia-specific stimuli.
Three Specific Aims are proposed: 1) To characterize at cellular and molecular levels the T cell response to a leukemia-specific peptide (bcr-abl) in the absence (autologous) and presence (allogeneic) of various degrees of major and minor histoincompatibility; (2) To characterize at cellular and molecular levels the T cell response to intact CML cells, compare this response to that generated by the bcr-abl peptide, and evaluate how alloreactivity alters these responses; and (3) To assess the repertoire of T cells in the peripheral blood of patients given DLI for CML and compare the in vivo T cell repertoire to that identified in vitro in Specific Aims 1 and 2 to distinguish alloreactive and leukemia-reactive T-cells.
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