Allogeneic bone marrow transplantation is thought to be curative in leukemia, in part, through the action of immunocompetent donor cells. The antileukemia or """"""""graft-vs-leukemia (GVL) effect of allogeneic BMT is a dramatic example of immunological reactivity against neoplastic disease, and the potential benefit from successful use of allogeneic BMT to treat malignancy justifies a thorough analysis in order to understand and manipulate the reaction. The GVL effect usually occurs in association with graft-vs-host disease (GVHD), but the precise relationship between the GVL reaction and clinical GVHD is controversial. There is clinical and experimental evidence for a GVL reaction that is independent of GVHD. Murine models and in vitro techniques provide a framework in which to conceptualize and study the dynamic balance between GVH and GVL reactions in man. In this revised proposal, we seek to evaluate methods to manipulate these reactions using strategies that can be readily accomplished in leukemia patients. The ultimate goals of this research are (i) to develop and test strategies for curing leukemic hosts while achieving long-term survival and (ii) to improve the safety and efficacy of BMT so that more patients can be treated successfully. To achieve these goals, well established murine models of allogeneic BMT will be used to test strategies for decreasing GVH reactivity without loss of the GVL effect and increasing GVL reactivity without GVHD when necessary. We propose to test three major hypotheses: (1) that selective ex vivo depletion of T-cell subsets in the BM inoculum can significantly improve long-term, leukemia-free survival after allogeneic BMT; (2) that GVH reactivity can be regulated in vivo without loss of the GVL effect using MoAbs administered after allogeneic BMT; and (3) that an ineffectual GVL reaction can be enhanced by interleukin-2 + CD8+ T-cells, by delayed infusion of donor lymphocytes, or by administration of immunoenhancing doses of anti-CD3 MoAb. Three murine models of allogeneic BMT with differing degrees of immunogenetic disparity between donor and host will be used. The kinetics and extent of donor chimerism will be assessed by flow cytometric analysis. Molecular probes will be used to monitor the persistence of leukemia along with bioassays. The effect of various pre- and post-BMT interventions on the development of donor-host-tolerance in BMT chimeras will be determined using a combination of in vitro and in vivo assays, including limiting dilution analysis. The proposed studies will help identify strategies and reagents that merit further evaluation in clinical BMT as well as those that require modification before use.
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