DENDRITIC CELL/T-CELL INTERACTIONS IN ALLOGENEIC TRANSPLANTATION

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Dendritic cells are bone marrow-derived leukocytes that are specialized to capture antigen and initial T cell-mediated immune responses. Dendritic cells express high levels of antigen presenting MHC products, as well as a number of accessory molecules that mediate T cell binding and costimulation. Dendiritic cells represent a distinct pathway of hematopoietic differentiation, during which many of the properties of phagocytes are sacrificed in exchange for their very high levels of MHC products and accessory molecules. These underlie dendritic cells efficient antigen presentation and activation of quiescent T cells. The identification of active cytokines and specific progenitors for dendritic cells have advanced the experimental study of these physiologic adjuvants in the context of normal and pathologic cell mediated immune responses. The subject will therefore apply these approaches to study dendritic c-T cell interactions in the setting of allogeneic transplantation. CFU-DC content will be compared between different transplantable sources of hematopoietic stem cells, stratified by age to ascertain the degree to which human dendritic cells early in life differ from adult counterparts with respect to stimulatory capacity at comparable levels of differentiation. The CFU content and development of candidate lymphoid dendritic cells will also be investigated, as these may prove more relevant to peripheral tolerance than myeloid dendritic cells. The MHC restriction of T cells emerging post- transplant will then be evaluated with respect to the kinetics and proportion of donor dendritic cell engraftment, and compared to clinical outcome parameters. Initial studies will utilize long term survivors of haploidentical parental allografts for congenital immunodeficiencies, but the focus will ultimately be on patients receiving mismatched allografts for hematologic malignancies. De novo and recall antigens will be assessed to distinguish donor-derived T lymphoid progeny in the engrafted host, from residual host or transplanted donor clones. Finally, the role of dendritic cells in eliciting a graft-vs-leukemia response, independent of GvH/HvG reactions, will be investigated in patients undergoing allogeneic transplantation for chronic myelogenous leukemia. The immunogenic potential of dendritic cells to generate autologous antigen specific CTL against leukemia cells expressing fusion gene peptides will also be studied.