Our basic understanding of immune function and cellular interactions within the hematopoietic system has improved dramatically in recent years. It is our hypothesis that these advances can be coupled with new methods for ex vivo cell processing and assessment of immune function to develop new strategies for human hematopoietic stem cell transplantation. This approach, which we have generally termed graft engineering, is based on our ability to selective manipulate specific populations of immature and mature cells and to selective transplant these cells at different times in a coordinated fashion. Graft engineering promises to reduce the toxicities associated with transplantation while facilitating the engraftment and function of engrafted stem cells and their diverse progeny. Our investigators will be accomplished through a series of integrated studies in 3 projects. Project 1 undertakes a series of clinical trials to examine the clinical and immunologic effects of depleting mature donor T cells from the stem cell graft followed by infusion of selective subsets of T cells at later times after hematopoietic engraftment. In conjunction with these clinical trials we will utilize novel measures of T cell reconstitution and complexity to determine the effects of these in vitro manipulations in vivo. Results of laboratory measures of immune reconstitution will be correlated with clinical outcomes. In Project 2, we will develop new methods for ex vivo generation of mature polyclonal T cell with diverse repertoire from hematopoietic progenitors. Preliminary results suggest that it will be feasible to develop artificial systems that support human T cell neogenesis in vitro. These 3 dimensional biomatrix systems will be used to establish in vitro parameters required for the generation of diverse populations of na ve T cells and to examine the effects of mixed chimerism on T cell neogenesis. If successful, the biomatrix systems may also allow us to expand the diversity of the T cell repertoire in vitro and enhance T cell reconstitution in vivo. In Project 3, we characterize the target antigens for graft-versus-host disease (GVHD) and the graft-versus leukemia (GVL) response in vivo. Better definition of these target antigens will allow us to develop methods for selective deletion or expansion of specific T cell populations that mediate these two responses. Taken together, the proposed studies in this program project will focus on developing a better understanding of T cell neogenesis in adults and on defining the immunologic mechanisms and target antigens of the donor immune response against recipient cells. It is hoped that these studies will lead to improved outcomes for patients with hematologic malignancies undergoing allogeneic stem cell transplantation and will also lead to new approaches for stem cell transplantation in patients with non-malignant hematopoietic diseases.
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