The program project """"""""Biology and Genetics of Marrow Allografts for Leukemia"""""""" is an integrated multidisciplinary program of basic and clinical research aimed at elucidating genetically controlled molecular characteristics of lymphoid normal hematopoietic and leukemic cells distinguishing a normal marrow donor from an allogeneic related or unrelated leukemic host which can induce, sustain or modulate the cellular interactions which contribute to engraftment or rejection, tolerance or graft-versus-host disease, leukemic resistance or relapse and immune reconstitution or prolonged immune deficiency. In this project, we propose to identify and characterize at the molecular level, microvariant disparities within the HLA complex and minor alloantigens expressed on donor hematopoietic cells which can stimulate marrow allograft rejection and are targeted by host T-cells in vivo. The contribution of these allodisparities to impairments or delays in the functional development of donor T-cells within the environment of an allogeneic leukemic host and their capacity to interact effectively with donor or host derived antigen-presenting cells will also be assessed. The anti-leukemic properties of a marrow allograft will be reexamined, through prospective studies of patients transplanted with conventional or T-cell depleted HLA-matched related and T-cell depleted HLA-compatible unrelated grafts correlating frequencies of host-reactive donor T-cells, and donor derived LAK cells capable of lysing host leukemic targets with the capacity of the graft to replace host cells in both lymphoid and hematopoietic lineages and to eradicate residual host leukemic cells detectable by pcr-amplified DNA hybridization techniques. A novel animal model system is also proposed for examining and characterizing human donor cell interactions with host leukemic cells both in vivo and in vitro which may contribute to the leukemic resistance conferred by a marrow allograft. Finally, novel approaches are proposed for molecular detection of CMV infection and the generation of donor lymphoid cells responsive to CMV antigens to augment host resistance in the post- transplant period. To complement and extend this program of basic research, the Program of Experimental Therapeutics in Transplantation proposes a series of randomized trials and single armed phase I and II studies designed to identify and assess potentially more effective cytoreduction regimens, novel T-cell depletion techniques, antibody targeted radiotherapy and strategies incorporating adoptive transfers of leukemia or virus reactive cells. By integrating these trials with ongoing laboratory investigations of the genetic and cellular basis of interactions between donor and host controlling engraftment, functional reconstitution of hematopoiesis and immunity, and resistance to leukemia and opportunistic viral infections, it is expected that new insights into the unique biology of marrow allografts and improved approaches to their application can be achieved.
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