In order for bone marrow transplantation to have an optimal long term impact on patients with hematologic malignancies, toxicity must be minimized without compromising anti-tumor efficiency. Graft vs-host disease (GVHD), a major contributor to the morbidity and mortality of BMT, can be abrogated to some degree by engineering the donor marrow graft so that the number of T cells infused within it is reduced However, reduction in the incidence of GVHD has been associated with an increased in disease recurrence post-PMT. The projects w4e propose to conduct over the coming years are intended to provide a clear assessment of the value of graft engineering in allogeneic marrow transplantation. We will help to define the critical cellular components of donor lymphocyte infusions (DLI) which contribute to graft-vs-host (GVH) and graft-vs-leukemia (GVL) activity. Specifically, we will be examining the effects of CD8 depletion on GVHD and GVL following DLI. Our goal is to safely restore anti-leukemic activity compromised by graft engineering without inducing GVHD. To evaluate this strategy, we will embark on a prospective randomized trial which will compare TCD-BMT followed by delayed infusion of donor lymphocytes to transplantation of marrow in which T cells are not manipulated. Clinical endpoints will include overall survival, cumulative incidence of GVHD, lymphohematopoietic chimerism, T cell receptor diversity, and T cell neurogenesis in the two arms. Another strategy that will be explored to reduce morbidity of transplantation is the use of non-myeloablative conditioning regimens. The relationship between the intensity of conditioning, the composition of the donor stem cell products, and the timing of donor lymphocyte infusion will be examined in a series of clinical studies. The techniques we establish to evaluate immune integrity will allow us to compare recovery of immune competence after myeloablative and non- myeloablative procedures. We will closely collaborate with Dr. Scadden's team of investigators who will be evaluating methods to influence the development and expansion of T lymphocytes with intact functional repertoires from stem cells using an artificial in vitro thymic system. Dr. Ritz and his colleagues will be studying the antigens that are targeted by donor lymphocytes infusions.
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