Allogeneic bone marrow transplantation (BMT) has been shown to provide potentially curative therapy for patients with a variety of diseases including hematologic malignancies, congenital immune deficiencies and metabolic disorders. One major obstacle in allogeneic BMT continues to be graft-versus-host-disease (GVHD) which occurs in 40-60% of patients with HLA-identical sibling donors and prohibits BMT in patients without HLA compatible donors. In this program project we propose a series of studies which include clinical trials of allogeneic BMT in patients with and without HLA matched donors as well as detailed studies of immunologic reconstitution. The overall goal of these studies will be to use the results of our immunological analysis to develop new strategies for immune modulation in BMT patients. The clinical trials will utilize our previous experience with in vitro depletion of T cells from the donor marrow with anti-Tl2(CD6) monoclonal antibody and rabbit complement to prevent GVHD. Patients will not receive other prophylactic immune suppressive therapies for prevention of GVHD post-BMT. This treatment removes mature T cells without depleting marrow stem cells or other lymphoid cells such as NK cells and B cells, and preliminary results suggest that this selective depletion of CD6+ cells can effectively prevent GVHD in patients with HLA-identical donors without increased risk of graft failure. Patients who engraft with CD6 depleted marrow will also form the basis for our analysis of immune dysfunction following allogeneic BMT. These patients, who do not have GVHD and are not receiving additional immune suppressive agents, will allow us to examine in detail the phenotypic and functional reconstitution of immunoregulatory T cells. This analysis during allogeneic reconstitution will be compared to results following autologous BMT in order to develop a better understanding of the profound but self-limiting immune deficiency that these patients experience. Detailed studies of immune reconstitution will also examine the effects of exogenous IL-2 on immune function following BMT, and this information will be used to develop clinical trials of low dose continuous infusion rIL-2 following BMT in order to augment immunologic reconstitution and enhance graft-vs-leukemia (GVL) activity in high risk patients. In project 3 we will use the sensitivity and specificity of polymerase chain reaction (PCR) to study the natural history and clinical significance of mixed chimerism following allogeneic BMT with CD6 T cell depleted marrow. Preliminary results using restriction fragment length polymorphisms (RFLP) have already shown that 50% of our patients develop stable mixed chimerism following BMT. Finally, we will also prospectively evaluate the use of PCR for the detection of residual tumor cells in patients with CML following allogeneic BMT in order to develop a better understanding of the mechanisms of GVL.
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