Bone marrow transplantation (BMT) has allowed the treatment of cancer patients with more intensive protocols of chemo/radiotherapy, thereby decreasing the incidence of relapse. The use of peripheral blood derived mononuclear cells in place of bone marrow has gained acceptance in those patients for whom BMT is not an option. In a retrospective analysis at the University of Nebraska Medical Center patients with intermediate grade non-Hodgkin's lymphoma (NHL) receiving high dose therapy with autologous BMT (AuBMT) (n=105) had a three-year event free survival (EFS) of 24%. This compares to a three-year EFS of 38% for patients with intrinsic bone marrow abnormalities who underwent high dose therapy with peripheral blood stem cell transplant (PBSCT) (n=53). We hypothesize that patients receiving a PBSCT would have an improved response rate, and T cell activity due to the infusion of greater numbers of mature T cells relative to BMT. Although the hematopoietic reconstitution of these patients has been described, little data has been obtained on their immune reconstitution. Thus, it is the overall intent of this proposal to examine the reconstitution of the immune system after PBSCT and compare the reconstitution observed after PBSCT to that observed after AuBMT and determine if this has a role in the therapeutic response of the PBSCT patients. The overall pattern of immune reconstitution in patients receiving PBSCT will be compared to that in patients receiving AuBMT to determine whether significant differences exist between these two groups of patients in either the extent, pattern, timing or longevity of this reconstitution and to correlate T cell reconstitution with clinical disease progression or lack thereof. Based on preliminary results in both preclinical and clinical studies, the hypothesis to be tested in this application is that PBSCT has significantly greater potential (compared to AuBMT) to reconstitute lymphocyte populations both phenotypically and functionally (especially T lymphocytes) after marrow ablative therapy with improved therapeutic activity. This hypothesis will be tested by examining the phenotypic, functional and molecular characteristics of peripheral blood lymphocytes in patients undergoing each therapy. Further, in conjunction with the clinical portion of this interactive RO1, we will correlate the various surrogates of immune function with EFS, time to disease progression, sites of relapse and survival to provide some insight into the therapeutic impact of functional T cells.
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