The applicant's broad objective is to decrease the infectious morbidity and mortality of long-term marrow transplant survivors and, at the same time, to provide insight into the physiology of immune memory. The part of the application leading to clinical outcome: Patients undergoing bone marrow transplantation are immunodeficient for at least one year after grafting due in part to the lack of B cells. The applicant desires to attempt to improve these patients' humoral immunity by providing them with B cells from their marrow donors at one to two months after grafting. The work is divided into 4 steps: (1) Work out the large scale separation of B cells from donor blood. (2) Establish the safety of transfusions of the enriched B cells. (3) Perform a pilot prospective randomized trial comparing the responsiveness to vaccines in B cell-transfused vs. control patients. (4) If the pilot results are encouraging, perform a definitive large prospective randomized trial comparing the number and severity of infections in B cell-transfused vs. control patients. In this application, support is requested only for steps (1)-(3). The part of the application leading to immunologic information: This application also seeks to determine (A) the approximate life span of naive and memory B cell clones following infusion into human beings, and (B) whether long-term antibody production is due to periodic differentiation of B cells into plasma cells or due to long-lived plasma cells. (A) To define the approximate life span of naive and memory B cell clones, serial measurements of the mounts of naive and memory B cells will be performed in both the B cell-transfused and control patients. The longer the life span of a particular B cell subpopulation, the longer after the transfusions should the B cell transfused patients have higher blood counts of this subpopulation compared to the controls. Therefore, the time period from transfusing B cells to the last time point at which significantly higher naive or memory B cell counts are detected in the B cell-transfused vs. the control patients will be called the approximate life span of the naive or memory B cell clones. (B) At the same time, the patients will be used to find out whether the long-term production of antibodies to recall antigens like smallpox virus is mediated through smallpox-specific B cells some of which periodically differentiate into plasma cells or by long smallpox-specific plasma cells. Compared to the controls, the B cell transfused patients will have received substantially more B cells but the same amount of plasma cells. Therefore, if several months after the B cell transfusion the B cell transfused patients have higher serum levels of smallpox IgG, it will be assumed that B cells rather than long lived plasma cells are responsible for the long term IgG production, and vice versa.
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