DONOR LEUKOCYTE ACTIVATION/PROLIFERATION POST-TRANSFUSION

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Leukocytes in allogeneic blood transfusions are responsible for many serious transfusion-related complications, including alloimmunization and graft-vs-host disease (GvHD), as well as for mechanisms of clearance of donor leukocytes following routine allogeneic transfusions have not been carefully studied. We developed sequence-specific PCR assays for quantitation of minor populations of allogeneic leukocytes in recipients. In preliminary studies of transfused elective surgery patients, and in a canine transfusion model, we found that following initial leukocyte clearance over the first 48 hours post-transfusion, there is a transient 1- 2 log increase in circulating donor leukocyte concentrations on days 3-5. In the canine model, the transient expansion phase was aborted by prior gamma-irradiation of donor blood, and was not observed following transfusions of alloimmunized dogs. W e hypothesize that this previously undetected allogeneic donor leukocyte expansion phase results from in vivo proliferation of donor T-lymphocytes reacting to HLA-mismatched recipient cells - ie, an abortive GvHD reaction. This attempted donor cell expansion, and the accompanying recipient alloimmune response to it (ie, graft rejection), may be critical elements in leukocyte-induced transfusion complications and immunomodulation. In this proposal, we plan to: (1) establish the frequency of detection and further characterize athe kinetics of the donor leukocyte clearance and expansion phases following transfusion of immunocompetent human recipients; (2) establish which donor leukocyte subpopulations(s) is/are involved, as well as the proliferation nd activation state of these cells; (3) characterize the corresponding activation and proliferation state of recipient leukocyte subpopulations; and (4) anticipating that the donor cell expansion phase consists of proliferating donor T-lymphocyte, characterize the clonality (with respect to T-cell receptor rearrangement) and immunological specificity of these cells. These studies should provide insight into the mechanisms and consequences of donor-recipient leukocyte interactions post-transfusion, which may lead to development of safer blood components and improved understanding of transfusion-induced immunosuppression and tolerance.