Blood transfusions (Tx) can produce rapid changes in both phenotype and function of peripheral blood mononuclear cells (PBMC). However, data on Tx-related changes in man have been derived primarily from patients rather than """"""""normal"""""""" recipients, and the contribution of the underlying disease to these findings is unclear. The present proposal is to study prospectively alterations among PBMC of normal human and canine Tx recipients. To date, Tx studies in normal dogs indicate: 1) Tx of recipient dogs with whole blood before transplantation results in rejection of DLA-identical littermate marrow grafts in 100%. 2) Removal of Ia-positive mononuclear cells from the Tx product reduces the risk of rejection. 3) Rejection can be partially abrogated by treating the recipient with immunosuppression directed at T lymphocytes. 4) Within hours of Tx, large activated T cells with cytotoxic/suppressor function can be detected among recipient PBMC. These data suggest that Tx-induced sensitization involves Ia-positive PBMC and leads to a rapid activation of recipient T lymphocytes which are presumably responsible for the subsequent marrow graft rejection. The present proposal is to 1) characterize the mononuclear cell populations responsible for inducing sensitization (and subsequent marrow graft rejection) using density gradients and monoclonal antibodies, 2) characterize the phenotypic and functional alterations in recipient PBMC following Tx, 3) based on those findings, investigate ways of abrogating sensitization by treating Tx recipients with monoclonal antibodies directed post-Tx de novo phenotypes and 4) attempt to prevent sensitization by removing or inactivating cells responsible for sensitization using monoclonal antibodies and UV irradiation. Finally, these studies will be expanded to the analysis of Tx-related alterations in normal human recipients. Well-defined monoclonal antibodies specific for human cells will allow a more detailed analysis of both the sensitizing and responding cell populations. Comparing in vitro results obtained in dogs and humans will allow for extrapolation of the in vivo results from the canine model to man, providing a basis on which to establish improved techniques for the preparation of Tx products.
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