The focus of this proposal is on patients transplanted with a llogeneic kidneys who subsequently lost their grafts. These patients, very frequently, develop broadly reactive leukocyte antibodies, especially after transfusions of blood components. This is in contrast to patients never transplated before, in whom blood transfusions seldom induce panel reactive antibodies. Once a highly sensitized status develops, it becomes extremely difficult for these patients to find a compatible kidney donor for a second transplant. We propose to investigate the mechanisms by which a previous transplant renders these patients at high risk of developing broadly reactive leukocyte antibodies. This is necessary to find rational ways to avoid such sensitiation to occur. Our preliminary data suggest (1) that the Ab response in these patients, most of whom received multiple transfusions, is directed to the transplant antigens, and (2), that even though blood transfusions elicit leukocyte antibodies they do not react with the leukocytes of the blood donor. We propose that blood transfusions may induce polyclonal B cell activation effects that may preferentially activate previously expanded memory clones, with or without the concomitant participation of re-stimulation with supertypci HLA determinants. These possibilities will be tested using blood transfusions matched for HLA antigens. In this study, the blood that most of these patients need at one time or another, will be obtained from donors of known HLA phenotypes. The blood donors will be fully HLA-matched or minimally mismatched for the Class I antigens with the patient. Donor selection will be accomplished by using a large file of HLA typed blood donors available at our laboratory. When an antibody response develops, as expected in most of these patients, detailed serological and biochemical specificity studies will be conducted to determine the involvement of the kidney and blood donor antigens. In addition to HLA-matched blood we will address the possibility of other blood components, such as blood extensively depleted of leukocytes and stored blood, as alternative sources of red cell replacement that may decrease the risks of inducing leukocyte antibodies in pretransplanted patients.
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