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Recipient sensitization to MHC antigens is among the most critical of problems currently facing clinical transplantation in terms of magnitude and impact. Approximately 20% of all patients awaiting kidney transplantation have elevated levels of broadly reactive alloantibodies, resulting from multiple transfusions. prior failed allografts.or pregnancy. These highlysensitized patients experience an increased rate of graft rejection, compared to unsensitized individuals. which is often irreversible and difficult to control by currently used immunosuppressive agents. The evidence suggests that the common denominator in the pathogenesis of allograft rejection in presensitized recipients is the combined cellular and humoral immune alloreactivity. Although the relative significance of these responses varies. all successful immunosuppressive therapies have common three elements of diminished or abrogated mononuclear cell activation, cytokine expression. and endothelial cell activation. The main target for the antibody-mediated damage, the vascular endothelium, may also be affected by nonspecific effector mechanisms, complement, coagulation. phagocytic cells. and their products. The dissection and better apprteciation of the complexity of the rejection cascade may be important for the much needed progress in the management of allograft rejection in sensitized hosts. and may provide insights relevant to the development of xenotransplantation.