The success rate of organ transplantation has increased considerably during the past 15 years with substantial improvements in one year graft and patient survival. However, late failure of the graft caused primarily by chronic rejection remains the major threat to long term survival. This form of rejection involves both the cellular (T cell-mediated) and humoral (antibody-mediated) arm of the immune response. T cells recognize graft alloantigens either directly as intact molecules or indirectly as processed peptides. We have shown that the indirect pathway of allorecognition is a major contributor to chronic rejection. Since chronic rejection cannot be treated by conventional immunosuppressive therapy, the development of strategies for induction of immunologic tolerance is required. Recently, we have demonstrated that both direct and indirect T cell alloreactivity can be regulated in vitro by a population of antigen specific T suppressor cells (Ts) which have the CD8+CD28- phenotype. Our working hypothesis is that tolerance can be achieved by the induction or transfer of allospecific T suppressor cells. Our long term objectives are to develop: a) Ts based markers for assessing the patient's potential to reject or tolerate the graft and b) Ts based strategies for tolerance induction. To meet these objectives we will first study the growth, differentiation and allopeptide specificity of in vitro generated Ts. Second, we will study the cellular and molecular events involved in Ts-mediated suppression. Third, we will explore the relationship between Ts frequency in transplant recipients and graft outcome. An animal model for induction of tolerance by transfer of Ts will be used. These studies will establish the role of allospecific Ts and their potential use for tolerance induction.
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