In the last five years we have studied human effector T cells in renal allograft rejection. T cell lines were established from needle biopsies of rejecting kidneys and the cell phenotypes, functions and specificities determined. We observed that the allograft appears to exert a strong selective influence over the responding T cell populations, so that even though the number of T cell clones that can contribute to an allospecificity can be relatively large, only a limited number of clonotypes appear to ultimately predominate and carry out the T cell effector functions in graft rejection. The selection is most apparent at the level of usage of the 8-chain of the T cell antigen receptor. In this application we propose to analyze the selection of the functional T cell repertoire involved in human allograft rejection by studying single cell clones of already established and phenotypically and functionally characterized allograft-derived T cell lines, in order to correlate the cell surface markers with the clones' function and specific alloreactivity. We will also analyze the selection of the T cell antigen receptor repertoire to determine if the same predominant beta-chain gene expressed in an allograft-derived cell line is also the predominant receptor used in vivo. Clonotypic antibodies reactive with the products of the predominant V genes will be generated and their ability to interfere with various effector functions of allograft-derived T cells will be examined. The long term goal of this project is to design ways of specifically eliminating or down-regulating the selected clonotypes in order to achieve prolonged graft survival.
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