This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have used a lymphocyte depleting model in rhesus macaques by administering a novel anti-CD3 immunotoxin fusion protein (IT) to recipient monkeys at the time of allogeneic renal transplantation. Monkeys treated with IT alone develop antibody to donor kidney within 3 weeks, rising serum Cr, and biopsy evidence of antibody-mediated rejection. We have defined the lymphocyte repopulation kinetics, alloantibody production, and antibody-mediated rejection in this model and used these data to measure the impact of treatment regimens aimed at preventing antibody-mediated rejection in addition to controlling acute rejection mediated by T cells. Lymphocyte depletion with anti-CD3 immunotoxin promotes homeostatic proliferation of central memory T cells, which is succeeded by a generalized alloimmune response including alloantibody production. Adequate control of acute cellular rejection episodes with tacrolimus and alefacept after T cell depletion allows for isolated monitoring of alloantibody production and antibody-mediated rejection events. Implementing this model for the application of B cell therapeutics may further elucidate mechanisms through which donor-specific antibodies mediate progressive allograft dysfunction and chronic rejection.
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