The major obstacle to indefinite allograft survival in solid organ transplant is chronic rejection. Although current immunosuppressive regimens have curtailed acute rejection, they have had little effect on the incidence of chronic rejection, and the pathogenesis of chronic rejection remains poorly understood. We propose to study T cell activation and effector mechanisms using a transgenic mouse model with a minor histocompatability antigen supplying donor tissue to recipients that are adoptively transferred with antigen specific T cell clones. Our hypothesis is that chronic rejection is mediated by CD4 T cells of the Th2 phenotype secreting profibrotic cytokines.
Our specific aims are to: (1) Test the hypothesis that CD4 T cells are necessary and sufficient for chronic rejection using a heterotopic mouse heart transplant model;(2) Test the hypothesis that chronic rejection depends on differentiation of CD4+ Th2 cells;(3) Test the hypothesis that Th2 cytokines cause chronic rejection. This system will provide a broadly applicable tool for further investigation of the role of costimulation and antigen presentation in chronic rejection and for studies of tolerance. ? ?
