Prolongation of allograft survival by administration of anti-CD45RB monoclonal antibody is due to alteration of CD45RBhi: CD45RBlo T-cell proportions

CD45RB monoclonal antibody (mAb) therapy is capable of prolonging allograft survival. We have previously shown that CD45RB mAb enriches the CD45RB(lo) T-cell population in vitro and in vivo by preferentially depleting CD45RB(hi) T cells. The present study assessed the importance of CD45RB(hi) T-cell depletion in murine cardiac allograft survival by infusion of naive CD45RB T-cell subsets. Here we show that naturally occurring CD45RB(lo)CD4+ T cells express regulatory transcription factor Foxp3 and have regulatory function, whereas CD45RB(hi)CD4+ T cells express low levels of Foxp3 and have effector function. Infusion of syngeneic CD45RB(hi) T cells significantly reduced graft survival after depletion of CD45RB(hi) T cells by CD45RB mAb. Reduction of graft survival also occurred when syngeneic CD45RB(hi) T cells were infused into rapamycin-treated mice, whereas survival was prolonged when CD45RB(lo) T cells were added. This indicates that an alteration in the balance between regulatory CD45RB(lo) and effector CD45RB(hi) T cells is critical to the immunologic function of CD45RB mAb. A strategy to eliminate effector T cells with consequent enrichment of the regulatory T-cell compartment may be an important new strategy in the prevention of rejection.