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Optimal activation of T cells requires two signals: antigen engagement through the T cell receptor and a costimulatory signal. Previous studies have shown that blockade of the CD28:B7 costimulatory pathway using the soluble fusion protein CTLA4Ig can prevent acute rejection of organ and tissue allografts; however, long-term engraftment has not been seen universally. This study was undertaken to define the role of donor antigen in inducing long-term allograft survival in CTLA4Ig-treated recipients.A murine cardiac allograft model was employed using BALB/c donors and C57BL/6 recipients. Additional donor antigen in the form of donor splenocytes was given at the time of transplantation. Recipients were treated with a single dose of CTLA4Ig 2 days after transplantation.We find that a single dose of CTLA4Ig prolongs cardiac allograft survival, but permanent engraftment is not observed unless the recipients receive an injection of donor-type splenocytes. Treatment of the donor cells with CTLA4Ig does not by itself prolong allograft survival, which indicates the need for systemic treatment of the recipient. Allografts from animals not receiving donor cells show classic histologic changes of chronic rejection, and most cease function from 1 to 4 months after transplantation. Lethal irradiation of the donor cells does not appreciably affect their ability to prevent late allograft loss.Donor cells are required to synergize with CTLA4Ig and prevent late cardiac allograft loss in the murine system. The fact that pretreatment of the donor cells alone is not effective suggests a role for antigen presentation by recipient antigen-presenting cells in the initiation of rejection. As lethal irradiation of the donor cells does not affect their ability to promote long-term engraftment, our data suggest that long-term microchimerism is not required to prevent chronic rejection in this model.