CD28-B7-mediated T cell costimulation in chronic cardiac allograft rejection - Differential role of B7-1 in initiation versus progression of graft arteriosclerosis

Provision of adequate T cell costimulation is critical for the development of acute and chronic allograft rejection. We have previously reported that early blockade of CD28-B7 T cell costimulation prevents the development of graft arteriosclerosis, in the LEW into F344 rat cardiac transplant model. In this study, we used the same model to examine the requirement for CD28-B 7-mediated T cell costimulation in the progression of established chronic r ejection and examined the individual roles of B7-1 (CD80) and B7-2 (CD86) c ostimulatory molecules. Late blockade of CD28-B7 T cell costimulation by th e fusion protein CTLA4Ig, which binds both CD80 and CD86, attenuated the de velopment of transplant arteriosclerosis, mononuclear cell infiltration, an d parenchymal fibrosis in this model. Selective blockade of CD80 using the mutant fusion protein Y100F mas as effective as CTLA4Ig in this regard. In contrast to CTLA4Ig, blockade of CD80 alone by Y100F was ineffective at pre venting early graft loss and prolonging graft survival when given early aft er transplantation. This study is the first to demonstrate that late blocka de of CD28-B7 T cell costimulation interrupts chronic cardiac allograft rej ection, and it indicates the importance of continued T cell activation in t his process. This study further defines functional differences between CD80 and CD86 costimulatory molecules in vivo.