Role of the ICOS-B7h costimulatory pathway in the pathophysiology of chronic allograft rejection

BACKGROUND: Inducible costimulator (ICOS) is the third member of the CD28 superfamily and has a unique role in T cell activation and function. Recent studies indicated that the ICOS-B7h pathway plays an important role in alloimmune responses. We further investigated the role of the ICOS pathway in the pathologic process of chronic rejection in vivo. METHODS: An established major histocompatibility complex class II disparate cardiac transplantation model was used. We treated mice with a blocking anti-B7h monoclonal antibody (mAb) either in the initiation phase (early blockade) or in the progression phase (delayed blockade) of disease. In addition, some mice received mAb in the entire period (whole blockade). At 6 weeks after transplantation, cardiac grafts were evaluated by histopathologic analysis in terms of vasculopathy, fibrosis, and cellular infiltration. The intragraft expressions of cytokines and chemokines were also examined by quantitative real-time polymerase chain reaction analysis. RESULTS: Early blockade of the ICOS-B7h pathway did not show any protective effect on chronic allograft rejection compared with untreated controls. In contrast, delayed blockade significantly inhibited the development of vasculopathy, fibrosis, and cellular infiltration (P=0.043, P=0.004, and P=0.03 vs. untreated control, respectively). Interestingly, whole blockade did not prevent the chronic rejection process. Furthermore, the inhibitory effect of delayed ICOS blockade on chronic rejection was associated with down-regulation of local intragraft expression of several cytokines and chemokines. CONCLUSIONS: These data suggest that the ICOS-B7h pathway is critical in the activation of effector/memory T cells that are necessary for the progression of chronic rejection and provide the rationale to develop novel and specific therapies to prevent this process.