Importance of ICOS-B7RP-I costimulation in acute and chronic allograft rejection

Primary T cell activation requires B7-CD28 and CD40-CD154 costimulation, bu t effector T cell functions are considered to be largely independent of the se costimulatory pathways. Although blockade of costimulation with cytolyti c T lymphocyte-associated antigen 4-immunoglobulin (CTLA-4-lg) or monoclona l antibody (mAb) to CD154 prolongs allograft survival, chronic rejection fo llows, which suggests that additional key costimulatory pathways are active in vivo. We found that both antibody to inducible costimulator (anti-ICOS) and an ICOS-Ig fusion protein suppressed intragraft T cell activation and cytokine expression and prolonged allograft survival in a manner similar to that in ICOS-/- allograft recipients. The combination of anti-ICOS therapy and cyclosporin A led to permanent engraftment. In addition, ICOS-B7RP-I c ostimulation was required for the development of chronic rejection after CD 40-CD 154 blockade. These data demonstrate a key role for the ICOS-B7RP-I p athway in acute and chronic rejection and highlight the benefits of targeti ng this pathway in combination with the use of conventional immunosuppressi ve agent.