A-420983

A420983 is a prototypic immunosuppressive agent that selectively targets T cells receiving an activation signal.Treatment with such an agent may allow long-term allograft survival and avoid harmful non-immune side effects common with other immunosuppressive therapies.Lck is an attractive target for inhibition of graft rejection because it is involved in this process on several levels.Signaling through Lck is involved in T cell cytokine production and generation of cytotoxic T lymphocytes (CTL), as well as generation of T cell help required for B-cell alloantibody generation.The present study demonstrates that the small mol. inhibitor of Lck, A420983, was able to inhibit T-cell responses in several systems.The authors have shown that A420983 is an effective therapy for prolonging graft survival in three models of transplantation in the mouse.In two organ transplant models, neonatal cardiac transplantation and skin transplantation.A420983 was able to significantly prolong graft survival as compared to grafts in vehicle-treated mice.In the islet transplant model isolated pancreatic islet cells from fully MHC-mismatched donors were protected from rejection by A420983 treatment for the entire test period.