The SPECIFIC AIMS in non-human primate kidney transplant model are to: 1) determine whether short-term costimulation blockade based therapy, a treatment that is not directly lympholytic, can be made more effective through use of concomitant treatment with drugs that enhance T-cell activation induced cell death (AICD), e.g. rapamycin or methotrexate (MTX). 2) determine short-term costimulation blockade based therapy, a treatment that is not directly lympholytic, can be made more effective through use of concomitant treatment with a cytoreductive anti-CD8 mAb. 3) determine whether short-term costimulation blockade based therapy can be made more effective through use of concomitant treatment with an Ig-related fusion protein (mutant IL-15/Fc) that blocks and temporarily destroys the IL-15/IL-15R network. 4) identify the time-related pattern of donor reactive T-cell frequency as well as cellular and molecular events that are involved in the acquisition and maintenance of allograft tolerance. 5) determine whether organ transplant recipients, who are withdrawn from a potentially tolerizing therapy can be monitored for incipient graft rejection so that, when needed, appropriate immunosuppressive therapy can be instituted before irreversible rejection takes place. 6) determine whether an idealized therapeutic and diagnostic protocol can be established through knowledge gained from the combined efforts of each of the components of this project.