GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES PROJECT 1: Genetically-engineered pig kidney transplantation in baboons: reducing the adaptive immune response and monitoring graft function (Project Lead: David K.C Cooper) PROJECT SUMMARY/ABSTRACT Considerable advances have been made in the results of life-supporting genetically- engineered (GE) pig kidney transplantation (Tx) in nonhuman primates (NHPs), with graft and recipient survival in months or even years. Since the barrier of the innate immune response has largely been overcome, we will direct most of our attention to (i) reducing the adaptive immune response, and (ii) investigating the potential physiological incompatibilities between pigs and NHPs. We will first test kidney transplants from pigs with the most advanced genetic- engineering to date, i.e., pigs with 8 genetic manipulations (8GE pigs), all aimed towards protecting the kidney from the primate immune response. We will compare two immunosuppressive regimens, in one using a novel costimulation blockade agent that has not been tested in a xenotransplantation model previously. Using the preferred regimen, we will then transplant kidneys from 8GE pigs additionally transgenic for expression of programmed death ligand 1 (PG-L1), which should allow successful organ Tx with a reduced exogenous immunosuppressive therapy. We predict that kidneys from these pigs, using the preferred immunosuppressive regimen, will function for 6 months in the absence of immune-related injury, thus allowing a comprehensive study of renal function to determine whether there are physiological incompatibilities that might require attention. Offering patients with end-stage renal disease a timely pig kidney transplant without excessive exogenous immunosuppressive therapy would allow many more patients to receive kidney transplants, and reduce the need for chronic dialysis. 1