Costimulatory blockade and infectious risk in solid organ transplantation

Costimulatory blockade has emerged as a promising alternative to conventional immunosuppression with the potential to reduce chronic allograft injury and minimize drug-related toxicities, including nephrotoxicity, cardiometabolic complications, and malignancies. Belatacept, the most extensively studied agent, has been associated with improved allograft function and reduced donor-specific antibody formation, although it is also associated with increased risk of acute, early graft rejection and increased risk for infections due to cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. These effects may reflect the impact of costimulatory blockade on naïve T cell activation, although relatively sparing memory responses. Susceptibility to infections is, therefore, influenced by prior infectious exposures and the maintenance of immune memory in the face of diverse adjunctive immunosuppressive programs. Next-generation approaches, including Fc-silent anti-CD154 antibodies and CD28-directed therapies, are in early clinical trials with infectious complications incompletely defined. Recently, immunosuppression for clinical xenotransplantation has included costimulatory blockade as a component of generally complex immunosuppressive regimens; intensive microbiological surveillance will provide insights into any associated xenozoonotic infections. Successful integration of costimulatory blockade in allotransplantation and clinical xenotransplantation requires further prospective trials coupled with robust microbiological surveillance.