Targeting CD28 to prevent transplant rejection

Introduction: The pivotal role of costimulatory pathways in regulating T-cell activation versus tolerance has stimulated tremendous interest in their manipulationfor therapeutic purposes. Of these, the CD28--B7 pathway is arguably the most important and best studied. Therapeutic targets of CD28 are currently used in the treatment of melanoma, autoimmune diseases and in transplantation. Areas covered: In this review, we summarize our current knowledge of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling, and review the current state and challenges of harnessing them to promote transplant tolerance. Expert opinion: Despite the success of belatacept, a first-in-class CTLA-4 fusion protein now clinically used in transplantation, it is apparent that we have only scratched the surface in understanding the complexities of how costimulatory pathways modulate the immune system. Our initial assumption that positive costimulators activate effector T cells and prevent tolerance, while negative costimulators inhibit effector T cells and promote tolerance, is clearly an oversimplified view. Indeed, belatacept is not only capable of blocking deleterious CD28--B7 interactions that promote effector T-cell responses but can also have undesired effects on tolerogenic regulatory T-cell populations.