Translating costimulation blockade to the clinic: lessons learned from three pathways

As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block these pathways has each taken a slightly different course. Both logistical and biological pitfalls have accompanied the translation of blockers of all three pathways into clinically applicable therapies, and the development of costimulatory blockade as a substitute for current standard-of-care calcineurin inhibitors has by no means reached completion. Collaboration between both the basic and clinical arenas will further propel the development of costimulation blockers currently in the pipeline, as well as of novel methods to target these critical pathways during transplantation.