Harnessing the immunotherapeutic potential of T-lymphocyte co-signaling molecules in transplantation

Alloantigen-specific T-cell triggered immunopathological events are responsible for rapid allograft rejection. The co-signaling pathways orchestrated by co-stimulatory and co-inhibitory molecules are critical for optimal T-cell effector function. Therefore, selective blockade of pathways that control T-cell immunity may offer an attractive therapeutic strategy to manipulate cell mediated allogenic responses. For example, CD28, CTLA-4 and CD154 receptor blockade have proven beneficial in maintaining T-cell tolerance against transplanted organs in experimental animal models as well as in clinical trials. Conversely, induction of co-inhibitory molecules may result in suppressed effector function. There are several other potential molecules that are known to induce immune tolerance are currently under consideration for clinical studies. In this review, we provide a comprehensive and updated analysis of co-stimulatory and co-inhibitory molecules, their therapeutic potential to prevent graft rejection, and to further improve their long-term survival.