ABSTRACT
Allograft rejection is a T cell dependent process. The realization that T cell activation requires signaling through both the T cell receptor for antigen (TCR) and costimulatory molecules, such as C D 28, provided new insight into the T cell response. Moreover, the realization that interference with such pathways could alter or block the immune response altogether, provided new strategies for the induction o f long-term engraftment through the targeting o f T cell signaling molecules. Specifically, interference with the interaction o f CD 28 with its B7 ligand on antigen presenting cells (APCs) during T C R engagement can induce anergy in T cell clones and prolong allograft survival in a number o f animal mod els. The identification o f CTLA-4 as a second ligand for B7 that has potent inhibitory activity in T cells, provided new insight into the nature of tolerance and the balance be tween positive and negative regulatory signals that regulate T cell activation. Understand ing the role o f CTLA-4 in allograft rejection and tolerance will assist in designing thera peutic strategies to manipulate positive and negative immunoregulatory pathways.
