Initiation of cardiac allograft rejection New developments in cellular and molecular mechanisms

Although cardiac transplantation has become a viable therapeutic option for end-stage heart disease, long-term success is limited by rejection and medical complications of immunosuppression. Earliest events in rejection revolve around T-lymphocyte recognition of foreign antigen through a panel of specialized cell surface proteins. This is followed by a cascade of signaling events, transcription of multiple genes, and cytokine production. The central importance of these events, collectively known as T-cell activation, to the rejection process is underscored by the clinical utility of cyclosporine, which prevents T-cell activation. The specific site of action of cyclosporine within the T cell has recently been elucidated at the molecular level, revealing important details of T-cell biology. Once the immune response has been initiated, localization of inflammatory cells to the graft requires alteration in the functional state of the vascular endothelium, which can then express adhesive ligands for immune effector cells. Recent evidence suggests that host natural killer lymphocytes may play a role in this process. Understanding the molecular details of these and other early events in rejection will facilitate the development of more specific and effective immunosuppressive therapies.