Mechanisms of Immunosuppressive Drugs

Immunosuppressive regimens for organ transplantation are broadly divided into induction, maintenance, and rescue therapies. Induction immunosuppression is an intense perioperative treatment intended to suppress anti-donor responses and prevent acute rejection during the early postoperative period (Nashan, BioDrugs 19:39–46, 2005; Halloran, N Engl J Med 351:2715–2729, 2004). Maintenance immunosuppression is long-term therapy intended to prevent rejection for the life of the graft. Rescue therapies are similar to induction, both in efficacy and toxicity, but the primary purpose is to reverse established graft rejection. Only a limited number of immunosuppressive agents are available for induction and rejection therapy, including monoclonal antibodies (alemtuzumab, basiliximab, daclizumab, muromonab-CD3) and polyclonal antibodies (antithymocyte globulin [rabbit], antithymocyte globulin [equine]). These agents can also be classified depending on their ability to deplete T cells into depleting agents (alemtuzumab, antithymocyte globulins, muromonab-CD3) or nondepleting agents (basiliximab, daclizumab). Maintenance immunosuppression consists of a variety of glucocorticoids, antimetabolites, calcineurin inhibitors, and mTOR inhibitors. They are used in many different combinations, depending on programmatic philosophy and patient needs. This chapter will review the cellular and molecular mechanisms of these agents.