Old Drugs for New: Contemporary Immunosuppressant Development

Clinical transplantation relies on our ability to chemically immunosuppress graft recipients without overt toxicity over a lifetime. The four areas of immunotherapy: (induction, basic maintenance, adjuvant and steroid therapy) have been available since the beginning of surgically successful transplantation almost 50 years ago. The development of new immunosuppressants continues to focus on these areas. Induction immunotherapy developments include the use of humanized antibodies, specific targets (basiliximab, daclizumab) and lymphocyte depletion (anti-thymocyte globulin, campath-1H). Promising results from pilot trials allow for subsequent low dose maintenance monotherapy. New inhibitors of calcineurin isoforms (ISATx247) may disassociate the anti-rejection effect from the toxicity of conventional calcineurin inhibitors. Revived investigation of older anti-proliferative or anti-metabolite drugs (rapamycin, mycophenolic acid, leflunomide) show promise in preventing B-cell responses and reducing chronic rejection but development of derivatives (everolimus, mycophenolate mofetil, ERL 080, MNA 279, MNA 715) may have a stronger commercial than experimental basis. Trials of steroid immunotherapy have focused on steroid elimination but trial of newer locally active steroids may be beneficial.