Immunosuppressive strategies for prevention of transplant rejection

Organ transplantation is the treatment of choice for end stage organ failure. This procedure has greatly benefited from the introduction of potent immunosuppressive drugs that suppress anti-allograft immune response, especially cyclosporin A (CsA) and FK506 which both inhibit calcineurin, a critical molecular switch of T-cell activation. However, use of these agents is limited by severe mechanism-based adverse effects, principally nephrotoxicity and neurotoxicity. Although newer immunosuppressants, including monoclonal antibodies (mAbs) to CD3 and IL-2 receptor (IL-2R). mycophenolate mofetil and more recently rapamycin, have contributed to mitigate the toxicity of calcineurin inhibitors and decrease the rate of acute graft rejection, the long-term graft survival is still a major problem due to poorly controlled chronic rejection. Late loss of transplant is all the more frustrating given the current penury in donated organs. There is therefore considerable incentive to discover more effective and safer immunosuppressive agents or methodologies affecting immunoregulatory pathways in a manner distinct from existing drugs. The patent literature of the last three years (1998 - 2000), reviewed here, reflects intense academic and industrial research towards this goal. Capitalising on recent advances in the understanding of T-cell activation and immune regulation, efforts have been focused on strategies that (a) inhibit signalling mechanisms and/or proliferation of T-cells, (b) interfere with cell surface molecules involved in immune cell interactions or (c) alter the trafficking/intragraft recruitment of lymphocytes responsible for graft rejection. Many of these patents claim for agents and modalities that may help achieve allograft tolerance, the ultimate goal of transplantation medicine. Special efforts were also devoted to xenotransplantation with hopes that this experimental technology will graduate to the clinic in a not too distant future.