Immunosuppressives in transplant rejection

Summary

A series of immunosuppressives is nowadays on the market or in advanced clinical development that are efficacious in prevention or treatment of rejection of a transplant in patients with end-stage organ failure. These can roughly be divided into lowmolecular-weight XENOBIOTICS, orally active drugs produced by microorganisms or chemical synthesis, and biologicals, (monoclonal) antibodies or rDNA fusion proteins. Most XENOBIOTICS work intracellularly and affect different pathways in lymphocyte activation and/or proliferation; since such pathways are not truly selective for LYMPHOCYTES, most of these drugs show inherent side-effects and generally have a low therapeutic window. However, the availability of novel agents with a broader therapeutic window, and refinements in combination treatment have greatly added to improved tolerability of immunosuppressive regimens. Broadly acting cytotoxic drugs with severe side-effects are gradually being replaced by compounds with a more selective action towards lymphoid cells, and corticosteroid-sparing regimens are being applied to reduce the adverse side-effects of corticosteroids. Most biologicals work by binding to cell surface molecules, resulting in inactivation or depletion of the target cells. Progress in this area has not only resulted in improved IMMUNOSUPPRESSION, but also in potential approaches to induce a status of unresponsiveness, i.e., TOLERANCE to the transplant. This is achieved either by efficient depletion of reactive cells or by inhibition of second signals in coreceptor blockade in T CELL activation. New paradigms in IMMUNOSUPPRESSION involve interference with cell trafficking (lymphocyte recirculation) that appears possible by using either innovative XENOBIOTICS or biologicals binding to cell ADHESION MOLECULES.