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In the search for new drugs, three criteria essential for safe clinical use emerged: specificity to cells of the immune system, weak potency against memory responses, and minimal side effects. It was not until 1979 that the next drug found to be clinically useful, cyclosporine (cyclosporin A), became available. This molecule was discovered by screening soil fungi for antifungal antibiotics, but it was initially set aside because of its immunosuppressive side effects in animals. It is a peptide of 11 amino acids that inhibits the calcineurin pathway of T-cell activation directed by the binding of major-histocompatibility-complex molecule-antigen complexes to T-cell antigen receptors. In fact, the calcineurin pathway was discovered when cyclosporine was used as a ligand to discover cyclophilin, and later the next component of the pathway, calcineurin. (3) Two other fungal products with immunosuppressive actions that are now in clinical use are sirolimus (rapamycin) and tacrolimus (FK 506). (4) Most striking is the fact that sirolimus and tacrolimus are macrolides that bind to the same cytoplasmic protein, FK-binding protein, but each of these complexes then binds to different third molecules; sirolimus binds to TOR (target of rapamycin), and tacrolimus to calcineurin. Inhibition of TOR blocks the entry of activated T cells into the G1 phase of replication. In functional terms, inhibition of the calcineurin pathway prevents the production of growth factors, such as interleukin-2, and inhibition of the TOR pathway prevents the cellular response to such growth factors.
Another recent addition to the armamentarium of immunosuppressive drugs is mycophenolate mofetil, which is converted in vivo to mycophenolic acid. This substance, a natural product of penicillium fungi, has a general mode of action on purine metabolism similar to that of azathioprine. Mycophenolate mofetil was developed as an agent that would prevent the proliferation of lymphocytes. (5) It inhibits the proliferation of T cells, B cells, and arterial smooth-muscle cells; most other tissues are relatively resistant to the drug because they have an alternative pathway for nucleotide acid synthesis. Mycophenolate mofetil causes bone marrow suppression much less often than does azathioprine, and the use of mycophenolate mofetil in combination with a calcineurin inhibitor and prednisone has resulted in substantially reduced rates of early rejection.
Various antibodies, made first against lymphocytes and later against specific molecules, have been used as adjunctive agents to improve the results of transplantation, either as rescue therapy in patients with acute rejection or as prophylaxis against rejection. Muromonab-CD3 (OKT3), a monoclonal antibody to the CD3 component of the T-cell antigen receptor, has been a mainstay for these purposes since the early 1980s, (6) but other murine monoclonal antibodies proved to be ineffective until the recent introduction of genetically engineered humanized monoclonal antibodies, in which most of the molecule is of human origin and only the antigen-binding sites are of murine origin. (7) In particular, antibodies against the interleukin-2 receptor have proved effective in preventing rejection, as reported by Beniaminovitz et al. in this issue of the Journal. (8) Under development is a new generation of engineered monoclonal antibodies and other protein ligands targeted to portions of the lymphocyte-activation pathways that are necessary for providing costimulatory signals to T cells after the binding of antigen to the T-cell antigen receptor.
Given the growing number of effective agents and the need to increase the long-term survival of grafts, which are in short supply, a substantial number of well-designed clinical trials will be required. Fortunately, we start with a good data base. The United Network for Organ Sharing maintains a registry of transplants in the United States, with over 10,000 kidney transplants added each year. In this issue of the Journal, Hariharan et al. (9) report that both graft survival at one year and the projected half-life of grafts have progressively improved from 1988 to 1995. The improvement is not attributable to any of the newer immunosuppressive drugs, because it took place in the era of treatment with cyclosporine, azathioprine, and prednisone. What the study does not address are the possible contributions of better clinical care, including perhaps better treatment of hypertension, more effective treatment or prophylaxis against serious infectious diseases, and an increased use of kidneys from cadaveric donors in HLA-matched recipients. One consequence of the continuous increase in the rate of graft survival at one year, which was already approaching 90 percent for cadaveric transplants in 1996, is that short-term graft survival is no longer a very useful criterion for evaluating the outcomes of transplantation. More attention must be paid to other end points, such as kidney function and episodes of rejection. As therapeutic targeting of very specific components of the immune pathways improves, whether through antibody-like large molecules or synthesized small molecules, it may be necessary to assess selected immune mechanisms by direct testing in patients in order to establish the end points for tolerance.
Charles B. Carpenter, M.D.
Brigham and Women's Hospital
Boston,
MA 02115 Warmly, lillian
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