Category:Immunosuppressants

An immunosuppressant is a medicine given to suppress the immune response, whether to permit transplantation of organ or tissue, to treat an autoimmune disease, or to control an exuberant inflammatory reaction. The category includes the systemic glucocorticoids, the antiproliferative antimetabolites, the calcineurin inhibitors, the mTOR inhibitors, the alkylating agents adapted from oncology, and the modern biologics that target specific cytokines and lymphocyte populations.

The category came into being with the transplantation of solid organs, and the founding observations belong to the zoologist Peter Medawar. In 1942 Medawar, then at Oxford, was asked by the Glasgow burns surgeon Thomas Gibson to investigate why a Glaswegian woman's skin grafts from a donor were repeatedly rejected. Medawar's experiments in rabbits over the following decade established that the rejection was immunological, that it accelerated on second exposure (the second-set phenomenon), and that the response was specific to the donor; he then showed in 1953, with Rupert Billingham and Leslie Brent, that injecting donor cells into a fetal mouse produced lifelong tolerance to that donor's tissues, the principle of acquired immunological tolerance.^[1] Medawar shared the 1960 Nobel Prize for the work, and the question of how to produce a comparable tolerance pharmacologically in an adult became the founding question of clinical transplantation.

The first medicine that gave a workable answer came from the cancer pharmacology of Gertrude Elion and George Hitchings at Burroughs Wellcome, who in the early 1950s had developed 6-mercaptopurine as a purine analogue antimetabolite for childhood acute lymphoblastic leukemia. In 1959 Robert Schwartz and William Dameshek at the New England Medical Center showed that 6-mercaptopurine could prevent rabbits from making antibodies against an injected foreign protein; the medicine was an immunosuppressant as well as a chemotherapeutic.^[2] Roy Calne at Cambridge, working from this lead, used a closely related prodrug, azathioprine, in combination with prednisolone, and in 1962 Joseph Murray at the Peter Bent Brigham Hospital in Boston performed the first successful kidney transplant between unrelated donor and recipient. The azathioprine-prednisone combination was the standard regimen for the next twenty years.

The transformative agent was found in soil. In 1969 the Sandoz microbiologist Jean Borel, on a hiking holiday in the Hardangervidda plateau of Norway, collected a sample of cold-climate soil for the company's broad screening programme; it yielded a fungus, Tolypocladium inflatum, whose secondary metabolite cyclosporin A was found in 1972 to suppress T-cell-mediated immunity without the bone-marrow toxicity of azathioprine.^[3] Cyclosporine was first given to human kidney-transplant recipients by David White and Calne at Cambridge in 1978 and was approved for clinical use in 1983; its introduction roughly doubled the one-year survival of cadaveric kidney transplants and opened the era of routine liver, heart, and lung transplantation. A second calcineurin inhibitor, tacrolimus (FK-506), was isolated by Fujisawa from Streptomyces tsukubaensis at Mount Tsukuba in 1984 and proved both more potent and somewhat less nephrotoxic than cyclosporine. The two medicines share a final common pathway: they form a complex with intracellular immunophilins that inhibits the calcium-dependent phosphatase calcineurin and so prevents the dephosphorylation of NFAT and the subsequent transcription of the interleukin-2 gene.

A parallel and equally productive product of soil screening was sirolimus, isolated by Suren Sehgal at Ayerst Laboratories in 1972 from Streptomyces hygroscopicus in a soil sample collected on Easter Island; the medicine retained the islanders' name for their island, Rapa Nui, and was originally pursued as an antifungal before its immunosuppressant action was recognised.^[4] Sirolimus and its derivative everolimus inhibit the mTOR kinase, a downstream node of the IL-2 receptor pathway, and so block the proliferative response of T cells to interleukin-2 rather than its production. The mycophenolic-acid prodrug mycophenolate mofetil, a selective inhibitor of inosine monophosphate dehydrogenase in lymphocytes, was added to the transplantation pharmacopoeia in 1995.

The autoimmune-disease side of the category was, until the 1990s, dominated by the same agents transposed from transplantation: glucocorticoids, methotrexate (the antifolate originally developed by Sidney Farber and Yellapragada Subbarow at Boston Children's Hospital in 1948 for childhood leukemia, then redeployed for psoriasis in the 1950s and for rheumatoid arthritis in the 1980s after the work of Michael Weinblatt at the Brigham), azathioprine, hydroxychloroquine, and cyclophosphamide. The mid-1990s brought the first of the targeted biologic medicines. The tumour necrosis factor inhibitors, proposed as a rheumatoid-arthritis therapy on the basis of work in Marc Feldmann and Ravinder Maini's London laboratory showing that TNF-alpha was the upstream driver of synovial inflammation, were brought to clinical use as etanercept (a soluble decoy receptor, Immunex/Amgen, 1998), infliximab (a chimeric monoclonal antibody, Centocor, 1998), and the fully human adalimumab (Abbott/AbbVie, 2002).^[5] The TNF inhibitors were the prototype for a class that has since extended through inhibitors of interleukin-1 (anakinra), interleukin-6 (tocilizumab), interleukin-17 (secukinumab), interleukin-12/23 (ustekinumab), and the small-molecule Janus kinase inhibitors (tofacitinib, baricitinib, upadacitinib).

The therapeutic role of an immunosuppressant carries a corresponding therapeutic cost. The pharmacology of the calcineurin inhibitors is dominated by nephrotoxicity, hypertension, hyperkalemia, and tremor; the mTOR inhibitors by pneumonitis and impaired wound healing; the antimetabolites by myelosuppression; the biologics by reactivation of latent tuberculosis, hepatitis B, and the deep fungal mycoses, and (for some agents) by demyelinating disease and a small but characteristic excess of lymphoma. The risk-benefit assessment of an immunosuppressive regimen, particularly a long-term one in autoimmune disease where the alternative is not death but disability, is among the more demanding judgments in internal medicine.

By mechanism:

• Systemic glucocorticoids (the foundational immunosuppressants): dexamethasone, methylprednisolone, prednisolone, prednisone
• Antimetabolites: methotrexate (also indexed as antifolate and DMARD), azathioprine, mycophenolate
• Calcineurin inhibitors: cyclosporine, tacrolimus
• mTOR inhibitors (where built): sirolimus, everolimus
• Alkylating agents used outside cancer: cyclophosphamide
• Biologic agents: TNF inhibitors including adalimumab, etanercept, and infliximab; the interleukin-pathway and lymphocyte-depleting monoclonal antibodies; the Janus kinase inhibitors
• Antimalarial-derived disease-modifying agents: hydroxychloroquine

The boundary of this category is "medicine prescribed to suppress an undesired immune response, whether in transplantation or in autoimmune disease." Medicines whose principal indication is cancer chemotherapy (the alkylating agents in oncologic doses, the cytotoxic antimetabolites, the antineoplastic monoclonal antibodies) are collected under antineoplastics; the small number of agents that cross both categories, principally methotrexate and cyclophosphamide, are listed under both. The intravenous immunoglobulin preparations are not in the strict sense immunosuppressants but immunomodulators, and although they are administered for some of the same conditions they are collected under immunomodulators. Topical preparations whose principal indication is dermatologic (the topical calcineurin inhibitors tacrolimus and pimecrolimus, topical corticosteroids) are listed under the appropriate route-specific category in addition to this one.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.