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The category came into being with the transplantation of solid organs, and the founding observations belong to the zoologist [[wikipedia:Peter Medawar|Peter Medawar]]. In 1942 Medawar, then at Oxford, was asked by the Glasgow burns surgeon [[wikipedia:Thomas Gibson (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 [[wikipedia:Rupert Billingham|Rupert Billingham]] and [[wikipedia:Leslie Brent|Leslie Brent]], that injecting donor cells into a fetal mouse produced lifelong tolerance to that donor's tissues, the principle of acquired immunological tolerance.<ref name="medawar1953">Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. ''Nature''. 1953 Oct 3;172(4379):603-606. PMID 13099277.</ref> 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 category came into being with the transplantation of solid organs, and the founding observations belong to the zoologist [[wikipedia:Peter Medawar|Peter Medawar]]. In 1942 Medawar, then at Oxford, was asked by the Glasgow burns surgeon [[wikipedia:Thomas Gibson (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 [[wikipedia:Rupert Billingham|Rupert Billingham]] and [[wikipedia:Leslie Brent|Leslie Brent]], that injecting donor cells into a fetal mouse produced lifelong tolerance to that donor's tissues, the principle of acquired immunological tolerance.<ref name="medawar1953">Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. ''Nature''. 1953 Oct 3;172(4379):603-606. PMID 13099277.</ref> 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 [[wikipedia:Gertrude B. Elion|Gertrude Elion]] and [[wikipedia:George H. Hitchings|George Hitchings]] at [[wikipedia:Burroughs Wellcome|Burroughs Wellcome]], who in the early 1950s had developed [[wikipedia:Mercaptopurine|6-mercaptopurine]] as a purine analogue antimetabolite for childhood acute lymphoblastic leukemia. In 1959 [[wikipedia:Robert Schwartz (immunologist)|Robert Schwartz]] and [[wikipedia:William Dameshek|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.<ref name="schwartz1959">Schwartz R, Dameshek W. Drug-induced immunological tolerance. ''Nature''. 1959 Jun 13;183(4676):1682-1683. PMID 13666859.</ref> [[wikipedia:Roy Calne|Roy Calne]] at Cambridge, working from this lead, used a closely related | The first medicine that gave a workable answer came from the cancer pharmacology of [[wikipedia:Gertrude B. Elion|Gertrude Elion]] and [[wikipedia:George H. Hitchings|George Hitchings]] at [[wikipedia:Burroughs Wellcome|Burroughs Wellcome]], who in the early 1950s had developed [[wikipedia:Mercaptopurine|6-mercaptopurine]] as a purine analogue antimetabolite for childhood acute lymphoblastic leukemia. In 1959 [[wikipedia:Robert Schwartz (immunologist)|Robert Schwartz]] and [[wikipedia:William Dameshek|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.<ref name="schwartz1959">Schwartz R, Dameshek W. Drug-induced immunological tolerance. ''Nature''. 1959 Jun 13;183(4676):1682-1683. PMID 13666859.</ref> [[wikipedia:Roy Calne|Roy Calne]] at Cambridge, working from this lead, used a closely related compound, [[wikipedia:Azathioprine|azathioprine]] (metabolically activated to 6-mercaptopurine), in combination with prednisolone, and in 1962 [[wikipedia:Joseph Murray|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 [[wikipedia:Jean Borel|Jean Borel]], on a hiking holiday in the [[wikipedia:Hardangervidda|Hardangervidda]] plateau of Norway, collected a sample of cold-climate soil for the company's broad screening programme; it yielded a fungus, ''[[wikipedia:Tolypocladium inflatum|Tolypocladium inflatum]]'', whose secondary metabolite [[wikipedia:Ciclosporin|cyclosporin A]] was found in 1972 to suppress T-cell-mediated immunity without the bone-marrow toxicity of azathioprine.<ref name="borel1976">Borel JF, Feurer C, Gubler HU, Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. ''Agents and Actions''. 1976 Jul;6(4):468-475. PMID 8969.</ref> [[Cyclosporine|Cyclosporine]] was first given to human kidney-transplant recipients by [[wikipedia:David White (surgeon)|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 [[:Category:Calcineurin_inhibitors|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. | The transformative agent was found in soil. In 1969 the Sandoz microbiologist [[wikipedia:Jean Borel|Jean Borel]], on a hiking holiday in the [[wikipedia:Hardangervidda|Hardangervidda]] plateau of Norway, collected a sample of cold-climate soil for the company's broad screening programme; it yielded a fungus, ''[[wikipedia:Tolypocladium inflatum|Tolypocladium inflatum]]'', whose secondary metabolite [[wikipedia:Ciclosporin|cyclosporin A]] was found in 1972 to suppress T-cell-mediated immunity without the bone-marrow toxicity of azathioprine.<ref name="borel1976">Borel JF, Feurer C, Gubler HU, Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. ''Agents and Actions''. 1976 Jul;6(4):468-475. PMID 8969.</ref> [[Cyclosporine|Cyclosporine]] was first given to human kidney-transplant recipients by [[wikipedia:David White (surgeon)|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 [[:Category:Calcineurin_inhibitors|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 [[wikipedia:Suren Sehgal|Suren Sehgal]] at Ayerst Laboratories in 1972 from ''Streptomyces hygroscopicus'' in a soil sample collected on [[wikipedia:Easter Island|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.<ref name="vezina1975">Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. ''Journal of Antibiotics''. 1975 Oct;28(10):721-726. PMID 1102508.</ref> 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 | A parallel and equally productive product of soil screening was sirolimus, isolated by [[wikipedia:Suren Sehgal|Suren Sehgal]] at Ayerst Laboratories in 1972 from ''Streptomyces hygroscopicus'' in a soil sample collected on [[wikipedia:Easter Island|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.<ref name="vezina1975">Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. ''Journal of Antibiotics''. 1975 Oct;28(10):721-726. PMID 1102508.</ref> 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 morpholinoethyl ester of mycophenolic acid, [[wikipedia:Mycophenolate mofetil|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|methotrexate]] (the antifolate originally developed by [[wikipedia:Sidney Farber|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 [[wikipedia:Michael Weinblatt|Michael Weinblatt]] at the Brigham), azathioprine, hydroxychloroquine, and cyclophosphamide. The mid-1990s brought the first of the targeted biologic medicines. The [[:Category:TNF_inhibitors|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|adalimumab]] (Abbott/AbbVie, 2002).<ref name="elliott1994">Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. ''Lancet''. 1994 Oct 22;344(8930):1105-1110. PMID 7934491.</ref> 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 autoimmune-disease side of the category was, until the 1990s, dominated by the same agents transposed from transplantation: glucocorticoids, [[Methotrexate|methotrexate]] (the antifolate originally developed by [[wikipedia:Sidney Farber|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 [[wikipedia:Michael Weinblatt|Michael Weinblatt]] at the Brigham), azathioprine, hydroxychloroquine, and cyclophosphamide. The mid-1990s brought the first of the targeted biologic medicines. The [[:Category:TNF_inhibitors|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|adalimumab]] (Abbott/AbbVie, 2002).<ref name="elliott1994">Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. ''Lancet''. 1994 Oct 22;344(8930):1105-1110. PMID 7934491.</ref> 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). | ||