Ciclosporin (cyclosporine) and the immunosuppression era

Ciclosporin (international nonproprietary name; also cyclosporine or cyclosporin A) is an immunosuppressant drug derived from a fungus that, on its introduction to clinical transplantation around 1978 and its regulatory approval in 1983, transformed organ transplantation from a hazardous, frequently fatal experiment into a routinely successful therapy.[1][2][3] By selectively suppressing the T-lymphocytes responsible for graft rejection while sparing much of the rest of the immune system, ciclosporin produced large gains in graft and patient survival and triggered the rapid expansion of transplant programs in the 1980s.[2][3] Its arrival is generally taken to mark the beginning of the modern immunosuppression era of transplantation.[2][3]

The pre-ciclosporin problem

Before ciclosporin, the prevention of rejection relied chiefly on total-body irradiation and on the combination of azathioprine and corticosteroids, introduced in the early 1960s.[1][4] These methods made cadaveric kidney transplantation possible but were crude: they suppressed the immune system broadly, so the dose required to prevent rejection often left patients fatally vulnerable to infection.[1][4] As a result, survival was poor across most organs, and many transplant programs, heart transplantation in particular, were curtailed in the late 1960s and 1970s.[1][4] See history of organ transplantation.

Discovery and development

Ciclosporin originated in a Sandoz (now Novartis) program in Basel, Switzerland, that screened soil-derived fungi for useful biological activity.[1][5] The compound was produced by the fungus now known as *Tolypocladium inflatum*, isolated from soil samples (including one from Norway) around 1970.[1][5] Its immunosuppressive activity was identified in early 1972 in screening work associated with Hartmann Stähelin, and Jean-François Borel and colleagues characterized its selective effect on lymphocytes with comparatively limited general cytotoxicity, the property that distinguished it from earlier agents.[1][5] The molecule's structure was determined at Sandoz in the mid-1970s.[1][5]

Crucial early clinical demonstration came from Sir Roy Calne and colleagues at the University of Cambridge, who showed around 1978 that ciclosporin could prevent rejection in human kidney transplantation, and from Thomas Starzl in the United States, who applied it (in combination with steroids) to liver transplantation.[1][2][3] Ciclosporin received U.S. Food and Drug Administration approval in 1983 under the trade name Sandimmune.[2][3]

Mechanism

Ciclosporin acts by binding an intracellular protein (cyclophilin); the resulting complex inhibits the enzyme calcineurin, blocking the signaling pathway that activates T-lymphocytes and the production of interleukin-2.[2][3] By targeting T-cell activation specifically, it suppresses the rejection response more selectively than the older broadly cytotoxic agents, although it carries its own toxicities, notably nephrotoxicity (kidney injury), hypertension, and others requiring careful blood-level monitoring.[2][3]

Impact and the broader immunosuppression era

The clinical effect of ciclosporin was dramatic. Graft and patient survival rates rose substantially across organs, the range of viable transplants expanded (including durable heart and liver transplantation), and the number of transplant centers and procedures grew rapidly through the 1980s.[2][3] Ciclosporin is consequently credited as the single pharmacological advance that converted transplantation into standard care.[2][3]

It was the first of the calcineurin inhibitors. In the late 1980s, tacrolimus (FK-506), a more potent calcineurin inhibitor first reported in clinical transplantation by Starzl's group, was developed and in many programs subsequently became the preferred agent.[3][4] Modern immunosuppression typically combines a calcineurin inhibitor with an antiproliferative agent (such as mycophenolate) and corticosteroids, often with antibody-based induction therapy, a multi-drug strategy whose foundation ciclosporin established.[3][4] See transplant immunology.

See also

• History of organ transplantation
• Transplant immunology
• Thomas Starzl · Christiaan Barnard
• Heart transplantation · Liver transplantation

References

• Borel JF, Kis ZL, Beveridge T. The history of the discovery and development of cyclosporine (Sandimmune). In: The Search for Anti-Inflammatory Drugs. Birkhäuser, 1995:27-63. https://link.springer.com/chapter/10.1007/978-1-4615-9846-6_2
• Tedesco D, Haragsim L. Cyclosporine: a review. J Transplant. 2012;2012:230386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503279/ ; doi:10.1155/2012/230386
• Watson CJE, Dark JH. Organ transplantation: historical perspective and current practice. Br J Anaesth. 2012;108(suppl 1):i29-i42. https://www.bjanaesthesia.org/article/S0007-0912(17)33476-X/fulltext ; doi:10.1093/bja/aer384
• Barker CF, Markmann JF. Historical overview of transplantation. Cold Spring Harb Perspect Med. 2013;3(4):a014977. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683917/ ; doi:10.1101/cshperspect.a014977
• Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr. 2002;114(12):433-437. PMID 12422576. https://pubmed.ncbi.nlm.nih.gov/12422576/