Surgery & Anesthesia · 1978
Ciclosporin in solid-organ transplantation (Calne)
cyclosporine; cyclosporin A
Through the 1960s and early 1970s, kidney transplantation was technically feasible but immunologically precarious. Azathioprine and corticosteroids blunted rejection in some patients but left others in a cycle of acute rejection episodes, high-dose steroid bursts, and eventual graft loss. One-year renal graft survival hovered around 50 percent at experienced centers, and liver transplantation remained largely experimental because the rejection burden was simply too great for available drugs to manage.
Cyclosporin A was isolated in 1970 from the fungus Tolypocladium inflatum by researchers at Sandoz in Basel. Jean-Francois Borel identified its unusual immunosuppressive properties in 1976, noting that it suppressed T-cell responses without the broad cytotoxicity of earlier agents. Roy Calne at Cambridge, already experienced with experimental transplant immunology, obtained the compound and began animal studies that produced striking improvements in graft survival.
Calne reported in the Lancet in 1978 that cyclosporin A, used as primary immunosuppression in seven cadaveric kidney transplants, controlled rejection in five patients. The results were not presented as a success story. Three recipients developed serious toxicity, including nephrotoxicity and hepatotoxicity, and Calne explicitly warned against overenthusiastic adoption. The drug had a narrow therapeutic window and its pharmacokinetics were not yet understood well enough for safe dosing.
What followed was a period of careful dose-finding work at Cambridge and other centers. Combining cyclosporin with lower doses of azathioprine and steroids rather than using it as a single agent reduced toxicity while preserving efficacy. By the mid-1980s, one-year renal graft survival at leading centers had risen from roughly 50 percent to above 80 percent. Liver and heart transplantation, previously constrained by the limits of azathioprine-based regimens, became clinically viable procedures at scale.
The mechanistic explanation arrived in parallel with clinical use. Cyclosporin blocks calcineurin, preventing nuclear factor of activated T-cells from entering the nucleus and thereby suppressing IL-2 transcription and T-cell proliferation. That mechanism became the template for a second calcineurin inhibitor, tacrolimus, introduced in the early 1990s, which offered a similar profile with somewhat different toxicity characteristics. Calcineurin inhibitors remain the core of most solid-organ transplant maintenance regimens in current practice.
Key People
- Roy Calne — Cambridge surgeon who introduced cyclosporin into clinical transplantation
- Jean-Francois Borel — Sandoz scientist who identified cyclosporin's immunosuppressive properties
- Thomas Starzl — Pioneer transplant surgeon who adopted cyclosporin for liver transplantation
Lancet, 1978
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