Ciclosporin in solid-organ transplantation (Calne)

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. Liver transplantation was still experimental: in the late 1970s more liver recipients died than were saved.

Cyclosporin A, a product of the fungus Tolypocladium inflatum, came out of drug screening at Sandoz in Basel, where Jean-Francois Borel described its immunosuppressive effects; it suppressed T-cell responses without the broad cytotoxicity of earlier agents, yet the company doubted it was worth pursuing. Roy Calne at Cambridge tested it on animal organ grafts, found results better than any other regimen, and persuaded Sandoz to make enough for clinical use.

Calne reported in the Lancet in December 1978 on seven dialysis patients given kidneys from mismatched cadaver donors and treated with cyclosporin A, at first alone; a cyclophosphamide analogue was later added in six. The results were not presented as a success story. The drug inhibited rejection but was clearly toxic to kidney and liver. Five patients left hospital with working grafts, two of them without steroids; one graft was removed because of infection, and one patient died of fungal infection. The authors wrote that further careful study was needed before the drug could be recommended.

What followed was a period of careful dose-finding work at Cambridge and other centers. Thomas Starzl showed that combining cyclosporin with prednisone reduced its toxicity. From 1980 both groups used it in liver transplantation, and by 1982 one-year survival had risen from 25 percent to 75 percent. In 1983 the US Surgeon General, C. Everett Koop, declared liver transplantation no longer experimental.

The mechanistic explanation arrived in parallel with clinical use. Cyclosporin blocks calcineurin, preventing nuclear factor of activated T-cells from entering the nucleus, which suppresses IL-2 transcription and T-cell proliferation. A second calcineurin inhibitor, tacrolimus, was introduced by Starzl in 1989 and approved by the FDA in November 1993, with a similar profile and somewhat different toxicity. Calcineurin inhibitors remain the core of most solid-organ transplant maintenance regimens in current practice.