Page 318 - Read Online

Page 8 of 17 Singh et al. Vessel Plus 2018;2:33 I http://dx.doi.org/10.20517/2574-1209.2018.28

IMMUNOSUPPRESSION IN HEART TRANSPLANTATION
Ciclosporin
Another notable feat in transplantation during this era was the discovery of Ciclosporin A. In 1976, J.F
Borel reported the immunosuppressive effects of a fungal metabolite (Tolypocladium inflatum) isolated
from Swiss soil samples. He noted that skin graft rejection in mice and graft-versus-host disease in mice
and rats were considerably delayed by cycloporin A. He also noted that it had a direct antilymphocytic ef-
fect by targeting an early stage of mitogenic triggering of the immunocompetent lymphoid cell and lacked
[64]
the myelosuppressive effects of cytostatic drugs used at the time . Roy Calne, who previously worked on
azathioprine, conducted in vivo immunosuppression with ciclosporin A on porcine cardiac allografts. His
group stated that “Ciclosporin A is more effective in suppressing rejection than any other drug that we
[65]
have used in pigs with orthotopic cardiac allografts” .
Terence English, a South African born surgeon who previously worked with Lord Russell Brock and Don-
ald Ross, nearly abandoned medicine to be a mining engineer. He visited Stanford on advice of his friend
[66]
Philip Caves in 1973 . He was truly impressed with the outcomes of heart transplant recipients at the
unit. In 1978, Terence English, sought approval from the Transplant Advisory Panel of the Department of
[67]
Health but was informed that there were no funds for a transplant programme . Given the moratorium,
the panel were not keen on “one-off” operations. He duly persisted but his initial attempt was unsuccessful
as the donor had arrested prior to implantation and sustained an irreversible brain injury. He persevered
and in July 1979, performed the first successful heart transplant in the United Kingdom. The recipient,
[68]
Keith Castle lived for 5 and a half years .
“He subsequently became the best possible advertisement for cardiac transplantation except for his inabil-
[68]
ity to give up smoking” Sir Terence English on Keith Castle .
Although initial reports on Ciclosporin were favourable, the improvements came with a price. Ciclosporin
[69]
was nephrotoxic when used over a long period . Other side effects include hypertension, hepatotoxicity,
[70]
gingival hyperplasia, hypertrichosis, involuntary tremor, and an increased risk of malignancy . With the
improvements in survival after the initial transplantation, the recipients were at risk of nephrotoxicity and
morbidities associated with immunosuppression primarily infections. These drawbacks however did not
offset positive impact Ciclosporin offered over previous methods. Immunosuppression formed the initial
challenges in cardiac transplantation with suboptimal immunosuppressive regimens either causing al-
lograft rejection or infectious complications from over-immunosuppression.

A European Multicentre trial evaluating renal graft survival at 1-year showed that Ciclosporin alone as a
[71]
first-line immunosuppressive agent was more effective than with azathioprine and steroids . Stanford’s
group meanwhile reported 1 and 5-year survival rates of 83% and 55%, respectively using a 3-drug protocol
[72]
of Ciclosporin A, azathioprine, and prednisone .
Tacrolimus
Tacrolimus (Tradename: Prograf®, Astellas Pharma US, Inc. Northbrook, IL) a calcineurin inhibitor like
Ciclosporin was discovered from a soil sample from the foot of Mount Tsukuba in Tokyo in 1984. It was
[73]
cultured from an actinobacter, Streptomyces tsukubaensis . It suppresses interleukin-2 production associ-
ated with T-cell activation, thus inhibiting the differentiation and proliferation of cytotoxic T cells. Thomas
Starzl once again led research into safety and efficacy of Tacrolimus at University of Pittsburgh Medical
[74]
School . Tacrolimus had a more limited adverse effect profile and comparative studies suggest superiority
over Ciclosporin in preventing allograft rejection while causing less antibody suppression [75,76] . The phar-
[77]
macokinetics were far more predictable than for micro-emulsion Ciclosporin .