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Organ Transplantation and Advances In Immunosuppressants

Dr. Thomas Starzl, identified immunosupppression, the preservation of organs and tissue matching as the primary factors involved in the very new specialty of organ transplantation. He traced the development of FK506, a new drug that was isolated in Japan in 1984 and reported publicly in Sweden in 1987.

Immunosuppression is the “heart and soul and philosophy” of transplantation, Starzl said. The clinical immunosuppressive regimens involved in the history of transplantation are: azothioprine + steroids, anti- lymphocyte globulin (ALG), cyclosporin + steroids (a major development), monoclonal ALG, and finally FK506. Although cyclosporin and FK506 are similar in action, they have no similarity in structure; they are fundamentally different molecules.

FK506 is similar to a new drug, Rapomycin, which is likely to undergo clinical trials in the next year or so. FK506, which has not yet been given a name, has a very brief history. Clinical trials began in 1989, and showed that FK506 is many times more potent than cyclosporin. The critical difference is that it inhibits interleukin 2 synthesis and expression, and has a specific action on T-helper lymphocytes.

Starzl said FK506 was first administered in an attempt to rescue patients rejecting liver transplants. The results were spectacularly successful and persisted over time, even in patients experiencing chronic rejection of a type that had been resistant to all other types of therapy. Similarly spectacular results were experienced in heart transplants. Results were not quite as good in kidney rescue, because the cases accepted involved kidneys that were burned out. However, moderate improvement in renal function is possible in patients with reasonable anatomic structure.

“Chronic graft versus host disease” has also been amenable to treatment with FK506 in some patients who have had bone marrow transplants, Starzl reported. Given the successes with rescues, FK506 has been initiated at the outset with patients undergoing primary live transplantation since the summer of 1989. Both patient and graft survival have improved significantly compared to the use of cyclosporin in both adult and pediatric patients.

The introduction of FK506 allowed the transplantation of pancreatic islets and of the intestine, which were previously not possible. On January 8, 1990 the first successful islet cell transplantation was carried out in a child who is still tumour-free and requires no insulin. Until recently, it was impossible to transplant the intestine alone because of the fierce rejection that was evoked. With FK506, rat experiments show that the grafts have the genetic composition both of the donor and the recipient within 10 days (beginning at 30 minutes). “This was a terrifically important development that was quickly confirmed in humans,” Starzl said. “Children can now be treated by small bowel transplantation for the first time in the history of the world.”

The use of FK506 has several advantages, he said. “It became possible to look forward rather quickly to discontinuing all steroid treatment,” and the complication of hypertension, a major factor with conventional treatment, is substantially reduced. Coronary angiograms of heart patients after one year showed little evidence of vascular complication. A penalty is that FK506 has approximately the same degree of nephrotoxicity as cyclosporin. However, it does not cause hirsutism, hyperplasia or facial brutalism, and therefore has very special advantages for pediatric patients.

In 1990, a randomized clinical trial carried out between cyclosporin and FK506 in kidney transplant patients was discontinued because of ethical problems related to patient satisfaction. A three-drug and two- drug trial was conducted with FK506 and steroids. Patient survival in both was 100%, and graft survival was 97%. “These discoveries always have a ripple effect,” Starzl said. “We are confident there is going to be a big explosion in the treatment of autoimmune diseases, both of childhood and in adults, very soon.” Furthermore, the connection between basic science and clinical research could not be better illustrated than with the development of FK506.