How A Miracle Drug Disarms The Body's Defenses

By Christine Gorman

Some of the immune system's biggest battles are directed not against harmful intruders but against potentially life-saving organ transplants. New hearts and kidneys in adults have become fairly commonplace, and top surgeons have even attempted the daunting feat of transplanting multiple abdominal organs into infants and toddlers. Today's organ recipients are indebted to a drug called cyclosporine, which has revolutionized transplantation technology in the past decade. Unlike immunological treatments for AIDS and cancer, cyclosporine works by temporarily suppressing the body's natural defenses, thus preventing the rejection of grafted tissue.

The miracle of cyclosporine comes at a steep price. The drug can cause severe damage to the kidneys as well as allow cancerous tumors to develop. Moreover, cyclosporine costs as much as $6,000 for a year's supply, and patients may need it for life. Still, declares Calvin Stiller, chief of transplantation at University Hospital in London, Ont., "cyclosporine clearly stands out as the most important medical discovery in transplantation. It changed the field."

Ever since the pioneering transplant operations of the 1960s, the chief obstacle to the full recovery of transplant patients has been the immune system's xenophobic zeal to destroy anything that is foreign to the body. Once the alien threat has been identified, agents known as helper T cells unleash the powerful immune response that attacks grafted tissue. During the 1970s, physicians found that they could minimize this reaction by more closely matching the MHC proteins, or immunological "dog tags," of a donor with those of the recipient. Even so, they could not completely eliminate the rejection response. To make matters worse, the only drugs available to weaken it shut down the defensive system completely, leaving patients vulnerable to viruses, bacteria or tumors. The triple threat of rejection, infection and malignancy kept transplant surgery to a minimum.

Enter cyclosporine. Discovered in 1970 by a scientist at Sandoz, a Swiss pharmaceutical company, the drug was nearly abandoned as worthless. Unexpectedly, however, researchers found that it was a highly selective suppressor of helper T cells. By preventing the activation of the T cells, the drug interferes with the body's instinct to attack a transplanted organ. Yet unlike other suppressants, it does not affect other parts of the immune system. Cyclosporine is thus able to dampen the rejection reaction while leaving a large part of the body's infection-fighting defenses intact.

Physicians began testing the drug on humans in 1978. The results were dramatic. Both rejection and infection continued to be problems, but survival rates one year after transplantation rose from 32% to 70% for liver patients and from 54% to 77% for kidney patients. "By early 1980," recalls Thomas Starzl of the University of Pittsburgh, a leading transplant surgeon, "we had a sense that there was a tremendous change in outlook in both kidneys and livers, and that enthusiasm quickly spread to the heart." Cyclosporine is highly toxic, however, and researchers have begun to look for alternatives. Ideally, they foresee a therapy that would prevent rejection but also persuade the immune system to tolerate a transplanted organ even after treatment is halted.

For now, surgeons and their patients must still walk the tightrope between the natural potency of the immune system and the perils of suppressing it. The balancing act is especially tricky in the most difficult of operations: multiple abdominal transplants. Doctors in the U.S. have tried such surgery only four times in the past four years. Just one patient, now seriously ill, survives. Ten-month-old Michael Steward of Chicago received a new liver, pancreas, small intestine and part of the stomach in February to correct a congenital defect. Last week, a record 6 1/2 months after a similar operation, three-year-old Tabatha Foster of Madisonville, Ky., succumbed to cancer. The lesson: physicians have a great deal more to learn before they can manipulate the immune system at will.

With reporting by Barbara Dolan/Chicago