Studies Yield New Hope for Transplant Patients : Medicine: Protein research may lead to more effective drugs for those suffering from autoimmune disorders.
Two scientific reports released Friday may lead to the development of new, more effective drugs both to prevent transplant rejection and to treat or even prevent such autoimmune diseases as rheumatoid arthritis, psoriasis and insulin-dependent diabetes.
Researchers in Massachusetts and New York said in the reports that they have deciphered the structure of a protein that plays a key role in suppressing the immune system.
The protein, found in certain white blood cells, binds to an extremely potent experimental immunosuppressive drug called FK506, which has been found to be nearly 100 times more powerful than the widely used cyclosporine.
Knowledge of the structure of the protein, researchers said, should allow them to design new drugs that are both more effective and more selective in their activity and thus have fewer side effects. Drugs such as cyclosporine have side effects that are too severe to allow them to be used for the long periods necessary to treat the large numbers of patients suffering from autoimmune disorders. If such a disorder is present, the immune system inappropriately attacks the body as if it were foreign tissue.
Knowledge of the shape of the protein will also produce insight into how the immune system functions, possibly leading to new ways to control that function.
One of the reports was in Friday’s Science magazine. The second is scheduled to appear Thursday in the British journal Nature, but was released early because of the great interest in the protein’s structure.
“This is an extremely competitive field of research, in part because immunosuppressants have the potential of becoming a multibillion-dollar market,” said chemist Jon Clardy of Cornell University, lead author of one new paper.
Virtually every pharmaceutical company in the country is believed to be pursuing research on the protein, called an immunophilin, because the stakes are so large, said Jonathan M. Moore of Vertex Pharmaceuticals in Cambridge, England. In addition to the roughly 16,000 transplant operations conducted in the United States every year, there are an estimated 2.1 million cases of rheumatoid arthritis, 2 million cases of psoriasis, and nearly 1 million cases of insulin-dependent diabetes--the three most common forms of autoimmune disease.
Transplant surgery underwent a revolution in the early 1980s with the discovery of cyclosporine, which was isolated from a fungus in southern Norway. Cyclosporine blocks the action of the specific white blood cells, called T-cells, that attack a transplanted organ and cause its rejection, but it does not disable the portions of the immune system that fend off microbial infections.
Those same T-cells are also key players in the attack on body parts that characterize autoimmune diseases. Researchers would like to be able to block the activity of those T-cells to slow the progress of the diseases or to prevent them.
Unfortunately, cyclosporine produces kidney damage, which has largely prevented its use.
More recently, transplant surgeons have been studying FK506, a drug isolated from a soil sample taken from Mt. Tsukuba in Japan. Because it is 100 times as potent as cyclosporine, surgeons are able to use much smaller doses of the drug, reducing side effects.
Two years ago, chemist Stuart L. Schreiber of Harvard University and Nolan Sigal of the pharmaceutical company Merck Sharpe & Dohme independently isolated T-cell proteins called immunophilins. One of these binds to cyclosporine. The other, called FKBP, binds to FK506 and another recently discovered immunosuppressive drug called rapamycin.
When the drugs bind to the immunophilins, the complex prevents the T-cells from attacking either a transplanted organ or the host’s own body.
In separate papers published in Science, Schreiber and his colleagues at Harvard reported that they have determined the atom-by-atom structure of FKBP as it exists when the protein is dissolved in solution, while Clardy and his colleagues at Cornell determined its structure as it exists in crystals.
A team headed by biophysicist Moore of Vertex reported in Nature that they have also determined the structure in solution.
One of the immediate goals of the researchers, in addition to the development of new drugs, is to discover how the immunophilins work. All they know for sure now is that when FK506 binds with FKBP, the complex somehow blocks the transmission of a signal from the T-cell’s membrane to its nucleus that starts it dividing in preparation for an immune attack on foreign tissues or organisms.
Intriguingly, the other new immunosuppressive drug, rapamycin, also binds FKBP, but the result is quite different. Somehow, that complex blocks a signal transmission within the nucleus itself.
That distinction has excited scientists because it means that using the two drugs together could be more effective at preventing transplant rejection than using either alone because they act by two different mechanisms.
