CINCINNATIóDiscovery of the mechanism of a drug being tested for the treatment of multiple sclerosis (MS) has revealed that itís not only more effective than first thought, but might also help in the management of other autoimmune diseases, organ transplant rejection and even cancer.
A research team led by the University of Cincinnatiís Bibiana Bielekova, MD, report new insights into the role of the MS drug daclizumab (Zenapax) in the March 27 early online version of the Proceedings of the National Academy of Sciences. The article will appear in print April 11.
The exact cause of MS is unknown, but one theory is that it may it be triggered by exposure to a viral infection or environmental influences. The disease takes different courses in different people and can go into remission for many years, recurring occasionally or progressing quickly into degeneration of all motor functions that control muscles, strength, vision and balance. The very progressive form of the disease can end in death.
Scientists have long thought that in MS the specific white cells (T-cells) that fight off infection actually turn on the body they are supposed to protect, attacking the myelin sheath that protects the nerves.
"Without the insulating cover, the nerve axons short-circuit, much like a damaged electric cord might," says Dr. Bielekova, director of UCís Waddell Center for Multiple Sclerosis. "Also, many nerve cells (neurons) do not survive without myelin sheath."
It was also believed that since activated T-cells need a growth factor called interleukin 2 for their function, drugs that can block the interaction of interleukin-2 and T-cells could be used to control MS.
Daclizumab is being tested against MS because it has already proved useful in preventing rejection of transplanted organs, "and we thought it works by inhibiting T-cell activation," Bielekova says.
Earlier research by Dr. Bielekova and her group showed that daclizumab benefits MS patients, especially those who have highly inflammatory MS. This latest study, sponsored by the National Institutes of Health (NIH), involved 22 MS patients.
"We monitored T-cell function in patients who were injected with the drug, expecting to see that the drug inhibited T-cell function," says Dr. Bielekova.
"We didnít see that at all. To our surprise the T-cells were functioning normally."
But something unexpected was happening
Ėthe numbers of T-cells circulating in the blood of patients taking daclizumab were declining by about 10 percent. Simultaneously, the number of immune cells known as "regulatory natural killer cells," which are very rare in normal human blood, increased.
Regulatory natural killer cells are known to proliferate in special conditions, such as pregnancy or bone marrow transplantation.
"Not only did the number of regulatory natural killer cells increase in patients treated with daclizumab," says Dr. Bielekova, "but that expansion correlated with the treatment outcomeóthe more these cells expanded, the better the MS patients did during the trial. And the longer the patients were on the therapy, the more regulatory natural killer cells they had and the better they responded to treatment."
"The best news is that natural killer cells are actually very efficient immune cells that fight viruses or cancers," says Dr. Bielekova, "so it appears that daclizumab doesnít damage the immune system. It only shifts the emphasis of the immune reaction from T-cells to natural killer cells. However, larger studies need to be performed to evaluate the safety of long-term daclizumab therapy."
The current results, however, suggest that daclizumab might also help in the management of autoimmune diseases, organ transplant rejection and perhaps even cancer, she says.
Having found one drug pathway that appears to be important for the treatment of MS, Dr. Bielekova says, "The hope is that we can learn how to enhance this pathway by drugs that can be taken orally, rather than injected."
As a result of these findings by Dr. Bielekovaís research team, daclizumab is now being tested as a possible MS treatment in a phase-2 trial across the United States, including UC, and Europe.
Dr. Bielekova is a member of the Neuroscience Institute, a collaborative of nine academic departments at UC College of Medicine, University Hospital and independent physician practice groups. The institute is dedicated to patient care, research, education and the development of new medical technologies.
The study was conducted at the Neuroimmunology Branch (NIB) of the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). Coauthors include Marta Catalfamo, PhD, of the National Cancer Institute (NCI); Susan Reichert-Scrivner, MS, Amy Packer and Magdalena Cerna, NINDS; Thomas Waldmann, MD, NCI; Henry McFarland, MD, NINDS, Pierre Henkart, PhD, NCI; and Roland Martin, MD, NINDS.
The NIH applied for two patents related to this discovery that have been bought by drug companies. Dr. Bielekova and three coauthors. Dr. Waldmann, Dr. McFarland and Dr. Martin, are each receiving patent royalty payments from the NIH.