Recent translational studies have led to a promising new therapy for multiple sclerosis. Research advances demonstrate that a monoclonal antibody called daclizumab effectively reduces disease activity through multiple mechanisms of action. According to a review article published in the Aug. 1 issue of Science Translational Medicine, these advances have also increased our understanding of the autoimmune processes that give rise to multiple sclerosis, and revealed potential targets for future therapies.

Multiple sclerosis (MS) is a debilitating autoimmune disease in which the body’s own immune system attacks the myelin sheath, a fatty substance that surrounds and protects the nerve fibers in the brain and spinal cord. This results in damaging inflammation which interferes with transmission of electrical signals between the brain and spinal cord and other parts of the body. Common symptoms of MS include problems with balance, coordination, vision, and even mental function.

“Previous research has shown that treatment with daclizumab significantly reduces MS lesion formation,” says John W. Rose, M.D., Professor of Neurology at the University of Utah, Chief of Neurology at Veterans Affairs Salt Lake City Health Care System, and author of the review article. “However, until recently, daclizumab’s mechanism of action was largely unknown.”

Monoclonal antibodies are proteins that preferentially bind to specific target cells, triggering the immune system to attack those cells. Daclizumab is a monoclonal antibody specific for CD25, a protein that is expressed on activated T cells, and binding of daclizumab to CD25 results in reduced T cell activation. Prior studies have suggested that a second mechanism of action for daclizumab is indirect expansion of a certain type of immune cell called CD56 bright natural killer (NK) cells, which serve to regulate activated T cells.

In his review article, Rose discusses a new daclizumab study conducted by Justin Perry, Ph.D., and the research team of Bibiana Bielekova, M.D., an investigator at the National Institute of Neurological Disorders and Stroke. This study, which is published in the same issue of the journal, demonstrated that treatment with daclizumab resulted in a reduction in inflammation-promoting cells called lymphoid tissue-inducer (LTi) cells, as well as an increase in regulatory CD56 bright NK cells. The researchers discovered that this shift in cell populations was due to binding of interleukin 2 (IL-2), a cell-signaling protein, to stem cells that give rise to immune cells.

Bielekova and colleagues found that MS patients treated with daclizumab displayed a decrease in active lesion formation, suggesting that LTi cells play an important role in the pro-inflammatory response that leads to MS lesions. The researchers also examined the cerebrospinal fluid of these MS patients for biomarkers for inflammation. They found that daclizumab treatment resulted in significant reduction of a small pro-inflammatory protein called CXCL13, a result which is consistent with a decrease in inflammation.

“In combination with previous findings, this new study demonstrates that daclizumab’s mechanisms of action are much more complex than we originally thought,” says Rose. “In fact, in MS patients, the indirect effect of daclizumab on LTi cell reduction and CD56 bright NK cell expansion seems to be a more important mechanism for controlling MS than direct inhibition of T cell activation. These unexpected discoveries highlight the importance of translational studies.”

Translational science refers to the long series of experiments that begins with laboratory research and ends with a clinical breakthrough that is relevant to patients. The goal of translational studies is to more efficiently translate the molecular and cellular discoveries of basic science into practical applications that can be used to treat or monitor human disease.

“This is an exciting time for multiple sclerosis research,” says Rose. “These recent advances have deepened our understanding of the disease and its potential therapeutic targets. Hopefully, MS patients will soon be able to harvest the benefits of this strong work.” 

Date: August 2, 2012
Source: University of Utah