Unique cell type in implicated in multiple sclerosis

Posted: August 2, 2012 at 3:13 am

ScienceDaily (Aug. 1, 2012) Researchers at the National Institutes of Health have found evidence that a unique type of immune cell contributes to multiple sclerosis (MS). Their discovery helps define the effects of one of the newest drugs under investigation for treating MS -- daclizumab -- and could lead to a new class of drugs for treating MS and other autoimmune disorders.

In these disorders, the immune system turns against the body's own tissues. Ongoing clinical trials have shown that daclizumab appears to help quiet the autoimmune response in MS patients, but its precise effects on the legions of cells that make up the immune system are not fully understood.

The new study, published in Science Translational Medicine, shows that one effect of daclizumab is to thin the ranks of lymphoid tissue inducer (LTi) cells. These cells are known to promote the development of lymph nodes and related tissues during fetal life, but their role during adulthood has been unclear. The new study marks the first time that LTi cells have been implicated in any human autoimmune disorder.

"While further study is required to confirm the role of LTi cells in autoimmunity, our results point to the cells as a promising target for the development of new drugs to treat autoimmune disorders," said Bibiana Bielekova, M.D., an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS).

Dr. Bielekova and her team found that among MS patients participating in clinical trials of daclizumab, the number of LTi cells was elevated in patients not receiving daclizumab compared to those on the drug. Patients receiving daclizumab also had reduced signs of inflammation in the cerebrospinal fluid (CSF) that surrounds the brain. And the researchers found that daclizumab appears to steer the body away from producing LTi cells, in favor of another cell type that counteracts autoimmunity.

In MS, the immune system attacks myelin, a material that insulates nerve fibers running throughout the brain and spinal cord. This typically leads to vision loss, and other sensory changes such as numbness and tingling, weakness, and fatigue. The disorder affects approximately 400,000 people in the United States. In about 85 percent of patients, MS starts as a relapsing-remitting form, in which symptoms come and go. Many patients eventually develop secondary progressive MS, in which symptom flare-ups are followed by worsening disability. Many medications are available to decrease the number of flare-ups, but no medication is effective at slowing the course of progressive MS.

The newer, sophisticated drugs for relapsing-remitting MS target key cells and molecules responsible for triggering and maintaining autoimmunity. Cytotoxic T cells, the immune system's specialized mobile infantry, are known to lead the attack. Antibodies, the immune system's guided missiles, appear to help reinforce it.

Daclizumab is a lab-engineered antibody, or monoclonal antibody, that alters signaling by interleukin-2 (IL-2), a key factor that mobilizes T cells. In a large clinical trial (NCT00109161), it has shown promise as an add-on therapy for patients taking the approved MS drug interferon-beta. Another ongoing trial (NCT00390221) is investigating whether or not daclizumab is effective as a stand-alone therapy for reducing relapses in MS.

The drug was designed to suppress T cell responses to IL-2, and it does so -- but Dr. Bielekova had found previously that this suppression is indirect and depends on other immune cells. For example, one effect of daclizumab is to stimulate the non-specialized counterparts of T cells, called natural killer cells. These cells in turn suppress T cell activity.

In their new study, Dr. Bielekova and her team discovered that daclizumab's stimulatory effect on natural killer cells is paired with an inhibitory effect on LTi cells. They found evidence that the drug, via its effects on IL-2 signaling, acts on a type of stem cell. The drug appears to decrease the likelihood that this stem cell will develop into LTi cells, and sway it toward becoming natural killer cells.

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Unique cell type in implicated in multiple sclerosis

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