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Aug 2, 2012

Unique Cell Type Found in Multiple Sclerosis

  • Researchers at NIH found evidence that a unique type of immune cell, lymphoid tissue inducer (LTi) cells, contributes to multiple sclerosis (MS). Their discovery helps define the effects of one of the newest drugs under investigation for treating MS, daclizumab. The scientists believe that their work could lead to a new class of drugs for treating this and other autoimmune disorders.

    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 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.

    Bibiana Bielekova, M.D., an investigator at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), 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. The researchers also found that daclizumab appears to steer the body away from producing LTi cells, in favor of another cell type that counteracts autoimmunity.

    Daclizumab is a mAb that alters signaling by interleukin-2 (IL-2), a key factor that mobilizes T cells. 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. 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.

    “This helps explain why natural killer cells are activated and their numbers are expanded by daclizumab therapy,” Dr. Bielekova said. Meanwhile, she notes, the drop in LTi cells was “intriguing” in itself, given the cells’ role in lymph node development.

    Inside lymph nodes, T cells and B cells are found in clusters called lymphoid follicles, where they wait for a signal that the body is under siege from infection. In autoimmune disorders, abnormal lymphoid follicles can develop and contribute to the autoimmune response. Secondary progressive MS, in particular, is associated with abnormal lymphoid follicles in the connective tissues (or meninges) surrounding the brain. These are believed to contribute to chronic brain inflammation in MS, eventually leading to shrinkage of the brain.

    Dr. Bielekova and her team reasoned that daclizumab, by suppressing LTi cells, should reduce the growth of lymphoid follicles. Since it is not possible to visualize these follicles in the live brain, the researchers measured the effects of daclizumab on markers of inflammation in the CSF. They found that CXCL13, a protein linked to lymphoid growth, and the IgG index, a measure of antibody production, decreased by an average of 50.4% and 13.5%, respectively, in trial participants who took the drug for 6.5 months.

    “To our knowledge, no other MS therapy reduces IgG index,” Dr. Bielekova said.

    She cautioned that this data provides only an indirect link between LTi cells and brain inflammation in MS. If further research confirms that the cells play an important role in MS or other autoimmune disorders, “pursuing the development of new drugs to selectively inhibit LTi cells could be a useful therapeutic strategy,” she remarks.


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