For release: Wednesday, May 18, 2011
Daclizumab is one of the newest therapies under study for treating multiple sclerosis (MS). It quiets the abnormal immune reactions that occur in people with MS by targeting a single molecule on immune cells. Beyond that, how daclizumab works is largely a mystery. Now, research from the National Institutes of Health has revealed insights not only into the drug's effects, but into the basic biology of the immune system.
The work was led by Bibiana Bielekova, M.D., an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS). She and her colleagues have been testing how daclizumab affects the immune cell responses of people with MS and healthy volunteers. Their latest findings are reported in Nature Medicine.*
In MS, the immune system attacks the brain and spinal cord, typically leading to fatigue, weakness, and a loss of vision and other sensations. The disorder affects approximately 400,000 people in the U.S.
Daclizumab is based on a molecule first developed in the lab of Thomas A. Waldmann, M.D., a senior investigator in the Metabolism Branch at NIH's National Cancer Institute (NCI). It is approved in the U.S. for preventing organ transplant rejection, and for several years, Drs. Waldmann and Bielekova have collaborated to study its potential for treating MS.
In two small trials, the NIH team found that daclizumab given in combination with the MS drug interferon-beta reduced the number of new lesions (areas of damage) in the brain. Just last year, a team based at University of Utah reported the results of the large, placebo-controlled CHOICE study. The study confirmed that using daclizumab as an add-on therapy helped patients whose symptoms had relapsed while they were taking interferon-beta.
Meanwhile, the NIH team is steadily unraveling how daclizumab works. Such research may help to predict how patients will respond to the drug, and to generate more potent derivatives. The drug is known to interfere with interleukin-2 (IL-2), a key signal that mobilizes immune cells to attack. However, the researchers are discovering that IL-2 signaling involves a surprisingly complex, intimate dance between immune cells. Their findings have relevance beyond MS, to a more general understanding of how the immune system functions in health and disease.
"It is difficult to study the human immune system under natural conditions. People are exposed to bacteria, viruses and other pathogens all the time, and they activate different immune cells in response. This makes it nearly impossible to sort out potentially subtle differences in the immune system of healthy individuals from those with a disease," said Dr. Bielekova. "A drug like daclizumab gives us a rare opportunity to study the immune system because it targets a single molecule, and we can measure what the immune system is doing before and after treatment."
One function of IL-2 is to activate T cells, which are the mobile infantry of the immune system. When the body is under siege by an infection, IL-2 serves as a clarion call for the T cell army to expand and attack. In MS and other so-called autoimmune diseases, for reasons that are not clear, T cells launch a misguided attack against the body's own tissues.
Daclizumab blocks the IL-2 receptor, which is found on T cells and other cell types. The drug specifically targets a piece of the receptor called CD25. When daclizumab was first tested against MS, researchers theorized that it was acting directly on T cells, shutting off their IL-2 receptors. However, in two recent studies, the NIH team found that daclizumab's effects on T cells are mostly indirect.
In a previous study, they found that daclizumab stimulates cells called natural killer cells, which in turn suppress T cells. That study was done by analyzing blood samples from MS patients who were taking daclizumab in clinical trials at NIH. Patients with the highest activation of natural killer cells had the most benefit from daclizumab, suggesting that a blood test for natural killer cells may serve as a good indicator of how patients are responding to the drug.
The NIH team also found a unique patient who benefited from daclizumab without the natural killer cell response. This prompted the researchers to investigate other effects of the drug. In Nature Medicine, they report that in addition to its effects on natural killer cells, daclizumab blocks CD25 on dendritic cells, whose job it is to prime T cells for battle by presenting them with a target (or antigen). They also discovered that CD25 is the key to an intricate maneuver that takes place between T cells and dendritic cells.
Just as people are born with innate talents and skills, T cells are born to recognize specific antigens. When a dendritic cell encounters an antigen, such as a piece of virus, its task is to activate the matching T cell, causing the cell to multiply and produce an army of clones.
Dr. Bielekova and her colleagues found that IL-2 and CD25 produced by dendritic cells are essential to this activation process. The findings show that when a dendritic cell finds the right T cell, it activates the T cell by releasing IL-2 at the site of contact. Meanwhile, the dendritic cell also simultaneously "lends" the T cell its CD25, because prior to activation, the majority of T cells do not have their own CD25. While the two cell types are in close contact, the CD25 connects with other components on the T cell surface and is assembled into a complete IL-2 receptor.
"This mechanism allows the dendritic cell to restrict the IL-2 signal only to the T cell that reacts to the right antigen," explains Dr. Bielekova. "This is an incredibly intimate type of crosstalk between the two cell types."
These findings could have relevance for how MS and other autoimmune diseases begin in the first place. With further study of the interleukin system and how it activates T cells, researchers may be able to discern why some T cells go rogue. Indeed, subtle genetic differences in CD25 and IL-2 have been observed in patients with autoimmune diseases.
- By Daniel Stimson, Ph.D.
Image caption: The intimate dance between a dendritic cell and a T cell. Left: The contours of the two cells are seen using a technique called bright field microscopy. The T cell is the smaller cell. Right: A yellow fluorescent probe against CD25 lights up the dendritic cell. The blue probe recognizes a T cell marker. Courtesy of Drs. Simone Wuest and Bibiana Bielekova, NINDS.
*Wuest SC et al. "A vital role for IL-2 trans-presentation in DC-mediated T cell activation in humans as revealed by daclizumab therapy." Nature Medicine, published online May 1, 2011.
Last Modified September 26, 2012