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Taking a fresh look at the immune attack in MS.

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* Researchers funded by the National MS Society are finding new possibilities for stopping MS immune attacks.

* New therapeutic strategies are evolving, thanks to better understanding of how attacks are triggered and carried out.

The main battleground for fighting disease activity in MS is the immune system, which launches attacks on the brain and spinal cord. Eight treatments currently are approved to modify MS, and each one addresses these attacks.

For example, Tysabri interferes with the movement of immune cells from the blood into the brain. Mitoxantrone broadly suppresses immune system activity. The latest therapies under investigation to treat MS aim at fine-tuning immune responses. For example, ocrelizumab binds to a molecule on immune B cells, eliminating them from the body. (See chart, page 59.)

So what's next for tackling immune activity in MS? Researchers funded by the National MS Society are hot on the trail of new ideas for more specific and longer-lasting ways of stopping the immune attack in MS in its tracks.

A new look at triggers

Studying what turns on the immune attack in MS can offer new targets for turning it off.

Robert Clark, MD, and Frank Nichols, DDS, PhD (University of Connecticut Health Center), have studied how the immune attack launches in both MS and rheumatoid arthritis. They recently made an important discovery relevant to MS.

Each person has millions of harmless bacteria, known as "commensal" bacteria, living inside of them. Dr. Clark and his colleagues have found that these bacteria produce lipids--fatty substances--that increase the severity of EAE, an MS-like disease, in mice. Now they are looking at the precise molecular pathways by which these lipids affect EAE. They are also looking at how the lipids function in blood and brain tissue from people with MS. Results so far suggest that these lipids are present in unique patterns in people with MS, compared with people who don't have MS.

Dr. Clark's results may provide the first direct evidence that these lipids play a role in triggering MS, yielding new targets for slowing or preventing immune attacks. Also, measuring the lipids' presence in the blood may serve as a new test for MS disease activity.

Dr. Clark's work is part of a new approach to understanding how the normally friendly germs that live in our intestines, mouths and other areas of the body may profoundly influence immune activity and disease susceptibility.

Howard L. Weiner, MD (Harvard Medical School)-who earned the 2007 John Dystel Prize for MS Research for his contributions toward understanding the development of the immune attack in MS and translating these findings into MS treatments--is exploring this new frontier in immunology as well. Dr. Weiner recently earned a pilot research grant to test whether bacteria in the gut differ between people with MS and those without MS. Since these bacteria are known to influence the immune response, such differences may help explain why the immune response goes awry in MS.

Our bodies have a number of different cell types that interact to either turn on or off an immune response, such as inflammation. Some immune cells have "pathogen sensors" that recognize invaders, such as viruses or bacteria. This can cause the cells to launch an attack against the pathogen.

The pathogen sensors on some immune cells may contribute to triggering the attack in MS.

Jenny Ting, PhD, and her colleagues at the University of North Carolina were among the teams that first described a family of specific pathogen sensors. Dr. Ting is a highly respected immunologist and microbiologist whose research has won awards from the American Society of Microbiology and is a National Institutes of Health Merit Awardee. With support from the Society, her team showed previously that one specific sensor was highly active during inflammation in mice with EAE.

Now her team is extending this work to study such sensors further. The results of this research should lead to better understanding of processes that trigger immune attacks in MS, and offer new targets for developing therapies to better turn off those attacks.

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Taking on T cells

T cells have long been recognized as major players in immune attacks in MS, but new research is making inroads on how these cells are activated and how they can be suppressed.

Gabriel Rabinovich, PhD, exemplifies the global reach of the Society's research program. He is investigating emerging technology called glycomics at the Universidad de Buenos Aires, with Society funding. Glycomics investigates the ways that sugar structures in the body may influence biological processes.

Dr. Rabinovich and his colleagues recently demonstrated that galectin-1 (a protein that binds to sugars, which is found at sites of brain injury and inflammation) can selectively bind to and destroy aggressive T cells. They have observed that distinct groups of immune cells have different sugar structures on their surfaces, and these structures determine whether the sugars bind to galectin-1 or not. Now the researchers are studying how the surfaces of aggressive immune cells differ from those that can calm immune attacks.

They aim to capitalize on this information to design therapies that will be tested in mice with EAE and in immune cells isolated from people with MS-important first steps before this novel approach can be tested in people.

Another novel approach is being taken by Society grantee Amy Lovett-Racke, PhD (Ohio State University), who has focused her research career on understanding how T cells operate in MS. Now she is delving into the genetic code that instructs T cells. Her team is studying recently discovered substances known as microRNAs (miRNAs), which regulate what proteins the cells produce.

They have found that miRNA levels are abnormal in T cells from people with MS, and also that this abnormality may affect development of important immune cells called T regs. T regs are "good guys"--they can dampen the activity of the bad, inflammatory T cells.

Now Dr. Lovett-Racke is investigating further the exact pathway by which this might happen. That understanding could provide a novel avenue for therapeutic intervention.

Research on the immune system already has yielded treatments that reduce MS disease activity. Pursuing novel avenues is sure to speed the development of more treatments that can stop the immune attack once and for all.

Sara Bernstein is manager, research information at the National MS Society and editor of Research Now.
What is the treatment   How does it affect the   What is the status
under study?            immune attack in MS?     of these trials?

Helminth-induced        Harmless parasitic       In phase I trials
immunomodulation        worms that may           for MS
therapy                 stimulate protective
                        immune response

Estriol                 Pregnancy hormone        In phase II trials
                        that decreases           for MS
                        inflammatory immune
                        response

Abatacept               An antibody that         In phase II trials
                        blocks an early step     for MS
                        in immune cell
                        activation

Ocrelizumab (F.         A humanized antibody     In phase III trials
Hoffman La Roche,       that binds to a          for MS
Ltd.)                   molecule on the
                        surface of select B
                        cells and depletes
                        them from the body

Daclizumab High         A humanized antibody     In phase III trials
Yield Process (DAC      that suppresses          for MS
HYP, Biogen Idec)       T cells by blocking
                        signals from an
                        immune messenger
                        protein

Lemtrada[TM]            A humanized antibody     Phase III trials
(alemtuzumab, Sanofi    that targets a           showed benefit;
Aventis)                protein on both T        company plans to
                        and B cells to shut      seek regulatory
                        down cell activity       approval from FDA in
                                                 the first quarter
                                                 of 2012

BG-12 (dimethyl         A chemical compound      Phase III trials
fumarate, Biogen        that promotes cells      showed benefit;
Idec)                   that can regulate the    company has applied
                        immune response          to the FDA for
                                                 approval for MS.

Aubagio[TM]             A compound that          Mixed results so far
(teriflunomide,         modulates responses      in two phase III
Sanofi Aventis)         of T cells within the    trials out of 5
                        immune system by         underway; FDA has
                        impairing the genes      accepted New Drug
                        that instruct these      Application for
                        cells                    review.

Here are a few of many immune-modulating strategies under
study in people with MS. Find more trials at
nationalMSsociety.org/clinicaltrials. (Phase I--small
early studies to determine safety; Phase
II--studies in larger numbers of people that begin to determine
effectiveness; Phase III--even larger, longer studies to better
understand effectiveness and possible side effects.)
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Title Annotation:Research Now
Author:Bernstein, Sara
Publication:Momentum
Geographic Code:1USA
Date:May 17, 2012
Words:1361
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