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Researchers discover neuroprotective role of immune cell(22/07/14)

A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer's disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.

The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.

"Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied," Dr. Trapp said. "We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer's disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection."

Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp's team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.

They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called "synaptic stripping"), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.

Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.

Source: Medical Xpress © Medical Xpress 2011-2014 (22/07/14)

Tolerance-directed immunotherapy: Future of MS treatment?(30/05/14)

It may take some time and require overcoming certain hurdles, but the future of multiple sclerosis (MS) management may lie in delivering therapies that make immune cells tolerant of specific antigens.

These "tolerance-directed" immunotherapies could eventually provide a safe, cost-effective, and highly efficient alternative to current approaches to MS treatments that suppress the immune system and inevitably lead to patients becoming more susceptible to infections, cancer, and other disorders.

Stephan D. Miller, PhD, Judy Guggenheim Research Professor of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, elaborated on the development of these precisely targeted immunotherapies in his opening lecture at the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS).

He is also a cofounder and member of COUR Pharmaceutical Development Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle platform.

As Dr. Miller explained, targeted tolerance-directed immunotherapies intervene in the autoimmune response, affecting only the pathogenic autoreactive T cells that react to a specific antigen. Such therapies reset those particular cells to actually avoid an immune response, rather than suppressing a response.

In the future, such new therapies may allow clinicians to shut down the underlying disease process instead of just controlling MS symptoms, said Dr. Miller, who has more than 30 years of experience in the field of autoimmune research.

New Way to Treat MS?

"We hope that our tolerance-directed therapy offers a new way to treat newly diagnosed MS patients to halt their disease in a safe and efficient manner by treating the root causes of the disease without the need to take a lifetime of immunosuppressive drugs and in a way that will avoid potential side effects, such as infections and increased rate of cancer," Dr. Miller told Medscape Medical News.

He and his colleagues have already proven the tolerance-directed approach to be safe and effective in a mouse model and, with a group of German researchers, have shown it to be effective in humans. The results of that published study of 9 patients with MS found that the tolerance-directed immunotherapy reduced the patients' immune system reactivity by 50% to 75% (Sci Transl Med. 2013;5:188ra75).

The drawback in that study, though, was that it used a method that involved extracting white blood cells, processing them to deliver myelin antigens so that the body would develop tolerance for them, and then reinfusing these treated white blood cells into the patients.

Dr. Miller and his colleagues are planning another trial of tolerance-directed immunotherapy. However, rather than using the relatively complicated and pricey extraction-processing approach, they hope to be able to deliver the therapy via biodegradable polymer-based nanoparticles: poly (D,L-lactide-co-glycolide) or PLG. It's the same technology used in absorbable sutures that dissolve after tissue heals.

"We are currently in the planning stages of this phase 1 trial using myelin antigen containing PLG nanoparticles in newly diagnosed MS patients," confirmed Dr. Miller, adding that his team hopes to carry out the study in collaboration with neurologists at the Multiple Sclerosis Center at Rush University Medical Center in Chicago.

If all goes well, the study should begin within the next 6 months to a year, said Dr. Miller.

This novel treatment approach has broad implications not only for the treatment of MS but also for a variety of other immune-mediated diseases, including type 1 diabetes and rheumatoid arthritis, and other conditions for which physicians want to manipulate the immune system, such as asthma, food allergies, and islet transplantation in diabetes. Immunologic tolerance, said Dr. Miller, is the "holy grail" for autoimmune diseases.

Broad Implications

Asked to comment on this approach, Corey Ford, MD, director, MS Clinic, and professor, neurology, University of New Mexico, Albuquerque, who introduced Dr. Miller's lecture, told Medscape Medical News that the idea of "tolerizing" the immune system has been around for a long time and that this is the mechanism by which the drug glatiramer acetate (Copaxone, Teva Pharmaceuticals) may be working.

"We have thought for a long time that MS may be triggered by antigens of some sort — we don't know what they are; maybe they're viruses or other environmental triggers — and that desensitizing the immune system to those could play a role in treatment."

Dr. Ford used the example of a patient who is allergic to penicillin. "You can desensitize that person to penicillin by giving him very small doses and gradually increasing the amount so his immune system becomes tolerant," he said.

Dr. Miller's tolerance-directed immunotherapy would in essence be "a more targeted way to desensitize a person with an autoimmune disease to the antigens" that might be triggering their disease, said Dr. Ford.

Dr. Ford agreed that there's still a lot of research needed to determine which antigens and what sequence of antigens are important.

The "good news," he said, is that the nanoparticles "are safe, can be given to humans, and are approved." And the fact that the framework or platform the antigen attaches to is biodegradable removes the worry about toxicity, he added.

"If you can make educated guesses about the right ones to use, maybe you have a treatment for a disease like MS and for many other conditions. This is a strategy that's a framework; it's not just a single disease-targeted approach."

Dr. Miller is cofounder and member of COUR PharmaceuticalDevelopment Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle (IMP) platform. The IMP particles are derived from Food and Drug Administration–approved, biodegradable polymer poly(lactic-co-glycolic-acid) that, when modified and built using proprietary IMPtechnology, provide therapeutic relief in numerous inflammatory conditions.

6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Opening Lecture. Presented May 28, 2014.

Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (30/05/14)

Genome study identifies three possible drug candidates for autoimmune diseases(02/05/14)

New pharmaceuticals to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.

In a study reported online April 17, 2014 in the journal Immunity, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.

The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.

"We examined what makes Th17 cells – which play a crucial role in multiple autoimmune diseases – distinct from other closely related T cells within the immune system," said Alexander Marson, MD, PhD, a leading T cell expert and member of the UCSF Diabetes Center. "Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice."

The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women's Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.

Drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.

Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.

Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said. "There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors," Marson said, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. "This is an entirely different and promising approach to fight autoimmune disease," he said.

"Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells," he said.

To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.

"Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome," Marson said. "This pushes the boundary of what's typically done."

In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, Marson said. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.

Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects. According to Marson, "This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases."

Source: MedicalXpress © Medical Xpress 2011-2014 (02/05/14)

OSU scientists discover possible treatment for MS and other autoimmune diseases(21/03/14)

Researchers tested the compound in mice that had a condition in which the immune system tries to eliminate foreign cells.

Oregon State University scientists have discovered a chemical compound that could be a safer alternative to treating autoimmune diseases, possibly bringing hope to people suffering from conditions caused by their immune system attacking their bodies.

Studies are still needed in humans, however. Autoimmune diseases can affect almost any part of the body and result in such diseases as colitis, multiple sclerosis and psoriasis.

“We mostly treat autoimmune diseases with high-dose corticosteroids or cytotoxic drugs to suppress the immune response, and the side effects can be very difficult to deal with,” lead researcher Nancy Kerkvliet said in a statement. “But if this chemical works in clinical studies, it could result in a safer alternative to conventional drugs.”

Kerkvliet and OSU professor Siva Kumar Kolluri tested thousands of chemical compounds and found that one of them, 10-CI-BBQ, binds to a protein inside T cells. The chemical and protein pass into the nucleus and change the cells into regulatory T cells, which shut down the immune response.

Researchers tested the compound in mice that had a condition in which the immune system tries to eliminate foreign cells. The disease can occur in humans when they receive stem cell or bone marrow transplants.

Daily injections completely suppressed the disease. The compound was rapidly metabolized and not toxic.

The research was published in the journal PLOS ONE.

Source © 2014 American City Business Journals. All rights reserved. (21/03/14)

New insights into immune response could lead to development of new treatments(19/03/14)

A team of biologists and engineers at the University of California, San Diego has discovered that white blood cells, which repair damaged tissue as part of the body's immune response, move to inflamed sites by walking in a stepwise manner. The cells periodically form and break adhesions mainly under two "feet," and generate the traction forces that propel them forward by the coordinated action of contractile proteins. Their discovery, published in the Journal of Cell Biology, is an important advance toward developing new pharmacological strategies to treat chronic inflammatory diseases such as arthritis, irritable bowel syndrome, Type 1 diabetes, and multiple sclerosis.

"The immune system requires the migration of white blood cells to the point of infection and inflammation to clear invaders and begin the process of digesting and repairing tissue. However, when the body fails to properly regulate the recruitment of these cells, the inflammation can become chronic resulting in irreversible tissue injury and loss of functionality," said Juan C. Lasheras, a professor in the departments of Mechanical and Aerospace Engineering and Bioengineering, and in the Institute for Engineering in Medicine. "Understanding the way in which these cells generate the necessary forces to move from the blood stream to the site of inflammation will guide the design of new strategies that could target specific mechanical processes to control their migration," Lasheras said.

Figuring out how white blood cells move required an interdisciplinary approach involving engineering and biological sciences. The lead author of the study is Effie Bastounis, a member of a team led by UC San Diego Jacobs School of Engineering professors Lasheras and Juan Carlos del Alamo, of the Department of Mechanical and Aerospace Engineering, and Richard A. Firtel, a professor of Cell and Developmental Biology in the Division of Biological Sciences. "This work was made possible through interdisciplinary approaches that applied mathematical tools to a basic question in cell biology about how cells move," stated Richard Firtel. "By first applying novel methodologies to study the amoeba Dictyostelium, an experimental system often used by cell biologists, we were able to discover the basic mechanisms that control amoeboid movement, which we then applied to understanding white blood cells."

The team used new analytical tools to measure, with a high degree of accuracy and resolution, the forces the cells exert to move forward. The novel methodology, which they have been refining during the last several years supported by grants from the National Institutes of Health (R01-GM084227 and R01-GM037830), is called Fourier Traction Force Microscopy. Before their study, scientists thought white blood cells did not move in a highly coordinated manner. Furthermore, their work discovered that cells move by not only extending themselves at their front and contracting their backs, but also by squeezing inwardly along their lateral sides pushing the front of the cell forward. These findings establish a new paradigm as to how cell move. The research team is currently extending their techniques, which they have used to study leukocytes and other types of amoeboid cells, to investigate the mechanics of cancer cell migration and invasion.

Source: MNT © 2004-2014 MediLexicon International Ltd (19/03/14)

Multiple Sclerosis might be predictable by blood tests(24/02/14)

Individuals who are suffering from Multiple Sclerosis might have a certain antibody inside their blood, perhaps permitting for early discovery with a blood test prior to any symptoms showing up. There is a potassium protein that contained the antibodies in question and they were found in over six of nearly 20 test subjects who did not have any MS symptoms during the time of testing. Yet each had ended up developing the disease by nine months after the test. Two other participants of the group ended up showing borderline existence of the antibodies.

The results of the entire group were measured against a control group of nearly 15 other people who were the same sex and age as the original group. These people did not have any of the unusual antibodies in their blood and none of them went on to develop MS. This test was held by a technical university located in Germany. The researchers plan on showing their findings at the American Academy of Neurology’s yearly meeting, which is set to be held in April.

Such findings are very positive for the sufferers of MS, as information might help lead to early exposure and also to possible positive treatment. Eventually there may even be prevention of Multiple Sclerosis. The research study’s leader, Dr. Viola Biberacher, stated that if such results could be repeated in bigger parts of the population, then the findings could possibly aid in finding MS earlier in patients. By discovering the disease before symptoms start to show up could mean that physicians and scientists might possibly be able to prepare and treat and maybe even stop some of the symptoms of MS.

These discoveries have also shown that antibodies that have developed in a protein known as KIR4.1, which has been discovered in several individuals with MS, came before the onset of the disease. This suggests a part of the auto antibody in the way of how MS might develop, Biberacher added.

Since the year 2008, Multiple Sclerosis diagnosis rates have risen almost 12 percent worldwide. There are over two and a half million people that are believed to be suffering from the incapacitating condition at this time. Presently there is not any sort of cure for MS either. It is an autoimmune disease which affects the insulating shields inside the cells of nerves throughout the spinal cord and brain.

It is believed that MS develops as the result of a genetic disposition, along with other exterior factors, such as having a deficiency of sun exposure. That seems to aid in the diseases advancement. Countries located in the northern part of the world, that have less sunlight seem to have a higher frequency of Multiple Sclerosis, with Canada having about 290 assessed cases for every 100,000 amount of their population. Sweden also has high rates of MS, with an estimated 190 cases for about every 100,000 individuals. But unlike these countries, doctors located in the United States are not obligated to report occurrences of the condition to the Centers for Disease Control. So the amount of official cases in America stays uncertain.

Biberacher is hopeful about treatments in the future. She stated that the next step of the process was to authorize findings in bigger groups and figure out just how many years there is before Multiple Sclerosis begins that the antibody response begins to start developing in the body. If the individuals who are suffering from Multiple Sclerosis do have such an antibody inside their blood, perhaps permitting for early discovery prior to any symptoms showing up will be available to them in the future.

Source: Guardian Liberty Voice (24/02/14)

New blood cells fight brain inflammation(17/02/14)

Hyperactivity of our immune system can cause a state of chronic inflammation. If chronic, the inflammation will affect our body and result in disease. In the devastating disease multiple sclerosis, hyperactivity of immune cells called T-cells induce chronic inflammation and degeneration of the brain. Researchers at BRIC, the University of Copenhagen, have identified a new type of regulatory blood cells that can combat such hyperactive T-cells in blood from patients with multiple sclerosis. By stimulating the regulatory blood cells, the researchers significantly decreased the level of brain inflammation and disease in a biological model.

The results are published in the journal Nature Medicine.

Molecule activate anti-inflammatory blood cells

The new blood cells belong to the group of our white blood cells called lymphocytes. The cells express a molecule called FoxA1 that the researchers found is responsible for the cells' development and suppressive functions.

"We knew that some unidentified blood cells were able to inhibit multiple sclerosis-like disease in mice and through gene analysis we found out, that these cells are a subset of our lymphocytes expressing the gene FoxA1. Importantly, when inserting FoxA1 into normal lymphocytes with gene therapy, we could change them to actively regulate inflammation and inhibit multiple sclerosis, explains associated professor Yawei Liu leading the experimental studies.

Activating own blood cells for treatment of disease

FoxA1 expressing lymphocytes were not known until now, and this is the first documentation of their importance in controlling multiple sclerosis. The number of people living with this devastating disease around the world has increased by 10 percent in the past five years to 2.5 million. It affects women twice more than men and no curing treatment exists. The research group headed by professor Shohreh Issazadeh-Navikas from BRIC examined blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They found that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.

"From a therapeutic viewpoint, our findings are really interesting and we hope that they can help finding new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curios whether this can be a new treatment strategy", says professor Shohreh Issazadeh-Navikas.

And this is exactly what the research group will focus on at next stage of their research. They have already started to test whether the new FoxA1-lymphocytes can prevent degradation of the nerve cell's myelin layer and brain degeneration in a model of progressive multiple sclerosis. Besides multiple sclerosis, knowledge on how to prevent chronic inflammation will also be valuable for other autoimmune diseases like type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis, where inflammation is a major cause of the disease.

Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (17/02/14)

Are infections driving T-cells to increase Multiple Sclerosis progression?(06/02/14)

Scientists recently uncovered a key finding that CD4 T cells are not involved with Multiple Sclerosis progression after recent trials revealed that a depleting CD4-specific antibody failed to affect MS. The question is: did the depleting CD4 specific antibody fail to affect MS, or was the experimental design flawed? Essentially, immunologists claim that CD4 cells are at the center of the immunological research world simply because they are involved with other aspects of immune responses in order to be able to do what they do.

Zastepa et al., (Neurology Jan. 2014) have looked at whether altered naïve CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). The researchers were able to compare naïve CD4 T-cell gene expression profiles of 19 patients with SPMS vs 14 healthy controls using a whole-genome microarray approach. They looked at surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) activation of naïve CD4 T cells isolated from healthy controls and patients with SPMS.

The researchers separated patients with SPMS into two subgroups: SP-1, which had a short duration of relapsing-remitting MS, and SP-2, which had a long duration of relapsing-remitting MS. They discovered that SP-1 patients upregulated many immune genes, within the TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients demonstrated down regulation of immune genes in comparison with healthy controls. They also found an SP-1-specific transcriptional signature of 3 genes which includes TLR4, TLR2 and chemokine receptor 1. These genes had a higher surface protein expression in SP-1 than SP-2. After researchers stimulated TCR for 2 days, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression.

The researchers suggest that changes in naïve CD4-T-cell biology, particularly that of TCR and TLR signaling pathways, identify MS patients with a rapid conversion to secondary progression. This is important because this identifies long-term disability in MS. In fact, certain proteins are in higher concentration on T cells from progressive MS patients that progress faster. What are these proteins doing you ask? That is not known as this time, however Toll-like receptors involved with microbe recognition and infections are important to the rate of progression. We know that blocking CD4 activity doesn’t stop progression, but the question is whether it changes the slope (rate of change). We expect to find this answer from the SP1 and tysabri trials.

Source: BioNews Texas (06/02/14)

Scientist explores new avenue to fight Multiple Sclerosis(09/01/14)

A research scientist at Albany Medical College has identified a potential path to providing relief of symptoms of multiple sclerosis (MS), a disease with few treatments that affects 350,000 Americans.

Writing in the Journal of Clinical Investigation, Dorina Avram, Ph.D., professor in the Center for Immunology and Microbial Disease at Albany Medical College, said she was able to eliminate symptoms in mice which have an MS-like disease by removing a single molecule to alter the immune system’s T-cells.

Dr. Avram said the work could highlight a new therapeutic strategy for MS, an autoimmune disorder that is more common in northern regions, including upstate New York.

“My team is thrilled that this work is showing such promise as a new approach toward treating this devastating disease that we see a lot of at Albany Med,” said Dr. Avram. She said while her current research involves animal studies, she has been meeting with neurologists at Albany Medical Center to discuss research strategies.

“Dr. Avram’s research is very exciting. Her results suggest that there may be new and very effective treatment options for people with MS,” said Michael Gruenthal, M.D., Ph.D., chair of neurology at Albany Medical Center. “More laboratory research is needed before we can consider research studies in people with MS. When there’s an opportunity to begin research in people with MS, we’ll be ready.”

In multiple sclerosis, the immune system mistakenly attacks normal cells and tissues in the central nervous system. The result is severe inflammation creating symptoms such as weakness, numbness, and loss of vision in one eye.

In the studies, Dr. Avram removed an immune system-controlling molecule called BCL11B from immune system T-cells, which weakened the immune reaction.

As part of a cascade of effects, removal of this molecule from the T-cells resulted in an increase in Interleukin 4 (IL-4), and consequently of retinoic acid, a metabolite of vitamin A critical for re-routing immune system cells from the central nervous system to the small intestine. Diminished T-cell infiltration into the central nervous system resulted in reduced severity and delayed onset of disease symptoms.

“We expected the T-cells to be less activated. What we did not expect was their diversion to the small intestine where they were rendered harmless,” Dr. Avram said. In another study, Dr. Avram vaccinated diseased mice in a manner to boost IL-4 and found the same effect.

“If this method works in people, we don’t expect it would provide a cure but rather an extended remission. Of course, we are still in the early phases of research but this is an important development that opens up new possibilities,” said Dr. Avram.

Source: HealthCanal (09/01/14)

Body's 'safety procedure' could explain autoimmune disease(06/09/13)

Monash University researchers have found an important safety mechanism in the immune system that may malfunction in people with autoimmune diseases, such as Multiple Sclerosis, potentially paving the way for innovative treatments.

Published in Immunity, the research, led by Head of the Monash Department of Immunology Professor Fabienne Mackay, described for the first time how the body manages marginal zone (MZ) B cells, which form a general first line of attack against germs, but are potentially harmful.

MZ B cells are integral to our defenses as they rapidly produce polyreactive antibodies that are capable of destroying a variety of pathogens. This first response gives the body time to put in place an immune reaction specific to the invading microbe.

However, MZ B cells have the potential to turn against the body. Some are capable of producing antibodies which attack healthy, rather than foreign, cells—known as an autoimmune response. Bacteria trigger MZ B cells irrespective of whether these cells are dangerous or benign, effectively placing anyone with a bacterial infection at risk of developing an autoimmune disease.

Professor Mackay's team has discovered the mechanism that regulates this response, ensuring that that the majority of infections do not result in the body attacking its own tissue.

"We found that while MZ B cells are rapidly activated, they have a very short life span. In fact, the very machinery which triggers a response leads to MZ B cells dying within 24 hours," Professor Mackay said.

"This means that in a healthy person, the potentially harmful immune cells are not active for long enough to cause in tissue damage. We now need to look at whether a malfunction in this safety feature is leading to some autoimmune diseases."

When MZ B cells are activated by bacteria, they express greater amounts of a protein known as TACI. When TACI binds to another protein as part of the immune response, this triggers the activation of the 'death machinery' inside MZ B cells. The detection of a pathogen sets of a chain reaction that both activates and then destroys MZ B cells.

Professor Mackay said this was an entirely new way of looking at the immune system.

"The research suggests that through evolution the immune system has not solely been vulnerable to infections but has learned to take advantage of pathogens to develop its own internal safety processes," Professor Mackay said.

"This says something important about our environment—pathogens are not always the enemy. They can also work hand in hand with our immune system to protect us against some immune diseases."

Source: Medical Xpress © Medical Xpress 2011-2013 (06/09/13)

New project investigates immune system's role in multiple sclerosis(27/08/13)

A $1.3 million grant from the National Institute of Neurological Disorders and Stroke could help Houston Methodist scientists better understand how the body's own immune system drives multiple sclerosis.

The five-year project will be led by Todd Eagar, Ph.D., an immunologist in the Department of Pathology and Genomic Medicine at Houston Methodist Hospital. Eagar is also the associate medical director of the Histocompatibility and Transplant Immunology program.

Using a model of multiple sclerosis (MS), Eagar's group will examine how two important cellular systems spur the development of MS. Eagar will also look at how these two systems affect the behavior of T and B cells, immune system stalwarts that in MS become inflammation-causing, autoimmune culprits of brain cell degeneration.

Past studies by Eagar and others suggest that dismantling either the Notch signaling pathway or a protein complex called gamma secretase can decrease the severity of MS symptoms in animal models. Notch is used by most cells, including T and B cells, for cell-cell communication. Gamma secretase turns on Notch. Eagar believes Notch may be at least partly responsible for T and B cell malfunction, and that suppressing gamma secretase -- thereby preventing Notch from being switched on -- might be the key to limiting MS-related damage.

"We think gamma secretase is important for T and B cells to talk to each other," Eagar said. "This project will look at how the interactions between T and B cells promote inflammation. We are very interested in how we can use drugs like gamma secretase inhibitors to suppress the immune system during phases of inflammation."

The present NIH-funded project will also help the scientists determine whether Notch and gamma secretase may be adequate drug targets in future human clinical trials.

Source: Newswise ©2013 Newswise, Inc (27/08/13)

Researchers find new clues to attack multiple sclerosis(16/08/13)

Multiple sclerosis (MS) is a disease that affects the central nervous system (the brain and spinal cord) with devastating consequences. What causes MS is still unknown, but it is clear that the disease is perpetuated by repeated attacks of the nervous system by cells from a person’s own immune system. Texas A&M University researchers in the College of Veterinary Medicine & Biomedical Sciences and the Texas A&M Institute for Neuroscience have uncovered a pathway that the brain cells use to blunt these attacking immune cells.

Andrew Steelman, Roger Smith, Jane Welsh and Jianrong Li have investigated how the brain cells called astrocytes produce a protein named galectin-9 and suppress the autoreactive immune cells that are capable of invading and damaging the central nervous system. Their work is published in the current issue of The Journal of Biological Chemistry.

“We and others have found that galectin-9 is increased in the MS brain, but what it does is not known,” explains Li, the senior author of the study.

“Because this protein is not normally found in the brain, we were particularly interested in how it becomes induced,” adds Steelman, the lead author of the paper. “The results of our study show that galectin-9 is turned on in astrocytes under inflammatory conditions and has the potential to kill autoimmune cells.”

Multiple sclerosis affects between 2 and 3 million people worldwide. It seems to affect women at least twice as often as men, and some studies now suggest it could be four times more prevalent in females.

Also, where a person lives seems to affect his or her odds of contracting the disease. The farther a person lives from the equator, the greater his or her chance of getting MS, and people in Scandinavian countries seem to be especially at risk. It usually strikes between the ages of 20 to 50, but in “recent years, there has been an increase in cases of pediatric MS, from age 10 and under,” Welsh, who has studied the disease for more than 25 years, notes.

“As for living far from the equator, some studies indicate that lack of UV light might be a factor in susceptibility to developing MS,” she adds. “We do know that a lack of vitamin D seems to increase the odds of contracting MS. The disease is influenced by certain factors such as viral infections, environmental factors and stress.”

The chances of getting MS are about 750 to 1, but if a parent or a sibling has the disease, the odds are greatly lowered to 1 in 100. It has struck some high-profile people through the years.

MS sufferers have included entertainers such as comedian Richard Pryor, talk show host Montel Williams, singers Alan Osmond of the Osmond Brothers and country’s Donna Fargo, actress Teri Garr, former NFL quarterback Roman Gabriel and FOX news commentator Neil Cavuto. Ann Romney, wife of presidential candidate Mitt Romney, said last year she has battled MS since 1998, and former Mouseketeer and actress Annette Funicello fought the disease the last 30 years of her life before dying in April.

There is no cure for MS. However, in recent years, several treatments have become available, and the most effective treatments are those that target the cells of the peripheral immune system, the researchers add.

“We now know that galectin-9 produced by the brain’s resident astrocytes can restrict the autoimmune cells in culture,” says Li, “but we need to learn more about what happens in the intact brain, and that is what we are currently working on.”

The researchers hope that a better understanding of interactions between the brain cells and the autoimmune cells may one day offer new therapeutic targets for attenuating MS.

The project was funded by research grants from the National Institutes of Health and the National Multiple Sclerosis Society. Steelman is supported by a fellowship from the National Multiple Sclerosis Society and Texas A&M.

Source: KBTX.com Gray Television, Inc. - Copyright © 2002-2013 (16/08/13)

How interferon beta proteins bind to cells and activate an immune response(24/07/13)

Monash University researchers have gained new insight into the early stages of our immune response, providing novel pathways to develop treatments for diseases from multiple sclerosis to cancer.

In a study published in Nature Immunology, a team of researchers led by Professor Paul Hertzog, of the Monash Institute of Medical Research (MIMR) and Professor Jamie Rossjohn, of the School of Biomedical Sciences, have characterised for the first time how interferon beta (IFNβ) proteins bind to cells and activate an immune response.

Produced when viral and bacterial infections are detected, interferon proteins are vital to the body's defences. They activate immune cells, such as macrophages, can interfere with virus replication, and can boost cells' resilience to infection. They also enhance later immune responses to cancers and other stresses.

There are at least 20 subtypes of interferons that are produced at different stages of the immune response. They appear to have different functions, but these functions and their triggers are generally not well understood. The mapping of INFβ - cell interaction is a breakthrough in the field.

Professor Hertzog of MIMR's Centre for Innate Immunity and Infectious Diseases said interferon function was vital for developing and refining therapies for incurable diseases such as lupus and multiple sclerosis.

"Interferon therapy is useful in treating a number of diseases; however these treatments have dose-limiting side effects. Further, interferons appear to drive some autoimmune diseases, raising the prospect of interferon blockers as treatment," Professor Hertzog said.

"The more refined our understanding of interferon function, the more we can tailor treatments to optimise effectiveness - whether by boosting or blocking their actions."

Lead author on the paper, Dr Nicole de Weerd, also of the Centre for Innate Immunity and Infectious Diseases, said the research provided new pathways for rational drug design.

"We found that when IFNβ binds to a cell, it transmits an unusual signal that seems linked to some of the toxic side effects of interferon therapy, like sepsis. This provides a promising avenue to pursue more selective activation of interferon action," Dr de Weerd said.

Professor Rossjohn and Julian Vivian from the Department of Biochemistry and Molecular Biology collaborated closely on determining the IFNβ interactions at the molecular level.

"During this seven-year study, we have had great support from the Australian Synchrotron," Professor Rossjohn said.

Source: Medical News Today © MediLexicon International Ltd 2004-2013 (24/07/13)