NUS researchers make breakthrough discovery that could lead to future treatment for multiple sclerosis(24/11/14)
The latest findings may provide an avenue for therapeutic intervention of multiple sclerosis. A multi-disciplinary research team from the National University of Singapore (NUS) has made a breakthrough discovery of a new type of immune cells that may help in the development of a future treatment for multiple sclerosis (MS).
Led by Professor Xin-Yuan Fu, Senior Principal Investigator from CSI Singapore and Professor at the Department of Biochemistry at the NUS Yong Loo Lin School of Medicine, and Dr Wanqiang Sheng, post-doctoral fellow at CSI Singapore, the team found that a new type of immune T helper cells named TH-GM cells play a crucial role in the immune system and pathogenesis of neuronal inflammation. The findings shed light on a possible new avenue for therapeutic intervention, which can be used independently or in conjunction with other treatment options to improve outcomes in the treatment of MS.
Working with Dr Yong-Liang Zhang from the Department of Microbiology at the NUS Yong Loo Lin School of Medicine, Prof Fu and his team showed that STAT5, a member of the STAT family of proteins, programs TH-GM and initiates the immune response to an auto-antigen in responding to a signal from an interleukin, IL-7, causing neuro-inflammation, pathogenesis and damage in the central nervous system. Blocking IL-7 or STAT5 would provide a significant therapeutic benefit for this disease. The study was first published online on 21 November in the journal Cell Research by Nature Publishing Group.
MS is the most prevalent autoimmune disease of the central nervous system, affecting about 2.5 million people globally, with cases showing a higher prevalence in Northern Europe. Despite many years of research, the causes of MS are largely unclear and the disease remains incurable.
This study offers an important insight into the mechanisms behind MS. Dr Richard Flavell, Chair of the Department of Immunology at Yale University, USA, and a world leader in the immunology field, noted that the results from the study may now provide a mechanistic link between IL-7/STAT5-mediated signalling and T helper cell-mediated pathogenicity.
The STAT family of proteins and their signalling pathway (called JAK-STAT) were originally discovered by Prof Fu and his colleagues in 1992. Disturbance of this pathway was shown to be a major cause for many kinds of inflammatory diseases. Novel medicines interfering with JAK-STAT have since been approved in the United States, Europe, and Singapore for the treatment of numerous diseases, and annual sales of medicines involving JAK-STAT are expected to exceed US$1.6 billion in 2016. The newly discovered IL-7-STAT5 by Prof Fu and his team in neuro-inflammation significantly expands this line of medical research, development and therapeutic intervention in a number of major diseases.
Moving forward, Prof Fu and his team are researching the physiological function of TH-GM to further the development of therapy for various human autoimmune diseases.
Source: National University of Singapore (24/11/14)
In multiple sclerosis, the immune system goes rogue, improperly attacking the body's own central nervous system. Mobility problems and cognitive impairments may arise as the nerve cells become damaged.
In a new study, researchers from the University of Pennsylvania and co-investigators have identified a key protein that is able to reduce the severity of a disease equivalent to MS in mice. This molecule, Del-1, is the same regulatory protein that has been found to prevent inflammation and bone loss in a mouse model of gum disease.
"We see that two completely different disease entities share a common pathogenic mechanism," said George Hajishengallis, a professor of microbiology in Penn's School of Dental Medicine and an author on the study. "And in this case that means that they can even share therapeutic targets, namely Del-1."
Because Del-1 has been found to be associated with susceptibility to not only multiple sclerosis, but also Alzheimer's, it's possible that a properly functioning version of this protein might help guard again that disease's effects as well.
Penn contributors to the study included Hajishengallis, Penn Dental Medicine postdoctoral researcher Kavita Hosur and Khalil Bdeir, a research associate professor at Penn's Perelman School of Medicine. They collaborated with senior author Triantafyllos Chavakis of Germany's Technical University Dresden and researchers from South Korea's University of Ulsan College of Medicine and other institutions. The work appears online in the journal Molecular Psychiatry.
In earlier studies, Hajishengallis, Chavakis and colleagues found that Del-1 acts as a gatekeeper that thwarts the movement and accumulation of immune cells like neutrophils, reducing inflammation. While neutrophils are needed to effectively respond to infection or injury, when too many of them accumulate in a tissue, the resulting inflammation can itself be damaging. Hajishengallis has found that gum tissue affected by periodontitis, a severe form of gum disease associated with inflammation and bone loss— had lower levels of Del-1 than healthy tissue.
While researching Del-1 in other tissues, such as gums and lungs, Hajishengallis and Chavakis found that Del-1 was also highly expressed in the brain. In addition, genome-wide screens indicate that the Del-1 gene may contribute to multiple sclerosis risk. For these reasons, the scientists hypothesized that Del-1 might prevent inflammation in the central nervous system just as it does in the gum tissue.
To test their theory, the researchers examined Del-1 expression in brain tissue from people who had died from MS. In MS patients with chronic active MS lesions, Del-1 was reduced compared to both healthy brain tissue and brain tissue from MS patients who were in remission at the time of their death. Similarly, Del-1 expression was reduced in the spinal cords of mice with the rodent equivalent of MS, experimental autoimmune encephalomyelitis (EAE).
Having confirmed this association between reduced Del-1 and MS and EAE, the scientists wanted to see if the reduction itself played a causal role in the disease.
Hajishengallis's and Chavakis's labs had previously utilized mice that lack Del-1 alone or Del-1 together with other molecules of the immune system. The researchers found that mutant mice lacking Del-1 had more severe attacks of the EAE than normal mice, with more damage to myelin, the fatty sheath that coats neurons and helps in the transmission of signals along the cell. Loss of this substance is the hallmark of MS and other neurodegenerative diseases.
Mice without Del-1 that had been induced to get EAE also had significantly higher numbers of inflammatory cells in their spinal cords at the disease's peak, a fact that further experiments revealed was due to increased levels of the signaling molecule IL-17.
Mice that were induced to get EAE that lacked both Del-1 and the receptor for IL-17 had a much milder form of the disease compared to mice that lacked only Del-1. These doubly depleted mice also had fewer neutrophils and inflammation in their spinal cords.
With a greater understanding of how Del-1 acts in EAE, the researchers were curious whether simply replacing Del-1 might act as a therapy for the disease. They waited until mice had had an EAE attack, akin to a flare-up of MS in human patients, and then administered Del-1. They were pleased to find that these mice did not experience further episodes of the disease.
"This treatment prevented further disease relapse," Chavakis said. "Thus, administration of soluble Del-1 may provide the platform for developing novel therapeutic approaches for neuroinflammatory and demyelinating diseases, especially multiple sclerosis."
The team is pursuing further work on Del-1 to see if they can identify a subunit of the protein that could have the same therapeutic effect.
"It's amazing that our work in periodontitis have found application in a central nervous system disease," Hajishengallis said. "This shows that periodontitis can be a paradigm for other medically important inflammatory diseases."
Source: Medical Xpress © Medical Xpress 2011-2014,Science X network (12/11/14)
Type 1 diabetes, ulcerative colitis, and multiple sclerosis are among the more well-known autoimmune diseases. But according to the AARDA, there are more than 150 rare autoimmune diseases, which affect around 50 million Americans. Even with this large number, scientists are still in the dark regarding interventions that can help cure these diseases. But this might change with the discovery of a molecule called NAD+ that has the potential to reverse autoimmunity.
What is autoimmunity?
When an intruding pathogen, such as a virus or bacterium, enters our bodies, our innate immune system gets activated, immediately sending out its soldiers (antibodies and immune cells) to identify and eliminate the pathogen, thus protecting us. But sometimes something goes wrong with this innate immunity and it starts regarding the body’s own tissues as foreign and repeatedly sends out soldier cells to attack them.
Autoimmune diseases can affect any part of the body, including the heart, brain, nerves, muscles, joints, lungs, kidneys, etc. There is still no established cause for autoimmunity, but genetic factors are considered to play a major role.
This new research conducted by Brigham and Women's Hospital (BWH) has identified NAD+ (Nicotinamide adenine dinucleotide), a naturally occurring molecule in living cells, plants, and food that has the potential to turn “destructive” cells that attack healthy tissues into “protective” cells. The molecule has also been found to reverse disease progression by restoring tissue damaged by the autoimmunity process.
"Our study is the first to show that NAD+ can tune the immune response and restore tissue integrity by activating stem cells," said Abdallah ElKhal, senior author, in a statement. "These findings are very novel and may serve for the development of novel therapeutics." The study is published online Oct. 7, in Nature Communications.
NAD+ plays an essential role in several metabolic processes. To test the action of NAD+ in pre-clinical trials, the scientists used experimental autoimmune encephalomyelitis, a pre-clinical model for human multiple sclerosis. They found that NAD+ could regulate the differentiation of immune cells called CD4+ T cells that have an established role in many aspects of autoimmune inflammation. Mice having NAD+ were administered with CD4+ T cells. They showed a significant delayed onset of disease, as well as a less severe form, therefore demonstrating the molecule's protective properties.
"This is a universal molecule that can potentially treat not only autoimmune diseases, but other acute or chronic conditions such as allergy, chronic obstructive pulmonary disease, sepsis, and immunodeficiency," said coauthor Stefan G. Tullius.
The scientists also successfully demonstrated the tissue-restoring capability of NAD+. This, they say, can benefit patients with advanced tissue damage caused by autoimmune diseases. The scientists are now exploring the other medical benefits of NAD+.
"Since this is a natural molecule found in all living cells, including our body, we hope that it will be well-tolerated by patients," said ElKhal. "Thus, we hope that its potential as a powerful therapeutic agent for the treatment of autoimmune diseases will facilitate its use in future clinical trials."
Source: Medical Daily © 2014 IBT Media Inc (08/10/14)
Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: Boosting autoimmunity to fight-off chronic neuroinflammation.
Schwartz M, Baruch K.
Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS).
As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy.
Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis.
Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis.
Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging.
Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self.
Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost protective autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.
Source: J Autoimmun. 2014 Sep 5. pii: S0896-8411(14)00127-9. doi: 10.1016/j.jaut.2014.08.002 © 2014 Elsevier Ltd & Pubmed PMID: 25199710 (11/09/14)
Breakthrough hope for MS treatment(03/09/14)
Scientists say they have discovered how to "switch off" autoimmune diseases such as multiple sclerosis.
Researchers at the University of Bristol, who describe the work as an "important breakthrough", say it could improve the lives of millions around the world.
In their research, published today in Nature Communications, the team reveal how to stop cells from attacking healthy body tissue.
The team discovered how cells convert from being aggressive to protecting against disease, rather than the body's immune system destroying its own tissue by mistake.
It is hoped the insight will lead to the widespread use of antigen-specific immunotherapy as treatment for many autoimmune disorders.
Conditions which could be affected by the research include multiple sclerosis (MS), type 1 diabetes, Graves' disease and systemic lupus erythematosus.
MS alone affects around 100,000 people in the UK and 2.5 million people worldwide.
Professor David Wraith, of the university's School of Cellular and Molecular Medicine, led the "exciting" research - which was funded by the Wellcome Trust.
"Insight into the molecular basis of antigen-specific immunotherapy opens up exciting new opportunities to enhance the selectivity of the approach while providing valuable markers with which to measure effective treatment," Professor Wraith said.
"These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat."
In the study, scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body's own tissue, while converting them into cells capable of protecting against disease.
This type of conversion has previously been applied to allergies, in a treatment known as "allergic desensitisation", but its application to autoimmune disorders has only recently been appreciated.
The researchers have now revealed how the administration of fragments of the proteins that are normally the target for the attack leads to correction of the autoimmune response.
Their work also shows that effective treatment can be achieved by gradually increasing the dose of antigenic fragment injected.
In order to analyse how this type of immunotherapy works, the scientists looked inside the immune cells themselves to see which genes and proteins were turned off by the treatment.
They found changes in gene expression that help explain how effective treatment leads to conversion of aggressor into protector cells.
The outcome is to reinstate self-tolerance, where an individual's immune system ignores its own tissues while remaining fully armed to protect against infection.
Researchers say that by specifically targeting the cells at fault, the immunotherapeutic approach avoids the need for immune suppressive drugs.
These drugs are often associated with side effects such as infections, development of tumours and disruption of natural regulatory mechanisms.
The treatment approach is currently undergoing clinical development through biotechnology company Apitope, a spin-out from the University of Bristol.
"Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy" is published in Nature Communications today.
Source: The Courier.co.uk © 2014 DC Thomson & Co, Ltd. (03/09/14)
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)
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.
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)
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)
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)
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)
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)
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)
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)