A study published by a team of investigators at the University of Tokyo’s Institute of Medical Science and Osaka University’s Graduate School of Engineering has presented new evidence demonstrating how Toll-like receptor 9 (TLR9) binds to pathogenic DNA, turning on the functions of the innate immune system. This novel discovery is important for the design of new therapeutic drugs for autoimmune diseases, such as multiple sclerosis (MS), targeting TLR9. The study was published in the new issue of Nature.
Toll-Like Receptors (TLRs) play a critical role in the early innate immune (non-specific first line of defense against pathogens) response to invading bacteria, viruses, and other foreign agents and are also involved in sensing the body’s internal alarm system to help activate other important components of its immune defenses. TLR9 detects the alarm system by recognizing a DNA sequence called Cytosine-phosphate-Guanine dinucleotide (CpG), a pattern that is specific to bacteria and viruses. This induces the release of interferon (IFN) and initiates the inflammatory response process. For autoimmune disease such as MS, studies have shown that TLRs and the release of IFN play a major role in the initiation of disease, triggering of relapses and regulation of damage.
Unfortunately, the exact structure of TLR9 and how it functions remained unknown, inhibiting advancement of treatments that specifically targeted these receptors. This study conducted by Professor Toshiyuki Shimizu PhD’s research group used crystallographic (molecular structure) data to evaluate TLR9’s ring-shaped form in three crucial states: as a free protein, bound to an inhibitor DNA, and bound to an agonist DNA. In the first two cases, TLR9 exists as a single ring, but when it binds to an agonist, like a DNA segment containing the CpG motif, two of its rings are bound together and form a dimer (chemical structure formed from two similar sub-units) that shares two DNA molecules.
In a statement explaining the importance of the study findings, Professor Shimizu said, “TLR9 is a promising drug target for treating viral infections, cancer, autoimmune diseases, and so on, so researchers have been trying to elucidate structurally how TLR9 recognizes pathogenic DNA ever since it was discovered more than a decade ago. This work represents a big step forward for drug development targeting TLR9, and also for our understanding of nucleic acid sensing by TLR9. TLRs have received significant attention due to their critical roles in the innate immune system, and our group has been focusing on the structural study of TLRs for many years. We believe that a precise understanding of TLR function should come from its visualization by structural analyses. Actually, we were quite surprised at the result of this study: the two DNA molecules, agonist and inhibitor, bound to completely different sites on TLR9, and the DNA molecules themselves had completely different structures, both of which we could never have predicted.”
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (20/02/15)
A team of scientists have uncovered a molecule that fights one of the main causes of inflammatory diseases and could be the key to improved treatments for diseases like Alzheimer's, arthritis and multiple sclerosis. The research team, led by Trinity and the University of Queensland Australia, showed the molecule, MCC950, could suppress the key activator in inflammatory diseases, NLRP3. The finding also confirms that inflammatory diseases all share a common process, even though the part of the body becoming inflamed might differ.
Researcher Luke O'Neill said drugs like aspirin or steroids can work in several diseases, but can have side effects or be ineffective, and what they have found is a potentially transformative medicine, which targets what appears to be the common disease-causing process in a myriad of inflammatory diseases. There is huge interest in NLRP3, both among medical researchers and pharmaceutical companies, and they feel their work makes a significant contribution to the efforts to find new medicines to limit it. MCC950 can be administered orally and will be cheaper to produce than current protein-based treatments, which are given daily, weekly, or monthly by injection.
More importantly, the new molecule also remains in the body for a shorter duration, allowing clinicians to stop the anti-inflammatory action of the drug if the patient ever needed to switch their immune response back to 100 percent, in order to clear an infection. So far, the results have shown great promise for blocking multiple sclerosis in a model of the disease, as well as in sepsis where, in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions. The study is published in medical journal Nature Medicine.
Source: dna © 2015 Diligent Media Corporation Ltd (18/02/15)
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)