Nerve and brain cells
A $500,000 drug development grant from the National Multiple Sclerosis Society (NMSS) was awarded to a partnership between a multiple sclerosis research team at the Icahn School of Medicine at Mount Sinai and Karyopharm Therapeutics Inc., a clinical stage pharmaceutical company. Dr. Patrizia Casaccia, MD, PhD, Professor in the Departments of Neuroscience and Genetics and Genomics, at Icahn School of Medicine at Mount Sinai, will be the academic lead. She will test the effectiveness of a novel Karyopharm compound that can be orally administered and aimed at stopping the progressive phase of the disease. With the 14-month grant, Dr. Casaccia also hopes to gather information that will help design future clinical trials for MS treatments.
Karyopharm specializes in the synthesis of Selective Inhibitors of Nuclear Export, also known as SINE compounds. These compounds are thought to prevent the cause of irreversible damage to neurons, by blocking the early stages of neurodegeneration. Dr. Casaccia's laboratory first identified nuclear export as an important mechanism related to the initial events occurring in neurons and eventually leading to neurodegeneration. As inhibitors, these novel compounds target the nucleus in neurons, and block the accumulation of toxic substances in the axons. Axons are coated with myelin, and they can be damaged because myelin is destroyed or because they can be directly attacked by toxic factors that accumulate during the MS disease process. Neurodegenerative symptoms result from loss of myelin. Electrical signals are transmitted from the cell body of the neuron down an axon to other nerve cells, muscles, and other cells. Signal transmission slows down and progressive disability results from damage to the axons and loss of neurons, due to neurodegeneration.
Dr. Casaccia underscored the new strategy in MS drug development. "What's unique about this work is that SINE compounds target and prevent nuclear export, which is critically important for the neurodegenerative phase of the disease," she said. Preliminary experiments in Dr. Casaccia's laboratory have been encouraging. In mouse models, oral administration of the new compound to mice with paralysis of the tail and hindlimb, allowed them to walk again.
"The idea of rebuilding the nervous system and protecting it from ongoing MS damage was just a dream a few years ago," said Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. "Now, because of efforts by the research community as well as focused investments by the Society, we can see a future where people with MS will have treatments that could restore what's been lost."
In partnering with Karyopharm Therapeutics Inc., Dr. Casaccia will test these oral compounds in preclinical models and unravel their mechanism of action. The work would not be possible if the National MS Society did not invest $500,000 with Karyopharm through Fast Forward, as part of a comprehensive approach to MS research and treatment focusing on accelerating commercial development of promising research discoveries.
"We look forward to collaborating with Dr. Casaccia, who has dedicated herself to advancing research in multiple sclerosis and other important diseases," said Karyopharm Founder, Chief Scientific Officer, and President of Research and Development, Sharon Shacham, PhD, MBA.
Fred Lublin, MD, Saunders Family Professor of Neurology and the Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center also applauded this research. "Developing novel approaches to treating the neurodegenerative component of MS is critically important for our efforts at halting this disease and then reversing the damage. Existing medications for MS only aim to reduce the number of relapses. They are not restorative to the nervous system."
Source: The Mount Sinai Hospital (22/11/13)
Sodium “overload” in the brain is one of the major factors to blame for the disabling symptoms of multiple sclerosis, researchers have found.
Pioneering work by scientists at University College London Hospitals shows high sodium levels are a major trigger for nerve cell damage. This damage is a key factor in devastating long-term effects of MS, such as walking difficulties and vision problems.
Experts predict the findings, published today, will lead to new treatments aimed at halting the progression of the disease.
The study, the first of its kind, will bring hope to thousands of people. In particular, it could benefit those with progressive forms of the illness where there is more disability.
Healthy people have normal levels of sodium in their nerve cells. However, the researchers discovered MS patients had above-average levels. This is because the cells are too weak to pump it out quickly enough, leading to a build-up of sodium which then causes long-term damage.
The study was funded by the MS Society and NIHR University College London Hospitals Biomedical Research Centre. Dr Susan Kohlhaas, the charity’s head of biomedical research, said: “We urgently need treatments for people with progressive forms of multiple sclerosis and the results of this study, and others funded by the MS Society, open up more options for researchers to investigate potential medicines that could slow or even stop the accumulation of disability.”
Multiple sclerosis affects at least 100,000 people in Britain. It is a condition of the central nervous system, in which the coating around nerve fibres is damaged, causing a range of symptoms. There is no cure. It is normally diagnosed in people between the ages of 20 and 40 and affects almost three times as many women as men.
The researchers used an MRI scanner to assess salt levels in the brains of patients. Ninety-seven people with MS took part in the study.
Dr David Paling, lead author of the study, said scientists would investigate ways of blocking the sodium build-up. “The study is important because it proves sodium accumulation in the nerves affects the progressive nature of the disease,” he said. “We can now move forward to plan trials with medications that prevent sodium from getting into cells and causing damage.
“In addition, we now have an effective test to check if these treatments are working for MS patients, instead of waiting five to 10 years.”
One MS sufferer who took part in the research was Dominic Weaver, 46, from west London. The sound engineer and dubbing mixer for television and film was diagnosed in 2011 and now walks using a stick. He said: “I can still walk but I don’t know if tomorrow I may not be able to get out of bed again. Any treatment which could halt the progression of the disease is a step forward.”
The findings are published this month in the journal Brain.
Source: The Evening Standard © Evening Standard Limited 2013 (12/07/13)
A medical test previously developed to measure a toxin found in tobacco smokers has been adapted to measure the same toxin in people suffering from spinal cord injuries and multiple sclerosis, offering a potential tool to reduce symptoms.
The toxin, called acrolein, is produced in the body after nerve cells are injured, triggering a cascade of biochemical events thought to worsen the injury's severity. Acrolein also may play an important role in multiple sclerosis and other conditions.
Because drugs already exist to reduce the concentration of acrolein in the body, being able to detect and measure it non-invasively represents a potential treatment advance, said Riyi Shi, a professor of neuroscience and biomedical engineering in Purdue University's Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.
"If the acrolein level is high it needs to be reduced, and we already have effective acrolein removers to do so," Shi said. "Reducing or removing acrolein may lessen the severity of symptoms in people who have nerve damage, but there has not been a practical way to monitor acrolein levels in nervous system trauma and diseases."
The toxin is present in tobacco smoke and air pollutants. A method had been developed previously to detect and measure acrolein in the urine of smokers, but it has not been used in people suffering from conditions in which the body produces acrolein internally.
"Based on this method, it was revealed that acrolein is significantly elevated in smokers and decreases following the cessation of cigarette smoke," Shi said. "However, such a method has not been widely used for conditions in which acrolein is elevated due to central nervous system damage or disease."
The researchers tested the method in laboratory animals.
"We wanted to see if higher levels of acrolein corresponds to greater severity of spinal cord injury, and the answer is yes," said Shi, who is working with Bruce Cooper, director of the Metabolite Profiling Facility in the Bindley Bioscience Center of Purdue's Discovery Park. "This means reducing acrolein may help to control symptoms."
New findings are detailed in a research paper that recently appeared online in the Journal of Neurotrauma. The paper, which also will appear in an upcoming print edition of the journal, was authored by doctoral students Lingxing Zheng, Jonghyuck Park, Michael Walls and Melissa Tully; Amber Jannasch, laboratory manager of the Metabolite Profiling Facility; and Cooper and Shi.
The method does not detect acrolein directly but determines the presence of a byproduct, or metabolite, of acrolein in the urine. The metabolite is a chemical compound called N-acetyl-S-3-Hydroxypropylcysteine, or 3-HPMA.
"Acrolein is very volatile, so it doesn't remain stable long enough to monitor, but one molecule of acrolein will make one molecule of 3-HPMA, which is very stable in urine," Shi said.
Laboratory rats were injected with different doses of acrolein, and findings showed that the detection technique is able to accurately measure these differences in acrolein concentration in the urine. The technique might one day be performed routinely in a doctor's office.
"The non-invasive nature of measuring 3-HPMA concentrations in urine allows for long-term monitoring of acrolein in the same animal and ultimately in human clinical studies," Shi said.
Two drugs have been shown to be effective in reducing acrolein levels in the body: hydralazine and phenelzine, which have been approved by the U.S. Food and Drug Administration for hypertension and depression, respectively.
The testing method could be used in conjunction with other measures to test patients for the progress of spinal cord disease.
"Nervous system trauma and diseases are like many other illnesses: A disease-associated marker can be critical for making a diagnosis, a therapeutic selection and a treatment evaluation," Shi said. "Therefore, determination of acrolein levels gives you more assurance that you have an intense biochemical imbalance and biochemical damage and that you should use an acrolein scavenger as a treatment. We used different levels of hydralazine to see if it causes a dose-dependent reduction of 3-HPMA and found that, in fact, it did. This shows that this method is capable of monitoring the decrease of acrolein through treatment with acrolein-removing medications."
Acrolein damages mitochondria, which provide energy for cells, and in multiple sclerosis compromises the myelin sheath surrounding a nerve cell's axon, preventing nerves from properly conducting electrical impulses. The toxin has a possible role in other diseases, including Alzheimer's disease, cancer and atherosclerosis.
"Due to widespread involvement of acrolein in the body, the benefits of this study have the potential to significantly enhance human health," Shi said. "For example, there is evidence that heightened levels of acrolein could diminish an individual's ability to recover fully from stroke and cancer."
In laboratory animals, hydralazine has been shown to delay onset of multiple sclerosis for several days, which could mean several years in humans. Tests with animals also suggests the drug could help to reduce the most severe symptoms once the disease has progressed.
Acrolein has been found to be elevated by about 60 percent in the spinal cord tissues of mice with a disease similar to multiple sclerosis. The toxin causes harm by reacting with the proteins and lipids that make up cells, including neurons.
The research is funded by the National Institutes of Health. Previous work was supported with funding from the state of Indiana.
Source: Imperial Valley News © Imperial Valley News 2013 (14/06/13)
Blocking the expression of just one protein in the brain delays the onset of paralysis in mice with a form of multiple sclerosis, say researchers at the School of Medicine.
Exactly why this happens is still unclear. It may be, in part, that blocking expression of the protein, SIRT1, enhances the production of cells that make the insulating myelin sheath necessary for the transmission of nerve signals. This myelin coating is damaged in autoimmune diseases such as multiple sclerosis and Guillain-Barre syndrome.
Although much more research is needed, the findings suggest that it may one day be possible to induce the brains of patients with myelin-associated diseases or injuries to heal themselves by selectively interfering with the activity of SIRT1.
“We are excited by the potential implications our study has on demyelinating diseases and injuries,” said Anne Brunet, PhD, an associate professor of genetics. “It’s intriguing because activating SIRT1 is typically considered to be beneficial for metabolism and health, but in this case, inactivating SIRT1 can provide protection against a demyelinating injury.”
Brunet, who is also a member of the Stanford Cancer Institute, is the senior author of the research, which was published online May 5 in Nature Cell Biology. Postdoctoral scholar Victoria Rafalski, PhD, is the lead author of the study.
Blocking SIRT1 expression appears to work by promoting the development of neural stem cells in the brain into a type of cell called an oligodendrocyte precursor. These cells, in turn, become the mature oligodendrocytes that wrap the long arms of neurons with myelin — a fatty material necessary to facilitate the transmission of the electrical impulses from one nerve cell to another. In humans, most myelination occurs during infancy and adolescence.
Diseases such as multiple sclerosis wreak havoc in the central nervous system by damaging this protective myelin coating and impeding communication between nerve cells.
Because SIRT1 is more highly expressed in the brains of mice with an inducible form of multiple sclerosis, Brunet and her colleagues wondered what role the protein might play in the generation or inhibition of oligodendrocytes. To find out, they created a laboratory mouse in which the gene for SIRT1 is selectively disrupted in neural stem cells when the mouse is injected with a drug called tamoxifen. This technique allows the researchers to effectively turn SIRT1 expression off at will in neural stem cells.
The researchers found that, over time, a subset of the nerve stem cells in which SIRT1 expression had been eliminated began to make proteins indicative of oligodendrocyte precursor cells and eventually began to look like typical oligodendrocytes. Growing the neural stem cells in culture yielded similar results; genetically engineered cells lacking active SIRT1 (or unmodified cells treated with a drug that specifically inhibits the activity of the SIRT1 protein) resulted in a marked increase in the proportion of cells expressing an oligodendrocyte-specific protein marker.
When normal mice and those with inhibited SIRT1 expression were injected with a compound that causes the demyelination of nerve cells, the SIRT1-inhibited mice recovered more quickly. Furthermore, they were protected for a time from the paralysis that develops after the onset of the multiple-sclerosis-like disorder.
“Our work suggests that SIRT1 may normally limit the proliferation of oligodendrocyte precursors and that it has to be inactivated to transiently increase the number of these myelinating cells,” Brunet said.
To understand more about how SIRT1 works in the brain, the researchers identified a panel of genes that are more highly expressed when SIRT1 is absent. These genes included several involved in growth factor signaling, cell metabolism and protein production. One, called PDGFRalpha, activates a pair of signaling pathways within the cell. Blocking those pathways significantly inhibited the increase in oligodendrocyte precursor cells seen when SIRT1 is missing.
“Our study highlights the possibility of pharmacological manipulation of multiple nodes of the pathway to expand the population of oligodendrocyte precursors,” said Brunet. “Approaches such as these could have important implications for regenerative medicine.”
Other Stanford authors of the study include research assistants Peggy Ho, PhD, and Adiljan Ibrahim; undergraduate student Jamie Brett (now an MD-PhD student at Stanford); graduate student Elizabeth Pollina; postdoctoral scholar Duygu Ucar, PhD; former research associate Jason Dugas, PhD; Ben Barres, MD, PhD, professor and chair of neurobiology; and Lawrence Steinman, MD, professor of pediatrics and of neurology and neurological sciences.
The research was supported by the California Institute for Regenerative Medicine, the National Institutes of Health (grant numbers R01 AG026648, F31NS064600 and R01 NS05599705), an AFAR grant, a National Brain Tumor Society grant, the Glenn Foundation for Medical Research, the National Science Foundation, the Guthy-Jackson Charitable Foundation and the National Multiple Sclerosis Society.
Source: Health Canal (10/05/13)
Neurons that control hunger in the central nervous system also regulate immune cell functions, implicating eating behaviour as a defense against infections and autoimmune disease development, Yale School of Medicine researchers have found in a new study published in the Proceedings of the National Academy of Sciences (PNAS).
Autoimmune diseases have been on a steady rise in the United States. These illnesses develop when the body's immune system turns on itself and begins attacking its own tissues. The interactions between different kinds of T cells are at the heart of fighting infections, but they have also been linked to autoimmune disorders.
"We've found that if appetite-promoting AgRP neurons are chronically suppressed, leading to decreased appetite and a leaner body weight, T cells are more likely to promote inflammation-like processes enabling autoimmune responses that could lead to diseases like multiple sclerosis," said lead author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.
"If we can control this mechanism by adjusting eating behaviour and the kinds of food consumed, it could lead to new avenues for treating autoimmune diseases," he added.
Horvath and his research team conducted their study in two sets of transgenic mice. In one set, they knocked out Sirt1, a signaling molecule that controls the hunger-promoting neuron AgRP in the hypothalamus. These Sirt1-deficient mice had decreased regulatory T cell function and enhanced effector T cell activity, leading to their increased vulnerability in an animal model of multiple sclerosis.
"This study highlights the important regulatory role of the neurons that control appetite in peripheral immune functions," said Horvath. "AgRP neurons represent an important site of action for the body's immune responses."
The team's data support the idea that achieving weight loss through the use of drugs that promote a feeling of fullness "could have unwanted effects on the spread of autoimmune disorders," he notes.
Source: Medical News Today ©2004-2013 MediLexicon International Ltd (28/03/13)
Multiple sclerosis, a brain disease that affects over 400,000 Americans, causes movement difficulties and many neurologic symptoms. MS has two key elements: The nerves that direct muscular movement lose their electrical insulation (the myelin sheath) and cannot transmit signals as effectively. And many of the long nerve fibers, called axons, degenerate.
Many scientists believe that axons are doomed once they lose the insulation, but a new study by graduate student Chelsey Smith and former undergraduate Elizabeth Cooksey in the Journal of Neuroscience shows axons can survive for long periods in rats even after losing myelin.
"This was the first study to demonstrate long-term axon survival after myelin deterioration," says senior author Ian Duncan, a professor in the School of Veterinary Medicine at the University of Wisconsin-Madison.
The mutant rats in the experiment have substantial myelin at first, but by eight weeks the essential myelin insulation is lost. "It was surprising," says Duncan, an expert in MS pathology. "Nine months is a relatively long period in a rat's lifetime, and there wasn't a loss of axons, so the assumption that axons must automatically die without myelin seems incorrect."
Normally, insulating myelin is made by supportive cells called oligodendrocytes that live alongside the axons. Duncan observes that oligodendrocytes and related cells also assist nerve cells by secreting growth factors that neurons may need to survive. "That is just speculation, but in our study, the oligodendrocytes were found in much greater numbers, probably in an attempt to produce more myelin, and we saw an overall increase in growth factor production."
Although oligodendrocytes definitely produce growth factors during early development in the rat, this study identified three neural growth factors that are produced by these helper cells in the older animals. "This paper was the first to show that oligodendrocytes continue to express growth factors in mature animals, and that could be important," Duncan says.
Growth factors are proteins that stimulate a wide range of growth and development, and their absence has been implicated in several neurological diseases. Duncan says more study of growth factors could suggest a route to preventing nerve fiber loss in MS and other myelin diseases.
Although other researchers have found that axons survive in mutant mice that fail to make myelin, Duncan notes that those animals lived only four months. "This survival was more than double that; it's a significant increase."
Scientists have known for decades that axons degenerate and disappear in MS, and that idea is now a major focus of scientific interest. "Much in vogue is the idea that you have to protect axons above and beyond everything else, that MS is not primarily a demyelinating disease, it's primarily an axonal disease," Duncan says. "Our finding shows that it is not absolutely certain that axons will degenerate when they are demyelinated. If we are correct in our speculation, we could potentially protect the axon if we can increase the amount of growth factor being produced by the helper cells."
source: Medical Xpress © Medical Xpress 2011-2012 (06/02/13)
World-leading experts in Magnetic Resonance Imaging from The University of Nottingham's Sir Peter Mansfield Magnetic Resonance Centre have made a key discovery which could give the medical world a new tool for the improved diagnosis and monitoring of neuro-degenerative diseases like multiple sclerosis.
The new study, published in the Proceedings of the National Academy of Science, reveals why images of the brain produced using the latest MRI techniques are so sensitive to the direction in which nerve fibres run.
The white matter of the brain is made up of billions of microscopic nerve fibres that pass information in the form of tiny electrical signals. To increase the speed at which these signals travel, each nerve fibre is encased by a sheath formed from a fatty substance, called myelin. Previous studies have shown that the appearance of white matter in magnetic resonance images depends on the angle between the nerve fibres and the direction of the very strong magnetic field used in an MRI scanner.
Based on knowledge of the molecular structure of myelin, the Nottingham physicists devised a new model in which the nerve fibres are represented as long thin hollow tubes with special (anisotropic) magnetic properties. This model explains the dependence of image contrast on fibre orientation in white matter and potentially allows information about the nerve fibres (such as their size and direction) to be inferred from magnetic resonance images.
Research Fellow Dr Samuel Wharton said: "While most MRI-based research focuses on tissue measurements at the millimetre length scale, our experimental scans on healthy human volunteers and modelling of the myelin sheath shows that much more detailed microscopic information relating to the size and direction of nerve fibres can be generated using fairly simple imaging techniques. The results will give clinicians more context in which to recognise and identify lesions or abnormalities in the brain and will also help them to tailor different types of scan to a particular patient."
Head of the School of Physics and Astronomy, Professor Richard Bowtell added "These results should be an important boost to the world of biomedical imaging which is a key research priority here at The University of Nottingham. We have a strong heritage of groundbreaking work in MRI at the Sir Peter Mansfield Magnetic Resonance Centre and the work was carried out using our 7T scanner which is the strongest magnetic field system for scanning human subjects in the UK."
Dr Nikolaos Evangelou, Clinical Associate Professor specialising in multiple sclerosis at the Nottingham University Hospitals Trust said: "This research opens new avenues of looking at the nerve fibres in the brain. The more we understand about the nerves and the myelin around them, the more successful we are in studying brain diseases, such as multiple sclerosis. The recent advances in our understanding and treatments of MS are based on basic, solid research such as the one presented by Dr Wharton and Bowtell."
The research will give scientists and clinicians all over the world a better understanding of the effects of nerve fibres and their orientation in magnetic resonance imaging and has potentially useful applications in the diagnosis and monitoring of brain and nervous system diseases like multiple sclerosis where there are known links to myelin loss.
Source: MedPage Today © MediLexicon International Ltd 2004-2012 (06/11/12)
Protein could undo MS nerve damage(05/10/12)
A protein that helps regenerate the protective covering around nerve cells is a “strong candidate” for drug development for diseases like multiple sclerosis, say researchers.
They have identified previously unrecognized properties of the naturally occuring protein, also finding that it enhances brain cell formation and survival.
The protein, pigment epithelium-derived factor (PEDF), has well-known anti-tumor generating properties. But its role in promoting growth of a type of brain cell and regenerating the protective myelin sheaths around nerve cells had not been known, the researchers say.
“Our investigation found that PEDF plays a key role in accelerating regeneration of the myelin sheath,” says study senior author David Pleasure, professor of neurology and pediatrics, and director of the Institute for Pediatric Regenerative Medicine, a collaborative initiative of the University of California, Davis, School of Medicine and Shriners Hospitals for Children Northern California.
“That makes PEDF a strong drug-therapy candidate, because it appears to encourage the regeneration of a type of brain cell called oligodendocyte and is able to repair the damage caused by demyelinative diseases, including MS.”
Pleasure and his colleagues identified PEDF’s functions on the adult central nervous system under both normal and pathological conditions in mouse-model research.
The study was conducted in male and female wild-type mice that were continuously infused with a PEDF/saline suspension. Control mice received daily infusions of saline alone. The study found that in the PEDF infused mice, the PEDF receptor was expressed in various areas of the brain, including the corpus callosum and subventricular zone, reflecting the extensive effects of PEDF.
“What’s unique about our findings is that we demonstrated that the continuous administration of recombinant PEDF into the normal adult mouse brain enhances production of glial cells in a critical portion of the brain,” says Jiho Sohn, a post-doctoral scholar and lead study author.
“In addition, we noted the maturation of oligodendrocyte progenitors in the bundle of nerve fibers that connect the left and right hemispheres of the brain.” The study also documented that PEDF infusion enhances production of oligodendroglial progenitor cells from endogenous neural stem cells in mice with corpus callosum demyelinative lesions.
Multiple sclerosis is one of several disease conditions brought about by demyelination, or damage to the protective sheath around nerve cells.
Demyelination impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.
Multiple sclerosis is believed to be caused by the body’s immune system attacking the myelin coating on the nerves. There are more than 2.5 million people world-wide with multiple sclerosis, for which there is no cure.
The study is published in The Journal of Neuroscience. Other study authors contributed from Cornell University, UC Davis, University of Tokyo, and Northwestern University.
The study was funded by the National Institutes of Health, National Multiple Sclerosis Society, Shriners Hospitals for Children, and a postdoctoral fellowship grant to Sohn from the California Institute for Regenerative Medicine.
Source: Futurity © 2009-2012 Futurity.org (05/10/12)
In multiple sclerosis, the immune system attacks nerves in the brain and spinal cord, causing movement problems, muscle weakness and loss of vision. Immune cells called dendritic cells, which were previously thought to contribute to the onset and development of multiple sclerosis, actually protect against the disease in a mouse model, according to a study published by Cell Press in the August issue of the journal Immunity. These new insights change our fundamental understanding of the origins of multiple sclerosis and could lead to the development of more effective treatments for the disease.
"By transfusing dendritic cells into the blood, it may be possible to reduce autoimmunity," says senior study author Ari Waisman of University Medical Center of Johannes Gutenberg University Mainz. "Beyond multiple sclerosis, I can easily imagine that this approach could be applied to other autoimmune diseases, such as inflammatory bowel disease and psoriasis."
In an animal model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE), immune cells called T cells trigger the disease after being activated by other immune cells called antigen-presenting cells (APCs). Dendritic cells are APCs capable of activating T cells, but it was not known whether dendritic cells are the APCs that induce EAE.
In the new study, Waisman and his team used genetic methods to deplete dendritic cells in mice. Unexpectedly, these mice were still susceptible to EAE and developed worse autoimmune responses and disease clinical scores, suggesting that dendritic cells are not required to induce EAE and other APCs stimulate T cells to trigger the disease. The researchers also found that dendritic cells reduce the responsiveness of T cells and lower susceptibility to EAE by increasing the expression of PD-1 receptors on T cells.
"Removing dendritic cells tips the balance toward T cell-mediated autoimmunity," says study author Nir Yogev of University Medical Center of Johannes Gutenberg University Mainz. "Our findings suggest that dendritic cells keep immunity under check, so transferring dendritic cells to patients with multiple sclerosis could cure defects in T cells and serve as an effective intervention for the disease."
Source: Science Codex (17/08/12)