Newswise — A newly developed DNA vaccine appears safe and may produce beneficial changes in the brains and immune systems of individuals with multiple sclerosis, according to an article posted online today that will appear in the October 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.
In patients with multiple sclerosis (MS), the immune system attacks the myelin sheaths that protect nerve cells in the brain and spinal cord, according to background information in the article. The nerve cell’s axon, which transmits messages to other neurons, is eventually destroyed. The cause of MS is unknown, but evidence points to the involvement of immune cells and antibodies that recognize and attack specific substances in the myelin, such as myelin basic protein. Certain cytokines, small proteins produced by cells that trigger inflammation, also may play a role.
Amit Bar-Or, M.D., of the Montreal Neurological Institute and colleagues tested a DNA vaccine, BHT-3009, that encodes a full-length human myelin basic protein. Between 2004 and 2006, the researchers administered the vaccine to 30 patients with relapsing-remitting MS [characterized by symptomatic periods and periods of remission] or secondary progressive MS [when symptoms progressively worsen, but there still may be periods of remission]. After one, three, five and nine weeks, participants received intramuscular injections of placebo or BHT-3009 (in doses of .5 milligrams, 1.5 milligrams or 3 milligrams), with or without 80-milligram pills of atorvastatin calcium, a lipid-lowering drug previously shown to be effective in autoimmune conditions. After 13 weeks, participants who initially received placebo received four injections of BHT-3009.
Magnetic resonance imaging (MRI) and other safety evaluations were performed at the beginning of the study, and again after five, nine, 13, 26, 38 and 50 weeks. “BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI and produced beneficial antigen-specific immune changes,” the authors write. These changes included a reduction in the number of cytokine-producing CD4+ T cells (a type of white blood cell) specifically targeting myelin proteins. This reduction was found in the blood as well as in the cerebrospinal fluid of three patients who voluntarily underwent lumbar puncture after completing the course of BHT-3009. Atorvastatin did not appear to provide additional benefit.
“There were no increases in clinical relapses, disability, drug-associated laboratory abnormalities, adverse events or the number and volume of contrast-enhancing [visible on MRI] lesions on brain MRI with BHT-3009 treatment compared with placebo,” the authors write. “In fact, there was a trend toward a decrease in the number and volume of contrast-enhancing lesions in the brain in patients treated with BHT-3009 compared with placebo.”
Based on these results, a phase 2b trial—a randomized clinical trial in approximately 290 patients—of BHT-3009 is already under way. “If successful in MS, antigen-specific DNA vaccines can be developed for prevention or treatment of related diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis,” the authors conclude.(ArchNeurol. 2007;64(10):(doi:10.1001/archneur.64.10.nct70002). Available pre-embargo to the media at www.jamamedia.org.)
Editor’s Note: The work described in this article was funded by Bayhill Therapeutics, Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
© 2007 Newswise. All Rights Reserved.
Tuesday, August 14, 2007
New Treatment Boosts Muscle Function in Myasthenia GravisNewswise — A new type of treatment significantly reduces the severity of muscle weakness in m
Newswise — A new type of treatment significantly reduces the severity of muscle weakness in myasthenia gravis (MG), giving hope for a new class of drugs to treat neurological disorders, according to a study published in the August 14, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.
The drug, oral EN101antisense, inhibits the production of acetylcholine esterase, which is an important enzyme in the function of the neuromuscular junction, where nerves connect with muscles. Antisense is a synthetic, short segment of DNA that locks onto a strand of mRNA and blocks production of specific proteins.
“This is the first time we’ve been able to show that antisense is effective and safe when taken orally for a neurological disease,” said study author Zohar Argov, MD, with Hadassah Hebrew University Medical Center in Jerusalem and member of the American Academy of Neurology. “Oral delivery of antisense has long been sought after since it is expected to improve patient compliance because daily injections won’t be needed.”
People with myasthenia gravis have increased fatigue and reduced strength in their voluntary muscles. Symptoms may also include a drooping eyelid, double vision, difficulty in swallowing, or slurred speech. Myasthenia gravis is believed to affect 20 out of every 100,000 people.
For the study, 16 people with myasthenia gravis were given daily doses of oral EN101 antisense for four days and monitored for one month. Four of the people later took the drug for a month. The study found that oral antisense reduced disease severity by an average of 46 percent, with patients experiencing improved muscle function, improved swallowing time and the disappearance of a drooping eyelid. Side effects reported during the study were dryness of eyes and mouth.
Experts say this discovery may have implications beyond myasthenia gravis. “Oral antisense may become another mode of therapy in neuromuscular disease and further study is needed,” said Argov. “However, these preliminary results should be evaluated with caution since this was an open label study.”
Argov says further research is underway to look at the effects of this drug over a longer period of time.
The study was supported by Ester Neuroscience Ltd., a biotechnology company.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.
For more information about the American Academy of Neurology, visit http://www.aan.com.
© 2007 Newswise. All Rights Reserved.
The drug, oral EN101antisense, inhibits the production of acetylcholine esterase, which is an important enzyme in the function of the neuromuscular junction, where nerves connect with muscles. Antisense is a synthetic, short segment of DNA that locks onto a strand of mRNA and blocks production of specific proteins.
“This is the first time we’ve been able to show that antisense is effective and safe when taken orally for a neurological disease,” said study author Zohar Argov, MD, with Hadassah Hebrew University Medical Center in Jerusalem and member of the American Academy of Neurology. “Oral delivery of antisense has long been sought after since it is expected to improve patient compliance because daily injections won’t be needed.”
People with myasthenia gravis have increased fatigue and reduced strength in their voluntary muscles. Symptoms may also include a drooping eyelid, double vision, difficulty in swallowing, or slurred speech. Myasthenia gravis is believed to affect 20 out of every 100,000 people.
For the study, 16 people with myasthenia gravis were given daily doses of oral EN101 antisense for four days and monitored for one month. Four of the people later took the drug for a month. The study found that oral antisense reduced disease severity by an average of 46 percent, with patients experiencing improved muscle function, improved swallowing time and the disappearance of a drooping eyelid. Side effects reported during the study were dryness of eyes and mouth.
Experts say this discovery may have implications beyond myasthenia gravis. “Oral antisense may become another mode of therapy in neuromuscular disease and further study is needed,” said Argov. “However, these preliminary results should be evaluated with caution since this was an open label study.”
Argov says further research is underway to look at the effects of this drug over a longer period of time.
The study was supported by Ester Neuroscience Ltd., a biotechnology company.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.
For more information about the American Academy of Neurology, visit http://www.aan.com.
© 2007 Newswise. All Rights Reserved.
Studies show that exposure to the airborne toxins generated by the WTC attacks triggered the development of sarcoidosis and sarcoidosis-like respirato
The death toll from 9/11 reached 2,750 when Felicia Dunn-Jones’s name was added to the official death list. An attorney, Dunn-Jones fled her office, located a block away from the towers, and died of sarcoidosis 5 months after the attack. Dust from exposure to Ground Zero has also directly contributed to the death of others not yet on the list such as James Zadroga, a 34-year old police officer. Of the 10,000 clients represented by attorney David Worby involved in a lawsuit accusing the city of negligence, 5 have recently died of sarcoidosis.
The confirmation of Dunn-Jone’s sarcoidosis came in a letter by Dr. Charles S. Hirsch, the city's Chief Medical Examiner on May 18 stating that "Accumulating evidence indicates that in some persons exposure to WTC dust has caused sarcoidosis or an inflammatory reaction indistinguishable from sarcoidosis.”
Chemical Dust Exposure and Sarcoidosis
Sarcoidosis, which is also known as Besnier-Boeck disease, is an autoimmune disorder that usually starts in the lungs or the lymph nodes of the chest cavity. Sarcoidosis of the thyroid gland can also develop. Since its identification in the 1860s, no direct cause of sarcoidosis had been identified.
Although airborne toxins had long been suspected, recent evidence confirms that toxins, such as those that clouded the World Trade Center, can trigger sarcoidosis. A pathologist for Ocean County, New Jersey concluded in April 2006 that the January 2006 death of James Zadroga was directly linked to 9/11 recovery operations.
Post WTC Sarcoidosis
As of May, 2007, twenty-six New York City Ground Zero firefighters and emergency medical service workers have developed evidence of a sarcoid-like granulomatous pulmonary disease. The condition, called World Trade Center sarcoid-like granulomatous pulmonary disease, consists of abnormalities in the pulmonary parenchyma, hilar and/or mediastinal adenopathies, clinical features resembling asthma, and, occasionally, involvement of the bones, joints, skin, or spleen.
Investigators had previously shown that even before 9/11, New York City firefighters and rescue personnel had an elevated incidence of sarcoidosis or sarcoid-like granulomatous disease linked to occupational or environmental exposures to organic dusts, metals, chemical dust, silica, and wood dust or smoke.
However, the incidence of sarcoidosis or sarcoid-like pulmonary disease increased significantly after 9/11 compared to the years before the World Trade Center dust exposure, particularly during the first 12 months following 9/11/2001.
The Proof
To determine whether prolonged, repeated exposure to airborne particulates might increase the risk of sarcoidosis or sarcoid-like granulomatous pulmonary disease in a population already at risk, the investigators followed fire department employees. Those with chest radiograph findings suggestive of sarcoidosis underwent additional evaluation using chest CT imaging, pulmonary function tests, airway challenge tests, and biopsies.
The investigators calculated an annual incidence rate of sarcoidosis and compared it with the 15 years before the World Trade Center attacks. They found that 26 patients, all at the World Trade Center site within 72 hours of the towers’ collapse, when particulate levels were highest, had evidence of new-onset sarcoidosis.
Conclusion
Studies of the 26 firefighters showed that 18 (69%) had findings that were consistent with asthma, and fifteen of these patients had clinical symptoms: cough, dyspnea, and/or wheeze exacerbated by exercise and/or irritant exposure, or improved by the use of bronchodilators. All patients had intrathoracic adenopathy, and six (23%) had extrathoracic disease, involving the spleen, abdominal and pelvic lymph nodes, bones, joints, skin, and, in one case, hematuria.
Half the patients were identified within the first year following exposure, indicating an annual incidence rate of 86 per 100,000. The remaining 13 patients were identified within the second to fifth years after 9/11, showing an annual incidence rate of 22 per 100,000.
The average annual incidence rate of sarcoidosis among firefighters during the 15 years before the World Trade Center attacks was 15/100,000, and among controls (rescue personnel without exposure to fire conditions) the rate was 12.9/100,000.
Resources
Carren Bersch, Zac’s Rocky Mountain High, From the Editor, Medical Laboratory Observer, August 2007, Vol 39 (8): 4.
The confirmation of Dunn-Jone’s sarcoidosis came in a letter by Dr. Charles S. Hirsch, the city's Chief Medical Examiner on May 18 stating that "Accumulating evidence indicates that in some persons exposure to WTC dust has caused sarcoidosis or an inflammatory reaction indistinguishable from sarcoidosis.”
Chemical Dust Exposure and Sarcoidosis
Sarcoidosis, which is also known as Besnier-Boeck disease, is an autoimmune disorder that usually starts in the lungs or the lymph nodes of the chest cavity. Sarcoidosis of the thyroid gland can also develop. Since its identification in the 1860s, no direct cause of sarcoidosis had been identified.
Although airborne toxins had long been suspected, recent evidence confirms that toxins, such as those that clouded the World Trade Center, can trigger sarcoidosis. A pathologist for Ocean County, New Jersey concluded in April 2006 that the January 2006 death of James Zadroga was directly linked to 9/11 recovery operations.
Post WTC Sarcoidosis
As of May, 2007, twenty-six New York City Ground Zero firefighters and emergency medical service workers have developed evidence of a sarcoid-like granulomatous pulmonary disease. The condition, called World Trade Center sarcoid-like granulomatous pulmonary disease, consists of abnormalities in the pulmonary parenchyma, hilar and/or mediastinal adenopathies, clinical features resembling asthma, and, occasionally, involvement of the bones, joints, skin, or spleen.
Investigators had previously shown that even before 9/11, New York City firefighters and rescue personnel had an elevated incidence of sarcoidosis or sarcoid-like granulomatous disease linked to occupational or environmental exposures to organic dusts, metals, chemical dust, silica, and wood dust or smoke.
However, the incidence of sarcoidosis or sarcoid-like pulmonary disease increased significantly after 9/11 compared to the years before the World Trade Center dust exposure, particularly during the first 12 months following 9/11/2001.
The Proof
To determine whether prolonged, repeated exposure to airborne particulates might increase the risk of sarcoidosis or sarcoid-like granulomatous pulmonary disease in a population already at risk, the investigators followed fire department employees. Those with chest radiograph findings suggestive of sarcoidosis underwent additional evaluation using chest CT imaging, pulmonary function tests, airway challenge tests, and biopsies.
The investigators calculated an annual incidence rate of sarcoidosis and compared it with the 15 years before the World Trade Center attacks. They found that 26 patients, all at the World Trade Center site within 72 hours of the towers’ collapse, when particulate levels were highest, had evidence of new-onset sarcoidosis.
Conclusion
Studies of the 26 firefighters showed that 18 (69%) had findings that were consistent with asthma, and fifteen of these patients had clinical symptoms: cough, dyspnea, and/or wheeze exacerbated by exercise and/or irritant exposure, or improved by the use of bronchodilators. All patients had intrathoracic adenopathy, and six (23%) had extrathoracic disease, involving the spleen, abdominal and pelvic lymph nodes, bones, joints, skin, and, in one case, hematuria.
Half the patients were identified within the first year following exposure, indicating an annual incidence rate of 86 per 100,000. The remaining 13 patients were identified within the second to fifth years after 9/11, showing an annual incidence rate of 22 per 100,000.
The average annual incidence rate of sarcoidosis among firefighters during the 15 years before the World Trade Center attacks was 15/100,000, and among controls (rescue personnel without exposure to fire conditions) the rate was 12.9/100,000.
Resources
Carren Bersch, Zac’s Rocky Mountain High, From the Editor, Medical Laboratory Observer, August 2007, Vol 39 (8): 4.
Friday, July 20, 2007
Body Clock Shift May Cause Sickness-Linked Fatigue
THURSDAY, July 19 (HealthDay News) -- As anyone who has battled the flu knows, "sick and tired" often go hand-in-hand.
Now, research suggests that illness-linked biochemistry may interfere with the body's "clock" to bring on the low-energy blahs.
Especially for patients battling chronic fatigue, the new findings "could pave the way for further exploration of the interaction between the immune system and the circadian system, hopefully leading to a better understanding of how daytime fatigue could be treated," said study co-lead researcher Thomas Birchler, of the University Hospital Zurich, in Switzerland.
His team published its findings in this week's online edition of the Proceedings of the National Academy of Sciences.
A sudden, profound loss of daytime energy is one of those "uh-oh" symptoms that signals the onset of acute illness, such as colds or influenza. Fatigue of a more chronic kind is also one of the most common and debilitating hallmarks of a wide variety of disorders, from cancer to autoimmune disease to Chronic Fatigue Syndrome.
Up until now, however, scientists knew little as to why fatigue so often accompanies illness.
In the new study, Birchler's team sought to determine how TNF-alpha -- an immune system inflammatory protein or "cytokine" -- might induce daytime tiredness.
A jump in TNF-alpha activity "is found in most of the acute and chronic infectious diseases and is also part of the inflammatory response in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease," Birchler explained.
TNF-alpha helps spur immune-fighting cells that then seek out and destroy the agent causing the illness.
However, the Swiss group's work with both cell cultures and mice found that TNF-alpha has other physiological effects.
"Besides the known functions of TNF-alpha to eliminate infectious agents, we provide evidence that TNF-alpha interferes with clock gene expression," Birchler said.
In other words, the cytokine may affect genes that, in turn, upset the body's normal sleep/wake rhythms -- the "biological clock." This circadian clock guides the daily cycle of alertness and fatigue that people typically feel when healthy, but TNF-alpha appears to help put this cycle into disarray.
According to the study, TNF-alpha activity also "impairs locomotor activity and induces increased rest periods in mice," Birchler noted.
From an evolutionary and survival standpoint, feeling listless and sleepy during short-term illness probably isn't such a bad thing, the Swiss expert said.
"There's evidence that sleep is a helper for the fight against infections, and sleep deprivation leads to worsened immune response," Birchler explained. "From an evolutionary standpoint, fatigue -- by preventing the affected individual from joining social life -- may thereby hinder spread of infectious agents in the population," he added. "Fatigue in animals may be a mechanism which puts pressure on the affected animal to hide and thereby be protected from enemies."
Unfortunately, many patients can suffer from a chronic, unending form of fatigue, usually linked to long-term illness. That kind of tiredness is not useful, Birchler said, and is often the leading complaint of people battling disease.
"So, in the short term, illness-linked fatigue is an advantageous adaptation, but in the long term not necessarily so," said Wilfred Pigeon, an assistant professor of psychiatry at the University of Rochester, N.Y., and the director of the university's Sleep & Neurophysiology Research Laboratory.
Pigeon said the Swiss findings are intriguing and "point the way to some potential therapeutic targets" to help patients ease chronic fatigue. "We probably don't want to tinker with it in flu, for instance, but we may want to tinker with those targets for people who have some chronic illness or autoimmune diseases," he said.
And that "tinkering" might not always come in the form of a pill, Pigeon said.
In numerous studies, exercise "has successfully alleviated fatigue symptoms," Pigeon noted. "Of course, people with Chronic Fatigue Syndrome or cancer-related fatigue really don't want to go to the gym, but, in fact, when they do go, it does alleviate [fatigue] symptoms," he said. The reasons for the effect remain unclear, he added, but "it would be interesting to look at exercise or other behavioral interventions to see if we actually change [clock] gene function."
More information www.Forbe.com
www.aarda.org
Now, research suggests that illness-linked biochemistry may interfere with the body's "clock" to bring on the low-energy blahs.
Especially for patients battling chronic fatigue, the new findings "could pave the way for further exploration of the interaction between the immune system and the circadian system, hopefully leading to a better understanding of how daytime fatigue could be treated," said study co-lead researcher Thomas Birchler, of the University Hospital Zurich, in Switzerland.
His team published its findings in this week's online edition of the Proceedings of the National Academy of Sciences.
A sudden, profound loss of daytime energy is one of those "uh-oh" symptoms that signals the onset of acute illness, such as colds or influenza. Fatigue of a more chronic kind is also one of the most common and debilitating hallmarks of a wide variety of disorders, from cancer to autoimmune disease to Chronic Fatigue Syndrome.
Up until now, however, scientists knew little as to why fatigue so often accompanies illness.
In the new study, Birchler's team sought to determine how TNF-alpha -- an immune system inflammatory protein or "cytokine" -- might induce daytime tiredness.
A jump in TNF-alpha activity "is found in most of the acute and chronic infectious diseases and is also part of the inflammatory response in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease," Birchler explained.
TNF-alpha helps spur immune-fighting cells that then seek out and destroy the agent causing the illness.
However, the Swiss group's work with both cell cultures and mice found that TNF-alpha has other physiological effects.
"Besides the known functions of TNF-alpha to eliminate infectious agents, we provide evidence that TNF-alpha interferes with clock gene expression," Birchler said.
In other words, the cytokine may affect genes that, in turn, upset the body's normal sleep/wake rhythms -- the "biological clock." This circadian clock guides the daily cycle of alertness and fatigue that people typically feel when healthy, but TNF-alpha appears to help put this cycle into disarray.
According to the study, TNF-alpha activity also "impairs locomotor activity and induces increased rest periods in mice," Birchler noted.
From an evolutionary and survival standpoint, feeling listless and sleepy during short-term illness probably isn't such a bad thing, the Swiss expert said.
"There's evidence that sleep is a helper for the fight against infections, and sleep deprivation leads to worsened immune response," Birchler explained. "From an evolutionary standpoint, fatigue -- by preventing the affected individual from joining social life -- may thereby hinder spread of infectious agents in the population," he added. "Fatigue in animals may be a mechanism which puts pressure on the affected animal to hide and thereby be protected from enemies."
Unfortunately, many patients can suffer from a chronic, unending form of fatigue, usually linked to long-term illness. That kind of tiredness is not useful, Birchler said, and is often the leading complaint of people battling disease.
"So, in the short term, illness-linked fatigue is an advantageous adaptation, but in the long term not necessarily so," said Wilfred Pigeon, an assistant professor of psychiatry at the University of Rochester, N.Y., and the director of the university's Sleep & Neurophysiology Research Laboratory.
Pigeon said the Swiss findings are intriguing and "point the way to some potential therapeutic targets" to help patients ease chronic fatigue. "We probably don't want to tinker with it in flu, for instance, but we may want to tinker with those targets for people who have some chronic illness or autoimmune diseases," he said.
And that "tinkering" might not always come in the form of a pill, Pigeon said.
In numerous studies, exercise "has successfully alleviated fatigue symptoms," Pigeon noted. "Of course, people with Chronic Fatigue Syndrome or cancer-related fatigue really don't want to go to the gym, but, in fact, when they do go, it does alleviate [fatigue] symptoms," he said. The reasons for the effect remain unclear, he added, but "it would be interesting to look at exercise or other behavioral interventions to see if we actually change [clock] gene function."
More information www.Forbe.com
www.aarda.org
Friday, June 15, 2007
Potential Role For Retinoic Acid In Autoimmune And Inflammatory Diseases Identified
Science Daily — An important finding, which could eventually lead to a new therapeutic approach for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, colitis, psoriasis and others, was announced today by researchers at the La Jolla Institute for Allergy & Immunology (LIAI). The studies, conducted in laboratory mice, demonstrated the role of retinoic acid, a substance derived when Vitamin A is broken down in the body, in regulating inflammation.
In these studies, published in the journal Science, the LIAI researchers showed that by manipulating the amount of retinoic acid in mice, they could affect the number of pro-inflammatory T cells, a type of white blood cell responsible for several autoimmune and inflammatory diseases. The finding is an important first step that, if eventually found to be true in humans, points to the potential of a new avenue of therapies using retinoic acid to treat these diseases.
"What's exciting about this finding is they've found that retinoic acid plays a role in modulating the switch between these two distinct (T cell) lineages -- the induced regulatory T cells, which are anti-inflammatory, and the TH-17 lineage, which promotes inflammatory responses, " said Casey Weaver, M.D., a University of Alabama, Birmingham, professor and prominent immunology researcher, who was key in the discovery of TH-17 in 2005.
Further, Dr. Weaver said, the LIAI researchers had developed a "mechanism by which you can prevent the development of the (inflammatory) lineage. This is very exciting because it provides a potential pharmacological application for this finding."
The LIAI team tested three approaches with retinoic acid. In one model, they injected the mice with retinoic acid, essentially giving them more of the substance than they would have through normal body processes. This suppressed the formation of pro-inflammatory T cells in the intestines of the mice, demonstrating that increases in retinoic acid reduced inflammation. In another approach, designed to test how reducing retinoic acid would affect inflammation, the team used an inhibitor to block retinoic acid in the mice.
This led to the decrease of anti-inflammatory T cells, showing that reducing retinoic acid increased inflammation. In a third, particularly exciting approach, the scientists treated T cells with retinoic acid in a test tube. When put back into the mice, these T cells prevented the formation of inflammatory T cells in the mice. This is especially noteworthy because combining the retinoic acid and T cells outside the body may avoid possible side effects that are more likely when scientists attempt to manipulate body processes internally.
"We found that you can control inflammation in a living animal with retinoic acid or you can treat cells with retinoic acid in a test tube and transfer them to the organism to suppress inflammation in vivo," said Dr. Cheroutre. "This may offer an important new avenue for treatment of autoimmune diseases like colitis and rheumatoid arthritis or other inflammatory diseases, as well as potentially providing a mechanism for the control of graft rejections, where you don't want the immune system to attack the grafted tissue."
The finding was published in a paper entitled "Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid." Hilde Cheroutre, Ph.D., led the research team, entirely from LIAI, in which Daniel Mucida, Ph.D., and Yunji Park, Ph.D., were key contributors.
Note: This story has been adapted from a news release issued by La Jolla Institute for Allergy and Immunology
www.aarda.org
In these studies, published in the journal Science, the LIAI researchers showed that by manipulating the amount of retinoic acid in mice, they could affect the number of pro-inflammatory T cells, a type of white blood cell responsible for several autoimmune and inflammatory diseases. The finding is an important first step that, if eventually found to be true in humans, points to the potential of a new avenue of therapies using retinoic acid to treat these diseases.
"What's exciting about this finding is they've found that retinoic acid plays a role in modulating the switch between these two distinct (T cell) lineages -- the induced regulatory T cells, which are anti-inflammatory, and the TH-17 lineage, which promotes inflammatory responses, " said Casey Weaver, M.D., a University of Alabama, Birmingham, professor and prominent immunology researcher, who was key in the discovery of TH-17 in 2005.
Further, Dr. Weaver said, the LIAI researchers had developed a "mechanism by which you can prevent the development of the (inflammatory) lineage. This is very exciting because it provides a potential pharmacological application for this finding."
The LIAI team tested three approaches with retinoic acid. In one model, they injected the mice with retinoic acid, essentially giving them more of the substance than they would have through normal body processes. This suppressed the formation of pro-inflammatory T cells in the intestines of the mice, demonstrating that increases in retinoic acid reduced inflammation. In another approach, designed to test how reducing retinoic acid would affect inflammation, the team used an inhibitor to block retinoic acid in the mice.
This led to the decrease of anti-inflammatory T cells, showing that reducing retinoic acid increased inflammation. In a third, particularly exciting approach, the scientists treated T cells with retinoic acid in a test tube. When put back into the mice, these T cells prevented the formation of inflammatory T cells in the mice. This is especially noteworthy because combining the retinoic acid and T cells outside the body may avoid possible side effects that are more likely when scientists attempt to manipulate body processes internally.
"We found that you can control inflammation in a living animal with retinoic acid or you can treat cells with retinoic acid in a test tube and transfer them to the organism to suppress inflammation in vivo," said Dr. Cheroutre. "This may offer an important new avenue for treatment of autoimmune diseases like colitis and rheumatoid arthritis or other inflammatory diseases, as well as potentially providing a mechanism for the control of graft rejections, where you don't want the immune system to attack the grafted tissue."
The finding was published in a paper entitled "Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid." Hilde Cheroutre, Ph.D., led the research team, entirely from LIAI, in which Daniel Mucida, Ph.D., and Yunji Park, Ph.D., were key contributors.
Note: This story has been adapted from a news release issued by La Jolla Institute for Allergy and Immunology
www.aarda.org
Sunday, June 10, 2007
Breakthrough Developments in Rheumatoid Arthritis Reported at Federation of Clinical Immunology Services Meeting in San Diego
Feinstein Researchers to present latest genetic findings on rheumatoid arthritis at San Diego conference.
Manhasset, NY (Vocus/PRWEB ) June 9, 2007 -- Peter K. Gregersen, MD, stares at x-rays of hands, searching out the telltale signs of inflamed joints and wrists from his research subjects with rheumatoid arthritis. With these clinical features at his side, he turns to the basic building blocks of life - the human genome - to figure out what makes these people susceptible to the disabling inflammatory condition.
Dr. Gregersen has finally closed the circle between key genes identified in his laboratory at the Robert S. Boas Center for Genomics and Human Genetics at The Feinstein Institute for Medical Research in Manhasset, NY and more than a 1,000 patients with rheumatoid arthritis. The genes will help tell the story of how the immune system works to create specific antibodies that in turn increase a person's risk for this crippling disease.
Helvetica, sans-serif; TEXT-DECORATION: none" href="http://www.feinsteininstitute.org/" alt="Link to website">The more patients and controls that we have, the more power we will have to pull out new genes and make associations. On Monday at the Federation of Clinical Immunology Services' (FOCIS) meetings in San Diego, CA, Dr. Gregersen and his colleagues will be presenting the lab's latest genetic findings. The group conducted genome-wide scans to identify polymorphisms, or genetic variants, that are associated with the inflammatory condition and can be used to understand the triggers of the disease. This will provide key insights into the pathways underlying rheumatoid arthritis and other autoimmune diseases. It may ultimately provide tests to predict who will respond to the available new treatments. Franak Batliwalla, PhD, also of The Feinstein Institute, will be presenting related studies on biomarkers and genetic influences on drug response at the same meeting. Identifying Immune System Mediators About one percent of the US population will develop rheumatoid arthritis, an autoimmune disease that leads to painful joint swelling. Scientists are cracking the genetic code that makes the immune system wage an attack on a person's joints. Over the last decade, Dr. Gregersen and his colleagues have been amassing a genetic database complete with siblings with rheumatoid arthritis (and some family members without it) in an attempt to single out those genes that are involved in the autoimmune process. In fact, in 2004, they identified a gene called PTPN2 that confers a two-fold risk for rheumatoid arthritis and a number of other autoimmune diseases. The Feinstein now holds the largest collection from rheumatoid arthritis patients in the world. Following the cellular pathway, it has been shown that PTPN22 influences the "trigger point" for activation of T-cells, immune cells that are normally called on to wage battle against infection. In autoimmune diseases like rheumatoid arthritis, PTPN22 appears to put people at higher risk of a wayward T-cell response. The group has since gone on to use modern genetic methods to search for single nucleotide polymorphisms, or SNPs, to identify players that have fallen under the radar of older methods. The group has discovered another signaling molecule that seems to increase a person's risk for rheumatoid arthritis by 30 percent. (The paper reporting the gene is in press.)
In collaborations with other scientists worldwide, Dr. Gregersen has also been able to show that certain markers are strongly linked to certain ethnic groups and others are not. "This will help us in figuring out what exactly is going on in this illness," he said. "It's pretty exciting." Early on in the rheumatoid arthritis research game, when HLA popped out as a major genetic player in the condition in the 1980s, Dr. Gregersen discovered that there was a shared bit of DNA that traveled in the disease. What took two years to identify in the laboratory - shared bands of genetic material - would take two days today. And that speed is what excites Dr. Gregersen. "We have the tools to get at these genes rather quickly now," he said. "The more patients and controls that we have, the more power we will have to pull out new genes and make associations." In another major breakthrough, scientists have discovered the importance of a substance called citrulline as a target for immune attack in rheumatoid arthritis (RA). This immune system antibody associated with rheumatoid arthritis recognizes citrulline, which seems to be a key player in the condition. Indeed, the HLA associations with RA have now been shown by Dr. Gregersen and others to directly regulate the immune response to proteins containing citrulline. Citrulline is formed when a specific enzyme comes in contact with arginine, one of 20 common amino acids in proteins. When one of the enzymes is present, nitrogen is removed from the chemical structure of arginine and it converts into citrulline. Laboratories have developed a test to measure for anti-cyclic citrullinated peptide antibody, or anti-CCP. It is now being used as a diagnostic for rheumatoid arthritis. Scientists are now finding that patients have CCP antibodies months or years prior to the illness, suggesting a way to identify the disease before it starts and perhaps offer treatments to stave off the symptoms. It turns out that those with these antibodies who also have a particular variety of HLA, a complex of genes that regulate immune function, have a 30 times higher risk of developing rheumatoid arthritis than those without these genetic risk factors. Scientists at the University of Colorado are now analyzing the genes from 2,500 first degree relatives of rheumatoid arthritis patients and testing CCP levels to see whether there is a way to predict, based on these measurements, who will go on to develop rheumatoid arthritis. Ultimately, understanding how the genes work to confer illness will help in the development of new treatments.Normal Control Genetic DatabaseIn addition, The Feinstein Institute is participating in a groundbreaking effort to release large amounts of genetic data on normal subjects for use by the scientific community. A key barrier to progress for many geneticists is the costs of obtaining genetic data from normal control populations to use for comparison to the genetic variation seen in people with disease.
In collaboration with the Children's Hospital of Philadelphia, The Feinstein will release genetics data on approximately 6,000 normal volunteers. A company that designs new genetic testing technology, Illumina, Inc. will maintain the database and make it available to scientists. The data will not include personal identifiers but scientists will have information on age and ethnicity to best match their groups to study.
About The Feinstein Institute for Medical Research: Headquartered in Manhasset, NY, and part of the North Shore-LIJ Health System, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimers disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. Feinstein investigators rank in the top 6th percentile of all grant awards funded by the National Institutes of Health. Feinstein Researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org.
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WWW.AARDA.ORG
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Manhasset, NY (Vocus/PRWEB ) June 9, 2007 -- Peter K. Gregersen, MD, stares at x-rays of hands, searching out the telltale signs of inflamed joints and wrists from his research subjects with rheumatoid arthritis. With these clinical features at his side, he turns to the basic building blocks of life - the human genome - to figure out what makes these people susceptible to the disabling inflammatory condition.
Dr. Gregersen has finally closed the circle between key genes identified in his laboratory at the Robert S. Boas Center for Genomics and Human Genetics at The Feinstein Institute for Medical Research in Manhasset, NY and more than a 1,000 patients with rheumatoid arthritis. The genes will help tell the story of how the immune system works to create specific antibodies that in turn increase a person's risk for this crippling disease.
Helvetica, sans-serif; TEXT-DECORATION: none" href="http://www.feinsteininstitute.org/" alt="Link to website">The more patients and controls that we have, the more power we will have to pull out new genes and make associations. On Monday at the Federation of Clinical Immunology Services' (FOCIS) meetings in San Diego, CA, Dr. Gregersen and his colleagues will be presenting the lab's latest genetic findings. The group conducted genome-wide scans to identify polymorphisms, or genetic variants, that are associated with the inflammatory condition and can be used to understand the triggers of the disease. This will provide key insights into the pathways underlying rheumatoid arthritis and other autoimmune diseases. It may ultimately provide tests to predict who will respond to the available new treatments. Franak Batliwalla, PhD, also of The Feinstein Institute, will be presenting related studies on biomarkers and genetic influences on drug response at the same meeting. Identifying Immune System Mediators About one percent of the US population will develop rheumatoid arthritis, an autoimmune disease that leads to painful joint swelling. Scientists are cracking the genetic code that makes the immune system wage an attack on a person's joints. Over the last decade, Dr. Gregersen and his colleagues have been amassing a genetic database complete with siblings with rheumatoid arthritis (and some family members without it) in an attempt to single out those genes that are involved in the autoimmune process. In fact, in 2004, they identified a gene called PTPN2 that confers a two-fold risk for rheumatoid arthritis and a number of other autoimmune diseases. The Feinstein now holds the largest collection from rheumatoid arthritis patients in the world. Following the cellular pathway, it has been shown that PTPN22 influences the "trigger point" for activation of T-cells, immune cells that are normally called on to wage battle against infection. In autoimmune diseases like rheumatoid arthritis, PTPN22 appears to put people at higher risk of a wayward T-cell response. The group has since gone on to use modern genetic methods to search for single nucleotide polymorphisms, or SNPs, to identify players that have fallen under the radar of older methods. The group has discovered another signaling molecule that seems to increase a person's risk for rheumatoid arthritis by 30 percent. (The paper reporting the gene is in press.)
In collaborations with other scientists worldwide, Dr. Gregersen has also been able to show that certain markers are strongly linked to certain ethnic groups and others are not. "This will help us in figuring out what exactly is going on in this illness," he said. "It's pretty exciting." Early on in the rheumatoid arthritis research game, when HLA popped out as a major genetic player in the condition in the 1980s, Dr. Gregersen discovered that there was a shared bit of DNA that traveled in the disease. What took two years to identify in the laboratory - shared bands of genetic material - would take two days today. And that speed is what excites Dr. Gregersen. "We have the tools to get at these genes rather quickly now," he said. "The more patients and controls that we have, the more power we will have to pull out new genes and make associations." In another major breakthrough, scientists have discovered the importance of a substance called citrulline as a target for immune attack in rheumatoid arthritis (RA). This immune system antibody associated with rheumatoid arthritis recognizes citrulline, which seems to be a key player in the condition. Indeed, the HLA associations with RA have now been shown by Dr. Gregersen and others to directly regulate the immune response to proteins containing citrulline. Citrulline is formed when a specific enzyme comes in contact with arginine, one of 20 common amino acids in proteins. When one of the enzymes is present, nitrogen is removed from the chemical structure of arginine and it converts into citrulline. Laboratories have developed a test to measure for anti-cyclic citrullinated peptide antibody, or anti-CCP. It is now being used as a diagnostic for rheumatoid arthritis. Scientists are now finding that patients have CCP antibodies months or years prior to the illness, suggesting a way to identify the disease before it starts and perhaps offer treatments to stave off the symptoms. It turns out that those with these antibodies who also have a particular variety of HLA, a complex of genes that regulate immune function, have a 30 times higher risk of developing rheumatoid arthritis than those without these genetic risk factors. Scientists at the University of Colorado are now analyzing the genes from 2,500 first degree relatives of rheumatoid arthritis patients and testing CCP levels to see whether there is a way to predict, based on these measurements, who will go on to develop rheumatoid arthritis. Ultimately, understanding how the genes work to confer illness will help in the development of new treatments.Normal Control Genetic DatabaseIn addition, The Feinstein Institute is participating in a groundbreaking effort to release large amounts of genetic data on normal subjects for use by the scientific community. A key barrier to progress for many geneticists is the costs of obtaining genetic data from normal control populations to use for comparison to the genetic variation seen in people with disease.
In collaboration with the Children's Hospital of Philadelphia, The Feinstein will release genetics data on approximately 6,000 normal volunteers. A company that designs new genetic testing technology, Illumina, Inc. will maintain the database and make it available to scientists. The data will not include personal identifiers but scientists will have information on age and ethnicity to best match their groups to study.
About The Feinstein Institute for Medical Research: Headquartered in Manhasset, NY, and part of the North Shore-LIJ Health System, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimers disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. Feinstein investigators rank in the top 6th percentile of all grant awards funded by the National Institutes of Health. Feinstein Researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org.
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WWW.AARDA.ORG
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Sunday, May 27, 2007
Autoimmune, rheumatic diseases linked to deeper aortic inflammation and risk of aneursym.
Autoimmune, rheumatic diseases linked to deeper aortic inflammation and risk of aneursym.
Rheumatoid arthritis, lupus, and other inflammatory rheumatic diseases are associated with a high rate of death from heart disease. One explanation is a greater susceptibility to atherosclerosis. Although atherosclerosis is linked to inflammation in healthy individuals as well, the mechanism of inflammation and the reason for accelerated atherosclerosis in patients with inflammatory rheumatic disease remain unclear. Does atherosclerosis result from systemic inflammation, a hallmark of these rheumatic diseases, or from local inflammation of vessels?
To shed light on the link between chronic inflammation and atherosclerosis, a team of researchers in Norway and the United States, affiliated with the Cleveland Clinic Foundation and Brigham and Women’s Hospital in Boston, focused on the aortas of recent recipients of coronary artery bypass graft (CABG) surgery, comparing biopsy specimens from patients with inflammatory rheumatic disease to those from patients without it. Their study, presented in the June 2007 issue of Arthritis & Rheumatism, affirms inflammatory rheumatic disease and smoking as independent predictors of vessel wall inflammation. The vascular inflammation might be a factor that promotes atherosclerosis and the formation of aneurysms.
Aortic samples were obtained during CABG surgery, performed at two cardiac centers in Norway, from 66 patients with inflammatory rheumatic disease and 51 control patients. The inflammatory rheumatic disease group included patients with rheumatoid arthritis, psoriatic arthritis, lupus, ankylosing spondylitis, polymyalgia and other diseases. Age, body mass index, family history of heart disease, and other traditional cardiovascular risk factors were similar in both groups. All specimens were evaluated, by light microscope, for evidence of chronic inflammatory cell infiltration in the aortic wall. This was achieved by counting and measuring the mononuclear cell infiltrates (MCI) in the aorta, with particular attention to the adventitia, the deepest layer of vascular tissue. Using statistical analysis, the relationship between these inflammatory infiltrates and established lifestyle risk factors for heart disease was also assessed.
In the adventitia (the deepest layer of the blood vessel wall), MCIs occurred more frequently in patients with inflammatory rheumatic disease — 47 percent of this group, compared with 20 percent of the control group. Along with greater prevalence, these inflammatory cells were larger in size. In the middle layer of the vessel wall (the media), MCIs were detected only in patients with inflammatory rheumatic disease. What’s more, MCIs were observed in 6 of 7 patients with a history of aortic aneurysm. In addition to inflammatory rheumatic disease, current smoking was independently associated with more pronounced chronic inflammatory infiltration in the inner adventitia.
In summary, inflammatory rheumatic diseases (many of which involve autoimmune mechanisms) are associated with much higher white blood cell infiltration in the middle and deepest layers of the blood vessel walls, and cigarette smoking worsens inflammation in the inner adventitia. Despite the limitations of its small sample size, this groundbreaking study of aortic inflammation in patients with inflammatory rheumatic disease indicates the need for further investigation into an inflammatory process that may increase vulnerability to dying from a heart attack or aneurysm (Courtesy of EurekAlert!, a service of AAAS).
www.aarda.org
Rheumatoid arthritis, lupus, and other inflammatory rheumatic diseases are associated with a high rate of death from heart disease. One explanation is a greater susceptibility to atherosclerosis. Although atherosclerosis is linked to inflammation in healthy individuals as well, the mechanism of inflammation and the reason for accelerated atherosclerosis in patients with inflammatory rheumatic disease remain unclear. Does atherosclerosis result from systemic inflammation, a hallmark of these rheumatic diseases, or from local inflammation of vessels?
To shed light on the link between chronic inflammation and atherosclerosis, a team of researchers in Norway and the United States, affiliated with the Cleveland Clinic Foundation and Brigham and Women’s Hospital in Boston, focused on the aortas of recent recipients of coronary artery bypass graft (CABG) surgery, comparing biopsy specimens from patients with inflammatory rheumatic disease to those from patients without it. Their study, presented in the June 2007 issue of Arthritis & Rheumatism, affirms inflammatory rheumatic disease and smoking as independent predictors of vessel wall inflammation. The vascular inflammation might be a factor that promotes atherosclerosis and the formation of aneurysms.
Aortic samples were obtained during CABG surgery, performed at two cardiac centers in Norway, from 66 patients with inflammatory rheumatic disease and 51 control patients. The inflammatory rheumatic disease group included patients with rheumatoid arthritis, psoriatic arthritis, lupus, ankylosing spondylitis, polymyalgia and other diseases. Age, body mass index, family history of heart disease, and other traditional cardiovascular risk factors were similar in both groups. All specimens were evaluated, by light microscope, for evidence of chronic inflammatory cell infiltration in the aortic wall. This was achieved by counting and measuring the mononuclear cell infiltrates (MCI) in the aorta, with particular attention to the adventitia, the deepest layer of vascular tissue. Using statistical analysis, the relationship between these inflammatory infiltrates and established lifestyle risk factors for heart disease was also assessed.
In the adventitia (the deepest layer of the blood vessel wall), MCIs occurred more frequently in patients with inflammatory rheumatic disease — 47 percent of this group, compared with 20 percent of the control group. Along with greater prevalence, these inflammatory cells were larger in size. In the middle layer of the vessel wall (the media), MCIs were detected only in patients with inflammatory rheumatic disease. What’s more, MCIs were observed in 6 of 7 patients with a history of aortic aneurysm. In addition to inflammatory rheumatic disease, current smoking was independently associated with more pronounced chronic inflammatory infiltration in the inner adventitia.
In summary, inflammatory rheumatic diseases (many of which involve autoimmune mechanisms) are associated with much higher white blood cell infiltration in the middle and deepest layers of the blood vessel walls, and cigarette smoking worsens inflammation in the inner adventitia. Despite the limitations of its small sample size, this groundbreaking study of aortic inflammation in patients with inflammatory rheumatic disease indicates the need for further investigation into an inflammatory process that may increase vulnerability to dying from a heart attack or aneurysm (Courtesy of EurekAlert!, a service of AAAS).
www.aarda.org
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