Work supported by the National Institute of Arthritis and Musculoskeletal Skin Diseases has led to the discovery of two genes responsible for ankylosing spondylitis (AS), an inflammatory and potentially disabling disease of the spine.
The discovery of the two genes – ARTS1 and IL23R – brings the scientific community closer to fully understanding AS, says John D. Reveille, M.D., professor and director of the Division of Rheumatology and Clinical Immunogenetics at the University of Texas (UT) Medical School at Houston, who led the study with Matthew A. Brown, M.D., professor of immunogenetics at Australia's University of Queensland.
In earlier studies of identical twins, Dr. Brown and his colleagues found that the cause of ankylosing spondylitis is more than 90 percent genetic. With the discovery of the newly identified genes, a large proportion of the genetic risk for AS has now been identified.
The IL23R gene, says Dr. Brown, plays a role in the immune system's response to infection. ARTS1 is involved in processing infectious agents into "bite-size chunks" that can be seen – and fought – by the body's immune system.
The recent discovery is based on work from the largest and most comprehensive genome-wide association scan conducted to date. In this part of the research project, investigators were searching for genetic information related to AS, as well as autoimmune thyroid disease/Graves' Disease, breast cancer and multiple sclerosis.
"This discovery, to me, is the most important since 1973, when HLA-B27 was discovered," says Reveille colleague Frank C. Arnett, M.D., professor of internal medicine and pathology and laboratory medicine at the UT Medical School. HLA-B27 is a powerful predisposing gene that increases the risk of getting AS by more than 100 times.
Dr. Arnett says the location of the genes and the fact they don't coincide with those of autoimmune diseases, such as rheumatoid arthritis, lupus or juvenile diabetes, helps refute the long-held notion that AS is an autoimmune disease. "It is looking more like AS is not an autoimmune disease, but really an unusual response to infection. These genes working together probably impair the immune system's ability to rid the body of some of these bacteria or their products."
He also believes this discovery could eventually lead to ways to immunize people against AS. "I think these give us the genetic handles to identify the pathways that are involved in AS. Once you know the dysregulated pathway, you can find a drug to either strengthen or inhibit the pathway."
In the meantime, Dr. Reveille says the two genes, along with HLA-B27, could also help physicians identify patients who are at the highest risk for developing AS. "For example, if you have a family member with AS, a simple blood test would be able to tell us if you are also at risk," he says. "We could offer screenings for people with inflammatory back pain. In the past, [testing for the HLA-B27 gene] was all we had. Now we potentially have more tests."
"This is a success story for genetics work," says Dr. Reveille. "I think it will lead the way for other work to be done."
AS is a chronic inflammatory arthritis characterized by joint stiffness, pain and extra bone growth that can result in partial or complete fusion of the spine. It typically strikes adolescent and young adult males. Currently there is no cure for the disease.
Friday, March 14, 2008
Discovery of a new switch of the immune response
At the Institut Curie, Inserm researchers, in collaboration with collegues from Dynavax(1), have discovered a new mechanism controlling the choice in humans between two lines of defence in the event of attack. In the presence of viruses or bacteria, the immune system can trigger a response that is rapid but devoid of memory – innate immunity – or a response that takes longer to put in place but is more specifically targeted – adaptive immunity.
The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers. This work is published in the 18 February 2008 issue of the Journal of Experimental Medicine.
The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens. At the Institut Curie, Vassili Soumelis(2) and his team have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system. Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.” In certain autoimmune diseases, like systemic lupus erythematosus(3) or Sjögren’s syndrome(4), this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
For more information on autoimmune diseases visit www.aarda.org
The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers. This work is published in the 18 February 2008 issue of the Journal of Experimental Medicine.
The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens. At the Institut Curie, Vassili Soumelis(2) and his team have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system. Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.” In certain autoimmune diseases, like systemic lupus erythematosus(3) or Sjögren’s syndrome(4), this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
For more information on autoimmune diseases visit www.aarda.org
There’s something uniquely frightening about autoimmune disorders, diseases that occur when the body attacks itself. But there’s increasing evidence t
Source (HealthNewsdigest.com) - Multiple sclerosis. Lupus. Type 1 Diabetes. What links these three afflictions, which exact a devastating toll on people who would otherwise be in the prime of their lives? They are all autoimmune diseases, and the 23.5 million Americans who suffer from these and nearly a hundred other chronic autoimmune illnesses signal a frightening trend. In
THE AUTOIMMUNE EPIDEMIC: Bodies Gone Haywire in a World Out of Balance—And the Cutting Edge Science That Promises Hope (Touchstone/Simon & Schuster; February 5, 2008; $25.00/hardcover; 0-7432-7775-9), author and lecturer Donna Jackson Nakazawa—herself afflicted with several autoimmune diseases—sounds a call to arms, taking readers inside today’s most prestigious scientific labs to show how “autogens” (heavy metals, toxins, pesticides, viruses, and everyday chemicals that can play a role in triggering autoimmunity) are putting an often unbearable load on the human immune system.
THE AUTOIMMUNE EPIDEMIC combines up-to-the-minute research from leading universities and hospitals, including Harvard University, Johns Hopkins Medical Institutions, and the National Institutes of Health, with the frontline perspective of Nakazawa and other autoimmune sufferers to explore vital topics including:What role chemicals, heavy metals, viruses, diet, and genes play in developing autoimmune disease The connection between autoimmune disease and allergies, the rates of which are likewise skyrocketing The disturbing fact that 75% of autoimmune sufferers are women—and one in nine women will be afflicted with these diseases Ways in which readers can lessen the multitude of exposures that threaten their immune systems and their overall health Why scientists now believe that even people who are not genetically predisposed to autoimmunity may fall ill The groundbreaking interventions from today’s top labs that promise to help halt the disease process THE AUTOIMMUNE EPIDEMIC calls for a halt in the proliferation of these debilitating, and often fatal, diseases—and provides the knowledge and the means to make a difference. As Dr. Douglas Kerr, director of the Johns Hopkins Transverse Myelitis Center states in the book’s foreword, “Reading The Autoimmune Epidemic is a necessary first step. Reading The Autoimmune Epidemic is a life-altering event. It needs to be.”ABOUT THE AUTHORDonna Jackson Nakazawa is an author and lecturer who specializes in family life and health issues. She has contributed to Parade and AARP The Magazine, and has appeared on ABC News and NPR radio. Nakazawa is also the author of Does Anybody Else Look Like Me? She lives in Maryland with her family
For more information on autoimmune diseases visit www.aarda.org
THE AUTOIMMUNE EPIDEMIC: Bodies Gone Haywire in a World Out of Balance—And the Cutting Edge Science That Promises Hope (Touchstone/Simon & Schuster; February 5, 2008; $25.00/hardcover; 0-7432-7775-9), author and lecturer Donna Jackson Nakazawa—herself afflicted with several autoimmune diseases—sounds a call to arms, taking readers inside today’s most prestigious scientific labs to show how “autogens” (heavy metals, toxins, pesticides, viruses, and everyday chemicals that can play a role in triggering autoimmunity) are putting an often unbearable load on the human immune system.
THE AUTOIMMUNE EPIDEMIC combines up-to-the-minute research from leading universities and hospitals, including Harvard University, Johns Hopkins Medical Institutions, and the National Institutes of Health, with the frontline perspective of Nakazawa and other autoimmune sufferers to explore vital topics including:What role chemicals, heavy metals, viruses, diet, and genes play in developing autoimmune disease The connection between autoimmune disease and allergies, the rates of which are likewise skyrocketing The disturbing fact that 75% of autoimmune sufferers are women—and one in nine women will be afflicted with these diseases Ways in which readers can lessen the multitude of exposures that threaten their immune systems and their overall health Why scientists now believe that even people who are not genetically predisposed to autoimmunity may fall ill The groundbreaking interventions from today’s top labs that promise to help halt the disease process THE AUTOIMMUNE EPIDEMIC calls for a halt in the proliferation of these debilitating, and often fatal, diseases—and provides the knowledge and the means to make a difference. As Dr. Douglas Kerr, director of the Johns Hopkins Transverse Myelitis Center states in the book’s foreword, “Reading The Autoimmune Epidemic is a necessary first step. Reading The Autoimmune Epidemic is a life-altering event. It needs to be.”ABOUT THE AUTHORDonna Jackson Nakazawa is an author and lecturer who specializes in family life and health issues. She has contributed to Parade and AARP The Magazine, and has appeared on ABC News and NPR radio. Nakazawa is also the author of Does Anybody Else Look Like Me? She lives in Maryland with her family
For more information on autoimmune diseases visit www.aarda.org
Saturday, August 18, 2007
New Research Shows How Chronic Stress Worsens Neurodegenerative Disease Course
Newswise — The evidence is accumulating on how bad stress is for health. Chronic stress can intensify inflammation and increase a person’s risk for developing central nervous system infections, neurodegenerative diseases, like multiple sclerosis (MS), and other inflammatory diseases, say researchers presenting at the 115th Annual Convention of the American Psychological Association (APA). These researchers have demonstrated for the first time that stress-related increases in central nervous system inflammation are behind the adverse effects of stress in an animal model of MS.
Researchers from Texas A & M University used mice to show what role social stress plays in the immune process to influence the course of an MS-like disease. They proposed that stress-induced increases of pro-inflammatory cytokines, which are proteins that regulate immune and inflammatory functions, inhibit the clearing of a virus and allow the inflammatory process to run amok. Stress, say the authors, may interact with viral infections to increase vulnerabilityto diseases such as MS. Meta-analysis of studies investigating the impact of stressful events in patients with MS show an increased risk of worsening symptoms of the disease.
In a series of experiments on mice, the authors showed that increases in a particular cytokine – interleukin-6 (IL-6), which is released during stress and regulates the part of the immune system that fights infection – can make socially stressed mice vulnerable to MS-like illnesses.
The researchers used a social disruption model (SDR) to simulate social stress for mice and then infected the mice with Theiler’s murine encephalomyelitis (TMEV). Infection with TMEV results in an acute infection of the central nervous system followed by a chronic autoimmune disease similar to that seen in humans with MS. Their laboratory has previously shown that exposure to social stress prior to infection exacerbates both the early viral infection and the later autoimmune demyelinating MS-like phase of the disease.
To create a stressful environment, researchers housed three young male mice together for several weeks. After the mice established a stable social hierarchy, researchers introduced an older aggressive male into the residence for a couple of hours. The intruder exhibits aggressive behavior – posturing, fighting, wounding, pursuit – that results in submissive behaviors and social defeat in the younger resident mice. This procedure was repeated for three consecutive nightly two-hour sessions with one night off, followed by an additional three nightly sessions. To keep the mice from getting used to the intruder, a new intruder was introduced for each session.
What they found was this stress appears to elevate levels of IL-6, which subsequently increases the severity of the MS-like illness. Furthermore, using specific IL-6 neutralizing antibody treatments during the stress exposure can prevent the stress-related worsening of the disease, said the authors.
In one experiment, they showed that mice exposed to social disruption had elevated central and peripheral levels of IL-6. However, infusing the neutralizing antibody into the brain prevented this stress-induced increase in IL-6. This demonstrated that the antibody could effectively reverse the stress-related increases in IL-6 in brain and in circulating blood.
Results from a second experiment showed that administering the IL-6 neutralizing antibody during the stress exposure prevented worsening of the TMEV infection. By blocking the stress-induced elevation of IL-6, TMEV infection was weakened, which lessened some of the disease symptoms, such as motor impairment, inflammation in the brain and spinal cord, and the viral level in the central nervous system. Based on these findings, Dr. Mary Meagher, the lead researcher, proposes that the adverse effects of stress-induced IL-6 on TMEV infection are enough to create a pro-inflammatory environment that interferes with the immune response to infection. Because the early immune response shapes the later specific immune response to infection, impairment of the early response could account for the increased viral level, prolonged viral infection, increased CNS inflammation, and the subsequent exacerbation of the chronic autoimmune disease.
There is a growing body of evidence in both animal and human studies that suggests that exposure to stress can increase and sustain the release of pro-inflammatory cytokines following an assault on the immune system. Thus, the present findings might help scientists unravel which biobehavioral mechanisms offset the adverse health effects of chronic social stress in humans. “Similar to mice exposed to repeated social defeat by an aggressive intruder, people exposed to chronic social conflict experience high levels of stress and consequent dysregulation of the immune system, thereby increasing vulnerability to infectious and autoimmune disease,” said Meagher. “The cytokine response during chronic stress appears to play a key role in exacerbating the acute CNS infection and the development of subsequent autoimmune responses.”
Furthermore, interventions that prevented or reversed the stress-induced increases in IL-6 in the mouse model may have implications for humans, said Meagher. It is possible that the adverse effects of social conflict on people who are vulnerable to certain inflammatory diseases may be prevented or reversed by treatments aimed at blocking increases in this cytokine. Recent evidence suggests that some potential interventions include certain anti-inflammatory drugs, exercise, antidepressant medication, omega-3 fatty acids, and mindfulness relaxation training. However, human clinical trials are needed to fully evaluate this issue.
Presentation: “Severe or Traumatic Stress and Inflammation in Multiple Sclerosis,” Mary W. Meagher, PhD, Texas A&M University
Session 1157 – Symposium: Traumatic Stress, Cardiovascular Disease, Metabolic Syndrome, and Neurodegenerative Disease, 11:00 – 11:50 AM, Friday, August 17, Moscone Center, Second Floor-West Building, Room 2020
Full text of the article is available from the APA Public Affairs Office
The American Psychological Association (APA), in Washington, DC, is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 148,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting health, education and human welfare.
Researchers from Texas A & M University used mice to show what role social stress plays in the immune process to influence the course of an MS-like disease. They proposed that stress-induced increases of pro-inflammatory cytokines, which are proteins that regulate immune and inflammatory functions, inhibit the clearing of a virus and allow the inflammatory process to run amok. Stress, say the authors, may interact with viral infections to increase vulnerabilityto diseases such as MS. Meta-analysis of studies investigating the impact of stressful events in patients with MS show an increased risk of worsening symptoms of the disease.
In a series of experiments on mice, the authors showed that increases in a particular cytokine – interleukin-6 (IL-6), which is released during stress and regulates the part of the immune system that fights infection – can make socially stressed mice vulnerable to MS-like illnesses.
The researchers used a social disruption model (SDR) to simulate social stress for mice and then infected the mice with Theiler’s murine encephalomyelitis (TMEV). Infection with TMEV results in an acute infection of the central nervous system followed by a chronic autoimmune disease similar to that seen in humans with MS. Their laboratory has previously shown that exposure to social stress prior to infection exacerbates both the early viral infection and the later autoimmune demyelinating MS-like phase of the disease.
To create a stressful environment, researchers housed three young male mice together for several weeks. After the mice established a stable social hierarchy, researchers introduced an older aggressive male into the residence for a couple of hours. The intruder exhibits aggressive behavior – posturing, fighting, wounding, pursuit – that results in submissive behaviors and social defeat in the younger resident mice. This procedure was repeated for three consecutive nightly two-hour sessions with one night off, followed by an additional three nightly sessions. To keep the mice from getting used to the intruder, a new intruder was introduced for each session.
What they found was this stress appears to elevate levels of IL-6, which subsequently increases the severity of the MS-like illness. Furthermore, using specific IL-6 neutralizing antibody treatments during the stress exposure can prevent the stress-related worsening of the disease, said the authors.
In one experiment, they showed that mice exposed to social disruption had elevated central and peripheral levels of IL-6. However, infusing the neutralizing antibody into the brain prevented this stress-induced increase in IL-6. This demonstrated that the antibody could effectively reverse the stress-related increases in IL-6 in brain and in circulating blood.
Results from a second experiment showed that administering the IL-6 neutralizing antibody during the stress exposure prevented worsening of the TMEV infection. By blocking the stress-induced elevation of IL-6, TMEV infection was weakened, which lessened some of the disease symptoms, such as motor impairment, inflammation in the brain and spinal cord, and the viral level in the central nervous system. Based on these findings, Dr. Mary Meagher, the lead researcher, proposes that the adverse effects of stress-induced IL-6 on TMEV infection are enough to create a pro-inflammatory environment that interferes with the immune response to infection. Because the early immune response shapes the later specific immune response to infection, impairment of the early response could account for the increased viral level, prolonged viral infection, increased CNS inflammation, and the subsequent exacerbation of the chronic autoimmune disease.
There is a growing body of evidence in both animal and human studies that suggests that exposure to stress can increase and sustain the release of pro-inflammatory cytokines following an assault on the immune system. Thus, the present findings might help scientists unravel which biobehavioral mechanisms offset the adverse health effects of chronic social stress in humans. “Similar to mice exposed to repeated social defeat by an aggressive intruder, people exposed to chronic social conflict experience high levels of stress and consequent dysregulation of the immune system, thereby increasing vulnerability to infectious and autoimmune disease,” said Meagher. “The cytokine response during chronic stress appears to play a key role in exacerbating the acute CNS infection and the development of subsequent autoimmune responses.”
Furthermore, interventions that prevented or reversed the stress-induced increases in IL-6 in the mouse model may have implications for humans, said Meagher. It is possible that the adverse effects of social conflict on people who are vulnerable to certain inflammatory diseases may be prevented or reversed by treatments aimed at blocking increases in this cytokine. Recent evidence suggests that some potential interventions include certain anti-inflammatory drugs, exercise, antidepressant medication, omega-3 fatty acids, and mindfulness relaxation training. However, human clinical trials are needed to fully evaluate this issue.
Presentation: “Severe or Traumatic Stress and Inflammation in Multiple Sclerosis,” Mary W. Meagher, PhD, Texas A&M University
Session 1157 – Symposium: Traumatic Stress, Cardiovascular Disease, Metabolic Syndrome, and Neurodegenerative Disease, 11:00 – 11:50 AM, Friday, August 17, Moscone Center, Second Floor-West Building, Room 2020
Full text of the article is available from the APA Public Affairs Office
The American Psychological Association (APA), in Washington, DC, is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 148,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting health, education and human welfare.
Wednesday, August 15, 2007
First human trial of DNA-based vaccine cheers MS researchers
First human trial of DNA-based vaccine cheers MS researchers
· Number and size of lesions drop sharply during tests · Scientists urge caution and call for further work
Ian Sample, science correspondent
The Guardian
Tuesday August 14 2007
The first human trial of a DNA-based vaccine to combat multiple sclerosis has been declared a success by doctors in America after tests on patients revealed signs that their condition had improved. However, the trial is only the first small step in developing an effective treatment against the debilitating degenerative disease, which affects about 85,000 people in the UK.
The vaccine works by dampening down the immune system, which is believed to become overactive in people who develop multiple sclerosis.
The disease is caused by a small group of immune cells that start to attack the body by targeting the fatty sheaths of myelin that coat nerves in the central nervous system. After waves of attacks, the nerves are eventually destroyed. The myelin coating helps to ensure that signals passed along the nerves travel quickly.
Doctors led by Amit Bar-Or at the Montreal Neurological Institute in Canada developed a vaccine which contains the strands of DNA that produce myelin.
In the trial, 30 patients had the vaccine injected into their muscles over one, three, five and nine weeks, with half also receiving a statin drug to boost the effect of the vaccine. The vaccine was administered at three different doses.
All of the patients in the study had the most common form of the disease, known as relapsing and remitting multiple sclerosis, in which symptoms come and go over long periods, or steadily worsen with spells of remission between.
The main purpose of the trial was to test the safety of the vaccine, the first to be tested in humans to treat an autoimmune disease such as MS.
Any side effects were brief and were considered to be mild or moderate, according to a report in the US journal Archives of Neurology.
The doctors went on to test blood from the patients to see how their immune systems had responded to the vaccine. They found that levels of immune cells that specifically attack myelin sheaths had fallen, along with levels of antibodies which are also implicated in the disease.
The doctors recorded eight relapses, though only one occurred in a patient who was receiving the experimental vaccine. After treatment, the patient continued on the trial and experienced no further relapses. All of the other relapses happened five to 29 weeks after the patients received their final dose of vaccine.
The patients were later given magnetic resonance imaging brain scans to examine the damage caused by the disease. As the disease progresses, it produces lesions which can be counted and measured. In the trial, the researchers saw the number of lesions fall by 18% to 64% in patients who were given the DNA vaccine alone. The size of the lesions also dropped, by between 38% and 83%. The statin drug did not seem to improve the vaccine's effectiveness.
The researchers were excited by the results, but cautioned against reading too much into the trial's findings. "We have demonstrated in this first, to our knowledge, in-human trial of a DNA vaccine for autoimmune disease that the approach is safe and well-tolerated. We describe evidence for induction of favourable trends on brain MRI, indicating a reduction in the inflammatory response in the central nervous system," they wrote.
The team has now begun a 12-month trial of 290 patients. If that is a success, it could pave the way for DNA vaccines for a range of other diseases caused by an over-active immune system, such as type I diabetes and rheumatoid arthritis.
· Number and size of lesions drop sharply during tests · Scientists urge caution and call for further work
Ian Sample, science correspondent
The Guardian
Tuesday August 14 2007
The first human trial of a DNA-based vaccine to combat multiple sclerosis has been declared a success by doctors in America after tests on patients revealed signs that their condition had improved. However, the trial is only the first small step in developing an effective treatment against the debilitating degenerative disease, which affects about 85,000 people in the UK.
The vaccine works by dampening down the immune system, which is believed to become overactive in people who develop multiple sclerosis.
The disease is caused by a small group of immune cells that start to attack the body by targeting the fatty sheaths of myelin that coat nerves in the central nervous system. After waves of attacks, the nerves are eventually destroyed. The myelin coating helps to ensure that signals passed along the nerves travel quickly.
Doctors led by Amit Bar-Or at the Montreal Neurological Institute in Canada developed a vaccine which contains the strands of DNA that produce myelin.
In the trial, 30 patients had the vaccine injected into their muscles over one, three, five and nine weeks, with half also receiving a statin drug to boost the effect of the vaccine. The vaccine was administered at three different doses.
All of the patients in the study had the most common form of the disease, known as relapsing and remitting multiple sclerosis, in which symptoms come and go over long periods, or steadily worsen with spells of remission between.
The main purpose of the trial was to test the safety of the vaccine, the first to be tested in humans to treat an autoimmune disease such as MS.
Any side effects were brief and were considered to be mild or moderate, according to a report in the US journal Archives of Neurology.
The doctors went on to test blood from the patients to see how their immune systems had responded to the vaccine. They found that levels of immune cells that specifically attack myelin sheaths had fallen, along with levels of antibodies which are also implicated in the disease.
The doctors recorded eight relapses, though only one occurred in a patient who was receiving the experimental vaccine. After treatment, the patient continued on the trial and experienced no further relapses. All of the other relapses happened five to 29 weeks after the patients received their final dose of vaccine.
The patients were later given magnetic resonance imaging brain scans to examine the damage caused by the disease. As the disease progresses, it produces lesions which can be counted and measured. In the trial, the researchers saw the number of lesions fall by 18% to 64% in patients who were given the DNA vaccine alone. The size of the lesions also dropped, by between 38% and 83%. The statin drug did not seem to improve the vaccine's effectiveness.
The researchers were excited by the results, but cautioned against reading too much into the trial's findings. "We have demonstrated in this first, to our knowledge, in-human trial of a DNA vaccine for autoimmune disease that the approach is safe and well-tolerated. We describe evidence for induction of favourable trends on brain MRI, indicating a reduction in the inflammatory response in the central nervous system," they wrote.
The team has now begun a 12-month trial of 290 patients. If that is a success, it could pave the way for DNA vaccines for a range of other diseases caused by an over-active immune system, such as type I diabetes and rheumatoid arthritis.
Tuesday, August 14, 2007
DNA Vaccine Against Multiple Sclerosis Appears Safe, Potentially Beneficial
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.
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.
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.
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