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
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Friday, June 15, 2007
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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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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