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CAMBRIDGE, Mass. - May 12, 2017 - ImmusanT, Inc., a clinical-stage company developing Nexvax2®, a therapeutic vaccine intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease, today announced the publication of positive data from two Phase 1 clinical trials of Nexvax2 in celiac disease. The manuscript, titled "Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies," was published online in The Lancet Gastroenterology and Hepatology. "The results of these two Phase 1 studies suggest that Nexvax2, a therapeutic vaccine evaluated for the management of celiac disease, demonstrates relevant bioactivity and target engagement," said Robert Anderson, MBChB, Ph.D., Chief Scientific Officer of ImmusanT. "Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease." As reported in the manuscript, the studies met their primary endpoints and established a maximum tolerated dose of Nexvax2. After the first dose, some participants experienced nausea and vomiting, similar to symptoms observed following gluten ingestion in celiac disease. Later doses of Nexvax2 had clinical effects similar to placebo. The acute immune response stimulated by Nexvax2 after the first dose was similar to eating gluten, but was reduced and absent after later doses. There was no apparent difference between placebo and Nexvax2 in duodenal histology following twice-weekly dosing at the maximum tolerated dose for eight-weeks. "Celiac disease has a variety of manifestations in both adults and children ranging from digestive symptoms to fatigue, headaches and fractures due to osteoporosis," said Ramnik Xavier, M.D., Chief of the Gastrointestinal Unit at Massachusetts General Hospital. "The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure." Dr. Xavier is also a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital, where his group performed integrative analysis of multidimensional data to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects. "In total, four Phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease. This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet," said Leslie J. Williams, Chief Executive Officer of ImmusanT. Celiac disease is an immune-mediated gastrointestinal disease caused by dietary gluten. Approximately 90% of celiac disease patients carry the human leukocyte antigen-DQ2.5 (HLA-DQ2.5) immune recognition gene. Currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD), which is onerous and often impractical. Persistent intestinal injury and frequent digestive symptoms in many patients are evidence of ongoing gluten exposure. Nexvax2, an epitope-specific immuno-therapy (ESIT) that consists of three immunodominant peptides, is designed to protect against gluten exposure. The Phase 1 trials were randomized, double-blind, placebo-controlled, multi-center studies evaluating the safety, tolerability, and relevant bioactivity of Nexvax2 in HLA-DQ2.5+ patients with celiac disease. In one study, patients received three fixed doses of Nexvax2 or placebo once per week over a three-week period. In the other study, patients received 16 fixed doses of Nexvax2 or placebo twice per week over an eight-week period. Both studies evaluated a range of fixed, intradermal dose administrations in a series of ascending dose cohorts, which included a crossover, double-blind, placebo-controlled oral gluten challenge in the screening and post-treatment periods. The primary outcome measures were the number and percentage of adverse events in the treatment period. The studies were conducted at sites in Australia, New Zealand, and the United States. Celiac disease is a T cell-mediated autoimmune disease triggered by the ingestion of gluten from wheat, rye and barley in genetically susceptible individuals. A gluten-free diet is the only current management for this disease. The community prevalence of celiac disease is approximately 1% in the U.S., but over 80% of cases go unrecognized. When a person with celiac disease consumes gluten, the individual's immune system responds by triggering T cells to fight the offending proteins, damaging the small intestine and inhibiting the absorption of important nutrients into the body. Undiagnosed, celiac disease is a major contributor to poor educational performance and failure to thrive in children. Untreated disease in adults is associated with osteoporosis and increased risk of fractures, anemia, reduced fertility, problems during pregnancy and birth, short stature, dental enamel hypoplasia, dermatitis, recurrent stomatitis and cancer. With no available drug therapy, the only option is a strict and lifelong elimination of gluten from the diet. Compliance is often challenging, and the majority of people continue to have residual damage to their small intestine in spite of adherence to a gluten-free diet. ImmusanT is a privately held biotechnology company focused on protecting patients with celiac disease against the effects of gluten. By harnessing new discoveries in immunology, ImmusanT aims to improve diagnosis and medical management of celiac disease by protecting against the effects of gluten exposure while patients maintain a gluten-free diet. The company is developing Nexvax2®, a therapeutic vaccine for celiac disease, and diagnostic and monitoring tools to improve celiac disease management. ImmusanT's targeted immunotherapy discovery platform can be applied to a variety of autoimmune diseases. Founded in 2010, ImmusanT is backed by Vatera Healthcare Partners. More information may be found at http://www. , or follow ImmusanT on Twitter.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--ImmusanT, Inc., a clinical-stage company developing Nexvax2®, a therapeutic vaccine intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease, today announced the publication of positive data from two Phase 1 clinical trials of Nexvax2 in celiac disease. The manuscript, titled “Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies,” was published online in The Lancet Gastroenterology and Hepatology. “The results of these two Phase 1 studies suggest that Nexvax2, a therapeutic vaccine evaluated for the management of celiac disease, demonstrates relevant bioactivity and target engagement,” said Robert Anderson, MBChB, Ph.D., Chief Scientific Officer of ImmusanT. “Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease.” As reported in the manuscript, the studies met their primary endpoints and established a maximum tolerated dose of Nexvax2. After the first dose, some participants experienced nausea and vomiting, similar to symptoms observed following gluten ingestion in celiac disease. Later doses of Nexvax2 had clinical effects similar to placebo. The acute immune response stimulated by Nexvax2 after the first dose was similar to eating gluten, but was reduced and absent after later doses. There was no apparent difference between placebo and Nexvax2 in duodenal histology following twice-weekly dosing at the maximum tolerated dose for eight-weeks. “Celiac disease has a variety of manifestations in both adults and children ranging from digestive symptoms to fatigue, headaches and fractures due to osteoporosis,” said Ramnik Xavier, M.D., Chief of the Gastrointestinal Unit at Massachusetts General Hospital. “The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure.” Dr. Xavier is also a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital, where his group performed integrative analysis of multidimensional data to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects. “In total, four Phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease. This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet,” said Leslie J. Williams, Chief Executive Officer of ImmusanT. Celiac disease is an immune-mediated gastrointestinal disease caused by dietary gluten. Approximately 90% of celiac disease patients carry the human leukocyte antigen-DQ2.5 (HLA-DQ2.5) immune recognition gene. Currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD), which is onerous and often impractical. Persistent intestinal injury and frequent digestive symptoms in many patients are evidence of ongoing gluten exposure. Nexvax2, an epitope-specific immuno-therapy (ESIT) that consists of three immunodominant peptides, is designed to protect against gluten exposure. The Phase 1 trials were randomized, double-blind, placebo-controlled, multi-center studies evaluating the safety, tolerability, and relevant bioactivity of Nexvax2 in HLA-DQ2.5+ patients with celiac disease. In one study, patients received three fixed doses of Nexvax2 or placebo once per week over a three-week period. In the other study, patients received 16 fixed doses of Nexvax2 or placebo twice per week over an eight-week period. Both studies evaluated a range of fixed, intradermal dose administrations in a series of ascending dose cohorts, which included a crossover, double-blind, placebo-controlled oral gluten challenge in the screening and post-treatment periods. The primary outcome measures were the number and percentage of adverse events in the treatment period. The studies were conducted at sites in Australia, New Zealand, and the United States. About Celiac Disease Celiac disease is a T cell-mediated autoimmune disease triggered by the ingestion of gluten from wheat, rye and barley in genetically susceptible individuals. A gluten-free diet is the only current management for this disease. The community prevalence of celiac disease is approximately 1% in the U.S., but over 80% of cases go unrecognized. When a person with celiac disease consumes gluten, the individual’s immune system responds by triggering T cells to fight the offending proteins, damaging the small intestine and inhibiting the absorption of important nutrients into the body. Undiagnosed, celiac disease is a major contributor to poor educational performance and failure to thrive in children. Untreated disease in adults is associated with osteoporosis and increased risk of fractures, anemia, reduced fertility, problems during pregnancy and birth, short stature, dental enamel hypoplasia, dermatitis, recurrent stomatitis and cancer. With no available drug therapy, the only option is a strict and lifelong elimination of gluten from the diet. Compliance is often challenging, and the majority of people continue to have residual damage to their small intestine in spite of adherence to a gluten-free diet. About ImmusanT Inc. ImmusanT is a privately held biotechnology company focused on protecting patients with celiac disease against the effects of gluten. By harnessing new discoveries in immunology, ImmusanT aims to improve diagnosis and medical management of celiac disease by protecting against the effects of gluten exposure while patients maintain a gluten-free diet. The company is developing Nexvax2®, a therapeutic vaccine for celiac disease, and diagnostic and monitoring tools to improve celiac disease management. ImmusanT’s targeted immunotherapy discovery platform can be applied to a variety of autoimmune diseases. Founded in 2010, ImmusanT is backed by Vatera Healthcare Partners. More information may be found at www.ImmusanT.com, or follow ImmusanT on Twitter.


News Article | April 25, 2017
Site: www.sciencedaily.com

An intestinal enzyme previously shown to keep bacterial toxins from passing from the gastrointestinal system into the bloodstream may be able to prevent or reduce the liver damage caused by excess alcohol consumption. In their report that will appear in the journal Digestive Diseases and Sciences and has been published online, a Massachusetts General Hospital (MGH) research team describes how oral doses of intestinal alkaline phosphatase (IAP) prevented the development of fatty liver in mouse models of both binge drinking and chronic alcohol consumption. The study also provides the first evidence of an expanded role of the liver's stellate cells in alcoholic liver disease. "Liver damage is one of the most devastating effects of excess alcohol consumption, and so blocking this process could save millions of lives lost to alcohol-related liver diseases such as cirrhosis and liver cancer," says Richard Hodin, MD, of the MGH Department of Surgery, the study's senior author. "Along with direct toxic effects on the liver itself, alcohol appears to damage the liver through its effects on the intestinal lining, allowing bacterial toxins from the gut to cross the barrier and reach the liver. Since we know that IAP works to maintain a healthy gut barrier by blocking passage of an important toxic molecule, we investigated its potential to protect the liver from alcohol-induce damage." Previous research by Hodin's group revealed that IAP helps to maintain a healthy intestinal microbial population by blocking the damaging effects of lipopolysaccharide (LPS), a molecule responsible for the toxic effects of several species of bacteria, and that the enzyme's anti-LPS effects could prevent the development of metabolic syndrome -- a constellation of symptoms including obesity, abnormal glucose and lipid metabolism, and fatty liver -- in mice fed a high-fat diet. Since LPS is known to play a role in alcohol-induced liver inflammation and its levels are known to rise with alcohol consumption, the MGH team investigated whether oral IAP supplementation could prevent alcoholic liver disease both by detoxifying the LPS released by gut bacteria and by preventing its passage from the gut into the liver's blood supply. The team conducted experiments in two mouse models of binge drinking -- either one large dose or three large doses given at 12-hour intervals -- and a model of chronic alcohol consumption -- steady alcohol consumption for 10 days. The results indicated that giving IAP either before or at the same time as an alcohol dose reduced levels of the ALT enzyme, a common sign of liver damage; reduced the accumulation of fat in the liver, the first sign of alcoholic liver disease; and reduced the production of inflammatory factors. While mice that did not receive the enzyme before or during an alcohol dose were found to have elevations in circulating LPS, decreased expression of the tight junction proteins that maintain the barrier function of the intestinal lining, and increased intestinal inflammation, IAP supplementation prevented those effects. Activation of the hepatic stellate cells, which recently have been shown to contribute to alcoholic fatty liver disease, was also prevented by pretreatment with IAP. Administering IAP after alcohol dosing had no protective effects. "Hepatic stellate cells are considered to be the central player in causing liver fibrosis -- scarring or cirrhosis -- which is the common endpoint leading to death in most liver diseases," says co-author Michael Choi, MD, of the MGH Gastrointestinal Unit. "Our results suggest that activated hepatic stellate cells are involved in even earlier stages of alcoholic liver disease and that activation can be prevented by pretreatment with IAP. Along with following up this study with human trials of IAP's protective effects, we also would like to know which gut bacterial components besides LPS are important in inducing liver inflammation, to understand more deeply the role of hepatic stellate cells in liver disease and to find ways to block their activation."


News Article | April 25, 2017
Site: www.eurekalert.org

An intestinal enzyme previously shown to keep bacterial toxins from passing from the gastrointestinal system into the bloodstream may be able to prevent or reduce the liver damage caused by excess alcohol consumption. In their report that will appear in the journal Digestive Diseases and Sciences and has been published online, a Massachusetts General Hospital (MGH) research team describes how oral doses of intestinal alkaline phosphatase (IAP) prevented the development of fatty liver in mouse models of both binge drinking and chronic alcohol consumption. The study also provides the first evidence of an expanded role of the liver's stellate cells in alcoholic liver disease. "Liver damage is one of the most devastating effects of excess alcohol consumption, and so blocking this process could save millions of lives lost to alcohol-related liver diseases such as cirrhosis and liver cancer," says Richard Hodin, MD, of the MGH Department of Surgery, the study's senior author. "Along with direct toxic effects on the liver itself, alcohol appears to damage the liver through its effects on the intestinal lining, allowing bacterial toxins from the gut to cross the barrier and reach the liver. Since we know that IAP works to maintain a healthy gut barrier by blocking passage of an important toxic molecule, we investigated its potential to protect the liver from alcohol-induce damage." Previous research by Hodin's group revealed that IAP helps to maintain a healthy intestinal microbial population by blocking the damaging effects of lipopolysaccharide (LPS), a molecule responsible for the toxic effects of several species of bacteria, and that the enzyme's anti-LPS effects could prevent the development of metabolic syndrome - a constellation of symptoms including obesity, abnormal glucose and lipid metabolism, and fatty liver - in mice fed a high-fat diet. Since LPS is known to play a role in alcohol-induced liver inflammation and its levels are known to rise with alcohol consumption, the MGH team investigated whether oral IAP supplementation could prevent alcoholic liver disease both by detoxifying the LPS released by gut bacteria and by preventing its passage from the gut into the liver's blood supply. The team conducted experiments in two mouse models of binge drinking - either one large dose or three large doses given at 12-hour intervals - and a model of chronic alcohol consumption - steady alcohol consumption for 10 days. The results indicated that giving IAP either before or at the same time as an alcohol dose reduced levels of the ALT enzyme, a common sign of liver damage; reduced the accumulation of fat in the liver, the first sign of alcoholic liver disease; and reduced the production of inflammatory factors. While mice that did not receive the enzyme before or during an alcohol dose were found to have elevations in circulating LPS, decreased expression of the tight junction proteins that maintain the barrier function of the intestinal lining, and increased intestinal inflammation, IAP supplementation prevented those effects. Activation of the hepatic stellate cells, which recently have been shown to contribute to alcoholic fatty liver disease, was also prevented by pretreatment with IAP. Administering IAP after alcohol dosing had no protective effects. "Hepatic stellate cells are considered to be the central player in causing liver fibrosis - scarring or cirrhosis - which is the common endpoint leading to death in most liver diseases," says co-author Michael Choi, MD, of the MGH Gastrointestinal Unit. "Our results suggest that activated hepatic stellate cells are involved in even earlier stages of alcoholic liver disease and that activation can be prevented by pretreatment with IAP. Along with following up this study with human trials of IAP's protective effects, we also would like to know which gut bacterial components besides LPS are important in inducing liver inflammation, to understand more deeply the role of hepatic stellate cells in liver disease and to find ways to block their activation." The co-lead authors of the Digestive Diseases and Sciences paper are Sulaiman Hamarneh, MD, MGH Department of Surgery; and Byeong-Moo Kim, PhD, MGH Gastrointestinal Unit. The study was supported by National Institutes of Health grants T32 DK007754 and P30 DK040561 and by the Ellison Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."


News Article | December 5, 2016
Site: www.eurekalert.org

Researchers from Massachusetts General Hospital (MGH) and the University of California, Riverside, have shown for the first time that RNA interference (RNAi) - an antiviral mechanism known to be used by plants and lower organisms - is active in the response of human cells to some important viruses. In their report receiving advance online publication in Nature Microbiology, the investigators document both the production of RNAi molecules in human cells infected with the influenza A virus and the suppression of RNAi defense by a viral protein known to block the process in a common animal model. "Viruses are the most abundant infectious agents and are a constant threat to human health," says Kate Jeffrey, PhD, of the Gastrointestinal Unit in the MGH Department of Medicine, co-corresponding author of the paper. "Vaccines are somewhat effective but can have limited use when viruses like influenza rapidly mutate from year to year. Identifying therapeutic targets within patients that could help them fight off an infection is a critical strategy for combating the spread of common, often-dangerous viruses." First described in the 1990s - a discovery that led to the 2006 Nobel Prize - RNAi is a process by which organisms suppress the expression of target genes through the action of small RNA segments that bind to corresponding gene sequences. Not only is RNAi used to regulate gene expression within an organism, it also can combat viral infection by silencing the activity of viral genes required for the pathogen's replication. Whether or not RNAi contributes to antiviral defense in mammals has been uncertain. The only previous demonstration - by researchers led by Shou-Wei Ding, PhD, a professor of Plant Pathology and Microbiology at UC Riverside and co-corresponding author of the current study - was done in embryonic stem cells and in newborn mice. Ding has been studying antiviral RNAi for more than two decades and also was the first to describe the action of the influenza virus protein NS1 in blocking RNAi in fruit flies. His team collaborated with investigators from Jeffrey's laboratory to investigate whether or not an RNAi response is induced in human and mouse cells infected with the influenza virus, one of many important viruses using RNA as its genetic material. Their experiments verified that influenza-A-infected mature human cells do generate the small RNA segments used in RNAi but that virally-produced NS1 blocks the processing of those molecules into the complexes that bind to and silence their target genes. If cells were infected with an influenza A mutant lacking NS1, they proceeded to produce large number of the molecular complexes required for RNAi, which include a protein called Argonaute that slices through the target gene. Experiments in cells with an inactivated form of Argonaute - which contributes only to the antiviral and not the gene regulation activity of RNAi - confirmed that they were observing an antiviral RNAi response. The observation that a viral protein called VP35, which is used by the Ebola and Marburg viruses to suppress RNAi, suggests that RNAi may also be active against those dangerous pathogens and other viruses that utilized RNA as their genetic code or in their replication cycle. "We now need to assess more directly the role of antiviral RNAi in human infectious diseases caused by RNA viruses - which include Ebola, West Nile and Zika along with influenza - and how harnessing or boosting the antiviral RNAi response could be used to reduce the severity of these infections," says Jeffrey, who is an assistant professor of Medicine at Harvard Medical School. "Bringing the expertise of Dr. Ding's team, which specializes in the RNAi biology of lower organisms, together with my group that specializes in mammalian immunology was a perfect match." The teams will continue to work together to investigate some of these questions. The co-lead authors of the Nature Microbiology paper are Yang Li, Jinfeng Lu and Shu-Wei Dong, University of California, Riverside; and Megha Basavappa, Massachusetts General Hospital. Additional co-authors are Alexander Cronkite, John Prior, Hans-Christian Reinecker and Sihem Cheloufi, MGH; Yanhong Han, Wan-Xiang Li and Fedor Karginov, UC Riverside; and Paul Hertzog, Hudson Institute of Medical Research, Victoria, Australia. Support for the study includes National Institutes of Health grants R01 AI107087, R01 AI52447 and R56 AI110579. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."


News Article | November 3, 2016
Site: www.eurekalert.org

A study led by investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and two academic medical centers in the Netherlands has begun to elucidate how differences in the gut microbiome - the microbial population of the gastrointestinal tract - affect the immune response in healthy individuals. The study is one of three related papers published in this week's issue of Cell, the other two looking at genetic and environmental influences, as part of the Human Functional Genomics Project (HFGP). "The underlying premise of the HFGP is that the immune system is a perfect target for studying human variation and the intersection of genes and the environment," says Ramnik Xavier, MD, PhD, chief of the MGH Gastrointestinal Unit, an institute member at the Broad and a principal investigator of the HFGP. "We know that some people are more susceptible to infections than others; some develop autoimmune diseases while most don't. In these studies we wanted to see how genes affect the immune system, how environmental factors affect susceptibility and in this investigation, whether and how the gut microbiome influences the immune system's response to various pathogens." The microbiome study - led by Xavier and Mihai Netea, MD, PhD, of Radboud University Medical Center in the Netherlands - analyzed blood and stool samples from 500 healthy Western European HFGP participants to look for individual variations in immune responses to pathogens, represented by production of molecules called cytokines; variations in the gut microbiome, and how those two factors relate to each other. Immune cells from individual participants were exposed to three bacterial stimulants - the commensal microbe B. fragilis, the common pathogen S. aureus, and a toxin produced by E. coli - and two forms of the Candida fungus. Their response was reflected in the production of cytokines, proteins through which immune cells exert many of their effects. Looking at possible relationships between immune responses and the microbiome in individual participants, the investigators found clear patterns by which both the population of the microbiome and its function, reflected in the production of proteins called metabolites, interact with the immune response. Some of those interactions depended on the particular pathogen, some on the cytokines, and some on both. Among the team's observations was how, depending on the specific pathogenic stimulus, breakdown of the amino acid tryptophan into the metabolite tryptophol can inhibit production of the cytokine TNF-alpha. They also identified an effect of palmitoleic acid - a fatty acid found in several dietary oils and known to suppress some immune activities - on production of the cytokine gamma interferon, although the precise mechanism is yet to be discovered. The Isselbacher Professor of Medicine in Gastroenterology at Harvard Medical School and a member of the MGH Center for Computational and Integrative Biology, Xavier says, "We still don't have all the components, but the overall picture suggests that variations in the gut microbiome change production of the metabolites that go on to educate or influence immune cells, leading to differential outcomes when immune cells are exposed to various infections." The accompanying studies, on which he is a co-author, found similar influences on immune response by environmental factors - including the season of the year as well as participants' age and gender - and most powerfully, by genetic differences. Among the next steps, Xavier notes, will be conducting similar studies in individuals with specific diseases and in participants from other parts of the world. "By understanding how all of these complex mechanisms - genetics, microbiome and environment - drive variations in the immune response, we may be able to identify factors responsible for individual patients' susceptibilities and better target therapies," he says. Melanie Schirmer, PhD, of the Broad Institute is lead author of the Cell paper. Additional co-authors are Hera Vlamakis, Eric Franzosa, and Curtis Huttenhower, Broad Institute; Sanne Smeekens Martin Jaeger, Marije Oosting, Trees Jansen, Liesbeth Jacobs and Leo Joosten, Radboud University Medical Center; and Marc Jan Bonder, Alexander Kurilshikov, Jingyuan Fu, Alexandra Zhernakova, and Cisca Wijmenga, University Medical Center, Groningen, the Netherlands. Support for the study includes National Institutes of Health grants U54DK102557 and R01DK092405, Juvenile Diabetes Research Foundation grant 17-2011-529, Crohn's and Colitis Foundation of America grant 20144126, and support from the Helmsley Charitable Trust Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."


News Article | November 4, 2016
Site: www.sciencedaily.com

A study led by investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and two academic medical centers in the Netherlands has begun to elucidate how differences in the gut microbiome -- the microbial population of the gastrointestinal tract -- affect the immune response in healthy individuals. The study is one of three related papers published in this week's issue of Cell, the other two looking at genetic and environmental influences, as part of the Human Functional Genomics Project (HFGP). "The underlying premise of the HFGP is that the immune system is a perfect target for studying human variation and the intersection of genes and the environment," says Ramnik Xavier, MD, PhD, chief of the MGH Gastrointestinal Unit, an institute member at the Broad and a principal investigator of the HFGP. "We know that some people are more susceptible to infections than others; some develop autoimmune diseases while most don't. In these studies we wanted to see how genes affect the immune system, how environmental factors affect susceptibility and in this investigation, whether and how the gut microbiome influences the immune system's response to various pathogens." The microbiome study -- led by Xavier and Mihai Netea, MD, PhD, of Radboud University Medical Center in the Netherlands -- analyzed blood and stool samples from 500 healthy Western European HFGP participants to look for individual variations in immune responses to pathogens, represented by production of molecules called cytokines; variations in the gut microbiome, and how those two factors relate to each other. Immune cells from individual participants were exposed to three bacterial stimulants -- the commensal microbe B. fragilis, the common pathogen S. aureus, and a toxin produced by E. coli -- and two forms of the Candida fungus. Their response was reflected in the production of cytokines, proteins through which immune cells exert many of their effects. Looking at possible relationships between immune responses and the microbiome in individual participants, the investigators found clear patterns by which both the population of the microbiome and its function, reflected in the production of proteins called metabolites, interact with the immune response. Some of those interactions depended on the particular pathogen, some on the cytokines, and some on both. Among the team's observations was how, depending on the specific pathogenic stimulus, breakdown of the amino acid tryptophan into the metabolite tryptophol can inhibit production of the cytokine TNF-alpha. They also identified an effect of palmitoleic acid -- a fatty acid found in several dietary oils and known to suppress some immune activities -- on production of the cytokine gamma interferon, although the precise mechanism is yet to be discovered. The Isselbacher Professor of Medicine in Gastroenterology at Harvard Medical School and a member of the MGH Center for Computational and Integrative Biology, Xavier says, "We still don't have all the components, but the overall picture suggests that variations in the gut microbiome change production of the metabolites that go on to educate or influence immune cells, leading to differential outcomes when immune cells are exposed to various infections." The accompanying studies, on which he is a co-author, found similar influences on immune response by environmental factors -- including the season of the year as well as participants' age and gender -- and most powerfully, by genetic differences. Among the next steps, Xavier notes, will be conducting similar studies in individuals with specific diseases and in participants from other parts of the world. "By understanding how all of these complex mechanisms -- genetics, microbiome and environment -- drive variations in the immune response, we may be able to identify factors responsible for individual patients' susceptibilities and better target therapies," he says.


Shimoyama S.,Gastrointestinal Unit
Hepato-Gastroenterology | Year: 2011

Background/Aims: Statin is the most promising agent in the improvement of blood lipid profiles, and a substantial risk reduction of subsequent cardiovascular events leads to a rapid increase in current prescription rates. However, statin use or a lower total cholesterol has been associated with an increased cancer risk, although some deny such an association. Whether a positive statincancer association exists or not remains a matter of debate because such a causal association, if any, may offset anticipated cardioprotective benefits from statins. So far, no statin-cancer association in gastric cancer has been systematically highlighted in the literature. Methodology: Original studies concerning the effect of statins on gastric cancer incidence were searched in PubMed Central published between 1993 and 2008. A manual search was additionally performed though reference lists in the retrieved manuscripts. Pooled gastric or upper gastrointestinal cancer risk ratio (RR) with 95% confidence interval (CI) was independently calculated by random effects model, provided by the Cochrane Library software Review Manager 5. Results: Six publications were considered finally eligible, three were for gastric cancer risk and three were for upper gastrointestinal cancer risk. Statin use proved no significant increase (RR; 1.37, 95% CI; 0.57-3.25) in gastric cancer risk, nor was there any evidence of increased risk (RR; 1.20, 95% CI; 0.94-1.53) even in upper gastrointestinal cancer. Conclusions: These results suggest that statins had no short-term effect on gastric or upper gastrointestinal cancer incidence. Further investigation of long-term associations between statin use and gastric cancer is warranted. © H.G.E. Update Medical Publishing S.A.


Purpose: Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies. Methods: Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins. Results: In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies. Conclusions: It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia. © 2011 Springer-Verlag.


Shimoyama S.,Gastrointestinal Unit
World Journal of Gastroenterology | Year: 2013

Aim: To investigate the association and quantify the relationship between diabetes mellitus (DM) and gastric cancer (GC) by an updated meta-analysis. Methods: The initial PubMed search identified 1233 publications. Studies not reporting GC or those not reporting actual number of GC were excluded. Twelve pertinent studies were retrieved from the PubMed database or from a manual search and considered for the meta-analysis. Pooled risk ratios and 95%CI were estimated by a random-effects model. Subgroup analysis was performed according to gender or geographical regions. Heterogeneity and publication bias were evaluated by I 2 and funnel plot analysis, respectively. Results: DM was significantly associated with GC with a RR of 1.41 (P = 0.006) (95%CI: 1.10-1.81). Subgroup analyses revealed that both sexes showed a significant association with GC, with a greater magnitude of risk in females (RR = 1.90; 95%CI: 1.27-2.85; P = 0.002) than in males (RR = 1.24; 95%CI: 1.08-1.43; P = 0.002). In addition, the link between DM and GC was significant in East Asian DM patients (RR = 1.77; 95%CI: 1.38-2.26; P < 0.00001) but not in Western DM patients (RR = 1.23; 95%CI: 0.90-1.68; P = 0.2). There was no evidence of publication bias, but the results indicated significant heterogeneity. Conclusion: This updated meta-analysis has provided evidence of positive DM-GC associations. The limited information on potentially important clinical confounding factors in each study deserves further investigation. © 2013 Baishideng. All rights reserved.

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