Walter and Eliza Hall Institute
Walter and Eliza Hall Institute
News Article | May 8, 2017
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 presentation of data demonstrating a novel method of identifying patients on a gluten-free diet with celiac disease. The study, conducted in collaboration with researchers from the Walter and Eliza Hall Institute, was presented in an oral presentation at Digestive Disease Week (DDW) 2017 in Chicago, Illinois. Celiac disease (CeD) is an immune-mediated gastrointestinal disease caused by dietary gluten predominantly in individuals who carry the human leukocyte antigen-DQ2.5 (HLA-DQ2.5) immune recognition gene, and shares key pathogenic and genetic features with organ-specific autoimmune diseases. Currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD). GFD is often adopted before evaluation for CeD, which renders current tests for CeD inaccurate and creates diagnostic and management uncertainty. Patients on a GFD who seek a diagnosis of CeD often refuse or cannot tolerate a gluten challenge for the duration typically needed for accurate results of tests for serological and histological markers of CeD. Because of this, a faster and more tolerable diagnostic is needed to identify patients on a gluten-free diet with celiac disease. “In this study, we have identified a distinct cytokine signature present in the serum of subjects with celiac disease 4 hours after the ingestion of gluten, suggesting that the measurement of serum cytokines following a single gluten challenge may allow for the identification of patients on a gluten-free diet with celiac disease,” said Dr. Bob Anderson, Chief Scientific Officer of ImmusanT. “We are hopeful that with additional studies, this could ultimately provide an improved alternative to current methods of testing for the diagnosis of celiac disease, which are cumbersome and often not well tolerated by the patient.” “Celiac disease is estimated to affect approximately 1% of the United States population, but over 80% of cases remain undiagnosed, as methods of diagnosis are invasive and inconvenient for patients,” said Leslie Williams, President and Chief Executive Officer of ImmusanT. “The study presented today provides rationale for continued development of this novel diagnostic method as we aim to provide a more sensitive, rapid and tolerable alternative to current tests for patients suffering from celiac disease.” In an oral presentation titled “Serum IL-2 and IL-8 are elevated within 4h after gluten ingestion in celiac disease (CeD) patients on glutenfree diet (GFD) – potential to resolve indeterminate diagnoses for patients on GFD,” Dr. Anderson presented data from a randomized, double-blind, placebo-controlled food challenge study that enrolled volunteers with HLA-DQ2.5+ celiac disease who were compliant with a gluten-free diet. In the study, 21 volunteers received either vital wheat gluten flour or a matched gluten-free flour drink over the course of 10 minutes. Serum chemokines and cytokines were measured 30 minutes prior to food challenge, then at four, six, and 24 hours after the challenge. Vital signs and patient-reported outcomes (CeD PRO) were recorded hourly. Results of the study demonstrated that, at 4 hours following food challenge, serum levels of the cytokine IL-8 were significantly higher after exposure to gluten than placebo (median fold change from baseline: gluten: 2.4 vs. placebo: 1.1, p=0.012). Serum levels of IL-2 were also significantly increased at 4 hours, confirming T-cell activation in response to gluten exposure (median fold change from baseline: gluten: 19.5 vs. placebo: 0.7, p=0.0001). 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. Digestive Disease Week® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 6-9, 2017, at McCormick Place, Chicago, IL. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at www.ddw.org. 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 | May 8, 2017
An international research team has revealed for the first time that testosterone protects males against developing asthma, helping to explain why females are two times more likely to develop asthma than males after puberty. The study showed that testosterone suppresses the production of a type of immune cell that triggers allergic asthma. The finding may lead to new, more targeted asthma treatments. One in nine Australians (2.5 million people) and around one in 12 Americans (25 million) have asthma, an inflammatory airway condition. During an asthma attack, the airways swell and narrow, making it difficult to breathe. In adults asthma is two times more prevalent and more severe in women than men, despite more being more common in boys than girls before puberty. In 2016, the city of Melbourne, Australia, experienced a 'thunderstorm asthma' event that was unprecedented internationally in its scale and severity of consequences, with almost 10,000 people visiting hospitals over a two-day period. Thunderstorm asthma refers to allergic asthma thought to be initiated by an allergy to grass pollen. Many people with no history of asthma experienced severe asthma attacks. Dr Cyril Seillet and Professor Gabrielle Belz from Melbourne's Walter and Eliza Hall Institute, with Dr Jean-Charles Guéry and his team at the Physiopathology Center of Toulouse-Purpan, France, led the study, published today in the Journal of Experimental Medicine. Dr Seillet said hormones were speculated to play a significant role in the incidence and severity of asthma in women. "There is a very interesting clinical observation that women are more affected and develop more severe asthma than men, and so we tried to understand why this was happening," Dr Seillet said. "Our research shows that high levels of testosterone in males protect them against the development of allergic asthma. We identified that testosterone is a potent inhibitor of innate lymphoid cells, a newly-described immune cell that has been associated with the initiation of asthma." The research team found that innate lymphoid cells - or ILC2s - 'sensed' testosterone and responded by halting production of the cells. "Testosterone directly acts on ILC2s by inhibiting their proliferation," Dr Seillet said. "So in males, you have less ILC2s in the lungs and this directly correlates with the reduced severity of asthma." ILC2s are found in the lungs, skin and other organs. These cells produce inflammatory proteins that can cause lung inflammation and damage in response to common triggers for allergic asthma, such as pollen, dust mites, cigarette smoke and pet hair. Professor Belz said understanding the mechanism that drives the sex differences in allergic asthma could lead to new treatments for the disease. "Current treatments for severe asthma, such as steroids, are very broad based and can have significant side effects," Professor Belz said. "This discovery provides us with a potential new way of treating asthma, by targeting the cells that are directly contributing to the development of allergic asthma. While more research needs to be done, it does open up the possibility of mimicking this hormonal regulation of ILC2 populations as a way of treating or preventing asthma. Similar tactics for targeting hormonal pathways have successfully been used for treating other diseases, such as breast cancer." A video related to this research can be found here. It is also under embargo for May 8th at 9 AM. This work was supported by the Australian National Health and Medical Research Council, the French National Center for Scientific Research, France, the French National Research Agency and the Victorian State Government Operational Infrastructure Support Program.
Robinson M.D.,Walter and Eliza Hall Institute |
Robinson M.D.,Garvan Institute of Medical Research |
Oshlack A.,Walter and Eliza Hall Institute
Genome Biology | Year: 2010
The fine detail provided by sequencing-based transcriptome surveys suggests that RNA-seq is likely to become the platform of choice for interrogating steady state RNA. In order to discover biologically important changes in expression, we show that normalization continues to be an essential step in the analysis. We outline a simple and effective method for performing normalization and show dramatically improved results for inferring differential expression in simulated and publicly available data sets. © 2010 Robinson and Oshlack; licensee BioMed Central Ltd.
Benjamini Y.,University of California at Berkeley |
Speed T.P.,University of California at Berkeley |
Speed T.P.,Walter and Eliza Hall Institute
Nucleic Acids Research | Year: 2012
GC content bias describes the dependence between fragment count (read coverage) and GC content found in Illumina sequencing data. This bias can dominate the signal of interest for analyses that focus on measuring fragment abundance within a genome, such as copy number estimation (DNA-seq). The bias is not consistent between samples; and there is no consensus as to the best methods to remove it in a single sample. We analyze regularities in the GC bias patterns, and find a compact description for this unimodal curve family. It is the GC content of the full DNA fragment, not only the sequenced read, that most influences fragment count. This GC effect is unimodal: both GC-rich fragments and AT-rich fragments are underrepresented in the sequencing results. This empirical evidence strengthens the hypothesis that PCR is the most important cause of the GC bias. We propose a model that produces predictions at the base pair level, allowing strand-specific GC-effect correction regardless of the downstream smoothing or binning. These GC modeling considerations can inform other high-throughput sequencing analyses such as ChIP-seq and RNA-seq. © 2011 The Author(s).
Blewitt M.,Walter and Eliza Hall Institute
Cold Spring Harbor perspectives in biology | Year: 2013
Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising from endogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes.
Buchert M.,Walter and Eliza Hall Institute
Oncogene | Year: 2015
Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.150. © 2015 Macmillan Publishers Limited
Huntington N.D.,Walter and Eliza Hall Institute
Immunology and Cell Biology | Year: 2014
Natural killer (NK) cells are the founding members of the innate lymphoid cell family and contribute to the rapid production of inflammatory mediators upon pathogen detection. The evolution of receptors for self major histocompatibility complex-I and stress-induced ligands also bestows upon NK cells an important effector role in the clearance of virus-infected and transformed cells. NK cells are dependent on the pleiotropic cytokine interleukin (IL)-15 for their development, differentiation and optimal function. Here I review the regulation of IL-15 in vivo, its role in driving NK cell differentiation and discuss the function of NK cell diversification with regard to innate immunity. © 2014 Australasian Society for Immunology Inc.
Tarlinton D.,Walter and Eliza Hall Institute
Current Biology | Year: 2012
Three recent papers provide striking insight into the mechanisms used to regulate B-cell differentiation. They demonstrate that B-cell fate choice can be stochastic, directed, inherited, or some combination of these, depending on the circumstances. The trick is going to be working out which is important when. © 2012 Elsevier Ltd.
Silke J.,Walter and Eliza Hall Institute
Current Opinion in Immunology | Year: 2011
In the past 2 years there has been an explosion of information regarding molecules that regulate TNF-R1 signalling, and even reviews published in 2010 are out of date. TNF-R1 activation of NF-κB is a text book example of a signal transduction pathway regulated by ubiquitin and many of the concepts concerning the different roles of ubiquitin chains were first outlined in TNF-R1 signalling. What was once a very simple pathway with clearly defined roles for ubiquitin in regulating TNF-R1 signalling has, however, now become so complicated that we have 'an embarrassment of riches' . The less polite might claim our pathways of TNF-R1 signalling look as complicated as a web constructed by a drug-addled spider . This review will pick apart only one small strand of the web, and will address the role of ubiquitin in the activation of NF-κB by TNF with a focus on interpreting in vivo results. Nevertheless some of the concepts, for example the role of linear ubiquitin chains in regulating signalling, may be applicable to the family in general. © 2011 Elsevier Ltd.
Vaux D.L.,Walter and Eliza Hall Institute
Annual review of cell and developmental biology | Year: 2014
The physicist Ernest Rutherford said, "If your experiment needs statistics, you ought to have done a better experiment." Although this aphorism remains true for much of today's research in cell biology, a basic understanding of statistics can be useful to cell biologists to help in monitoring the conduct of their experiments, in interpreting the results, in presenting them in publications, and when critically evaluating research by others. However, training in statistics is often focused on the sophisticated needs of clinical researchers, psychologists, and epidemiologists, whose conclusions depend wholly on statistics, rather than the practical needs of cell biologists, whose experiments often provide evidence that is not statistical in nature. This review describes some of the basic statistical principles that may be of use to experimental biologists, but it does not cover the sophisticated statistics needed for papers that contain evidence of no other kind.