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Angels Camp, CA, United States

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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.


News Article | May 10, 2017
Site: www.eurekalert.org

Revelations about a protein expressed in fetal cells could provide novel insights into its function and future immunosuppressive therapies. Researchers at Hokkaido University together with colleagues in Japan have uncovered the structure of a protein that protects embryos from being attacked by their mothers' immune system. Further understanding of this protein could give rise to immunosuppressive therapies. Trophoblasts are cells found in the outer layer of the developing embryo that form part of the placenta. They express a type of protein called human leukocyte antigens-G (HLA-G) which interacts with receptors on the maternal cells to suppress immune responses to the embryo during pregnancy. The structures of HLA-G1, the major form of HLA-G, are well understood. Interestingly, individuals whose cells lack HLA-G1 could be born and healthy. Researchers believe this is because they can express another form, HLA-G2, which should compensate for the loss of the former's function. But the structure of HLA-G2 has been largely unknown. In a study published in the Journal of Immunology, the team investigated the structure of HLA-G2 by a single particle electron microscopy. Surprisingly, the structure of HLA-G2 was completely different from HLA-G1, but was similar to another class of human leukocyte antigens called HLA class II. This suggests that the HLA-G gene evolved from the same ancestral gene as HLA class II. They also found that HLA-G2 make pairs called homodimers which strengthen the binding to the receptors. HLA-G1 is also known to form homodimers but in a different manner. Furthermore, their biochemical analysis revealed that HLA-G2 bound strongly to a leukocyte immunoglobulin-like receptor B2 (LILRB2), but not to LILRB1. By contrast, HLA-G1 binds strongly to both receptors. Previous research by the Hokkaido University team showed that, in addition to its protective role during pregnancy, the HLA-G2 protein had an anti-inflammatory effect when injected into collagen-induced arthritis mice. "A narrower target specificity of HLA-G2 could be advantageous in developing immunosuppressive drugs with less side-effects. We suggest further investigations to elucidate the structure of the HLA-receptor complex for a more precise understanding of this interaction," says Katumi Maenaka, the corresponding author at Hokkaido University.


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 | May 10, 2017
Site: www.sciencedaily.com

A new study has generated the first comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes that regulate the body's immune system.


The blood group typing market is projected to reach USD 3.12 billion by 2021 from USD 1.95 billion in 2016, at a CAGR of 9.8%. Growth in the blood group typing market is primarily attributed to the increasing demand for blood and blood products, growing number of road accidents and trauma cases that necessitate blood transfusion, need for blood grouping during prenatal testing, and increasing usage of blood group typing in forensic sciences. Stringent regulatory standards for blood transfusion are also expected to fuel the growth of the blood group typing market during the forecast period. Based on product and service, the market is segmented into consumables, instruments, and services. The consumables segment is further categorized into antisera reagents, anti-human globulin reagents, red blood cells reagents, and blood bank saline. The consumables segment is expected to grow at the highest CAGR during the forecast period. The increase in blood donation rates and major surgical procedures (including organ transplant procedures) are the key factors driving the growth of this segment. Based on test type, the market is segmented into antibody screening, HLA typing, cross-matching tests, ABO blood tests, and antigen typing. The antibody screening segment is expected to grow at the highest CAGR during the forecast period. The growth of this market segment is primarily driven by the increasing prevalence of chronic disorders and growing demand for the early diagnosis of diseases. Key Topics Covered: 1 Introduction 2 Research Methodology 3 Executive Summary 4 Premium Insights 5 Market Overview 6 Blood Group Typing Market, By Product and Service 7 Blood Group Typing Market, By Technique 8 Blood Group Typing Market, By Test Type  9 Blood Group Typing Market, By End User 10 Blood Group Typing Market, By Region 11 Competitive Landscape 12 Company Profiles 13 Appendix For more information about this report visit http://www.researchandmarkets.com/research/8vhgc9/blood_group To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/blood-group-typing-market-to-reach-3-billion-by-2021---rising-need-for-blood-grouping-during-prenatal-testing---research-and-markets-300455371.html


News Article | May 10, 2017
Site: www.eurekalert.org

A study led by researchers at Vanderbilt University Medical Center (VUMC) and the University of Arizona College of Pharmacy has generated the first comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes that regulate the body's immune system. The catalog could help identify individuals who are at risk for certain autoimmune diseases, or who may generate antibodies that attack their own tissues in response to an infection. The report, published in this week's issue of the journal Science Translational Medicine, supports the power of electronic health records (EHRs) to advance understanding, treatment and ultimately prevention of disease, said senior author Joshua Denny, M.D., M.S., professor of Biomedical Informatics and Medicine at Vanderbilt. The report confirmed a slew of previously described associations and identified some potential new associations. "In one fell swoop we essentially replicated decades of research on autoimmune associations with the HLA," said Jason Karnes, Ph.D., Pharm.D., co-first author of the paper with Lisa Bastarache, M.S. The researchers published the catalog online at http://www. . "To my knowledge no other investigations have made this level of data available" to the wider research community, Karnes said. Karnes is an assistant professor in the University of Arizona College of Pharmacy in Tucson. He contributed to the study as a former postdoctoral fellow in Clinical Pharmacology at Vanderbilt. Bastarache is lead data scientist in the Vanderbilt Center for Precision Medicine, which Denny directs. HLAs (human leukocyte antigens) are proteins expressed on the surfaces of cells that -- like nametags -- enable the immune system to distinguish "self" tissues of the body from "non-self," such as invading pathogens. Individual variations in HLA genes also have been linked to adverse drug reactions, rejection of transplanted organs and autoimmune diseases including type 1 diabetes and rheumatoid arthritis, in which the immune system mistakes normal tissue for a foreign invader and attacks it. Previous studies have identified associations between the HLA system and individual "phenotypes," including autoimmune and other diseases, symptoms and other characteristics. The current investigation -- called a "phenome-wide association study" or PheWAS -- scanned patients' entire "phenome" of all health characteristics as noted in the EHR. Prior studies have typically studied only one or a handful of diseases at a time. By studying many diseases at once this study was able to show that many HLA types affect multiple diseases but in different ways. For example, some HLA types place a person at risk for both type1 diabetes and rheumatoid arthritis, while others place one at risk for type 1 diabetes but protected against rheumatoid arthritis. The study was made possible by DNA databases maintained at VUMC and the Marshfield Clinic Personalized Medicine Research Project in Marshfield, Wisconsin. To date, more than 230,000 samples from different individuals have been stored in BioVU, Vanderbilt's massive DNA database. Genetic samples are linked to the corresponding EHRs in which identifying information has been deleted to protect patient privacy. From the genetic code, the researchers inferred which HLAs would be expected to be expressed in nearly 29,000 individuals whose DNA samples were stored in BioVU and another 8,400 samples provided by Scott Hebbring, Ph.D., and colleagues from the Marshfield Clinic. The EHRs from these individuals were screened for the presence of nearly 1,400 different phenotypes that could be linked to the HLA genes. Type 1 diabetes was the strongest previously described HLA association confirmed by the study but the researchers also found evidence for several new potential associations with multiple sclerosis and cervical cancer. The latter is known to be driven by a viral infection. It's thought that people with certain HLA variants may -- in response to an infection, for example -- generate antibodies that attack their own tissues, Denny said. This suggests that certain auto-immune diseases could be prevented in high-risk people by identifying and treating their co-infections first, he said. Denny directs the Data and Research Center of the federal All of Us Research Program, formerly the Precision Medicine Initiative Cohort Program, which is recruiting a million or more Americans for a landmark study of genetic, environmental and lifestyle factors that affect their health. "Just imagine what we'll be able to do with a million people," he said. "That will produce truly comprehensive catalogs of all these kinds of associations across HLA and everything else. The detail with which we'll be able to resolve these questions will be staggering." Other Vanderbilt faculty members who contributed to the current study were Elizabeth Phillips, M.D., Dan Roden, M.D., and Simon Mallal, MBBS.


Patients who were included in the study all had Goodpasture disease and fulfilled the following key diagnostic criteria: (1) serum anti-α3(IV)NC1 IgG by enzyme-linked immunosorbent assay (ELISA), (2) linear IgG staining of the GBM and (3) necrotizing and crescentic glomerulonephritis. HLA-DR15 typing of patients was done by monoclonal antibody staining (BIH0596, One Lambda) and flow cytometry. Blood from HLA-typed healthy humans was collected via the Australian Bone Marrow Donor Registry. HLA-DR15, HLA-DR1 and HLA-DR15/DR1 donors were molecularly typed and were excluded if they expressed DQB1*03:02, which is potentially weakly associated with susceptibility to anti-GBM disease2. Studies were approved by the Australian Bone Marrow Donor Registry and Monash Health Research Ethics Committees, and informed consent was obtained from each individual. Mouse MHCII deficient, DR15 transgenic mice and mouse MHCII deficient, DR1 transgenic mice were derived from existing HLA transgenic colonies and intercrossed so that they were on the same background as previously described4. The background was as follows: 50% C57BL/10, 43.8% C57BL/6, 6.2% DBA/2; or with an Fcgr2b−/− background: 72% C57BL/6, 25% C57BL/10 and 3% DBA/2. To generate mice transgenic for both HLA-DR15 and HLA-DR1, mice transgenic for either HLA-DR15 or HLA-DR1 were intercrossed. FcγRIIb intact HLA transgenic mice and cells were used for all experiments, except those in experimental Goodpasture disease, where Fcgr2b−/− HLA transgenic strains were used. While DR15+ mice readily break tolerance to α3(IV)NC1 when immunized with human α3 or mouse α3 , renal disease is mild4. As genetic changes in fragment crystallizable (Fc) receptors have been implicated in the development of nephritis in rodents and in humans18, Fcgr2b−/− HLA transgenic strains were used when end organ injury was an important endpoint. For in vitro experiments, cells from either male or female mice were used. For in vivo experiments both male and female mice were used, for immunization aged 8–12 weeks and for the induction of experimental Goodpasture disease aged 8–10 weeks. Experiments were approved by the Monash University Animal Ethics Committee (MMCB2011/05 and MMCB2013/21). HLA-DR15-α3 and HLA-DR1-α3 were produced in High Five insect cells (Trichoplusia ni BTI-Tn-5B1-4 cells, Invitrogen) using the baculovirus expression system essentially as described previously for HLA-DQ2/DQ8 proteins19, 20. Briefly, synthetic DNA (Integrated DNA Technologies, Iowa, USA) encoding the α- and β-chain extracellular domains of HLA-DR15 (HLA-DR1A*0101, HLA-DRB1*15:01), HLA-DR1 (HLA-DR1A*0101, HLA-DRB1*01:01) and the α3 peptide were cloned into the pZIP3 baculovirus vector19, 20. To promote correct pairing, the carboxy (C) termini of the HLA-DR15 and HLA-DR1 α- and β-chain encoded enterokinase cleavable Fos and Jun leucine zippers, respectively. The β-chains also encoded a C-terminal BirA ligase recognition sequence for biotinylation and a poly-histidine tag for purification. HLA-DR15-α3 and HLA-DR1-α3 were purified from baculovirus-infected High Five insect cell supernatants through successive steps of immobilized metal ion affinity (Ni Sepharose 6 Fast-Flow, GE Healthcare), size exclusion (S200 Superdex 16/600, GE Healthcare) and anion exchange (HiTrap Q HP, GE Healthcare) chromatography. For crystallization, the leucine zipper and associated tags were removed by enterokinase digestion (Genscript, New Jersey, USA) further purified by anion exchange chromatography, buffer exchanged into 10 mM Tris, pH 8.0, 150 mM NaCl and concentrated to 7 mg ml−1. Purified HLA-DR15-α3 and HLA-DR1-α3 proteins were buffer exchanged into 10 mM Tris pH 8.0, biotinylated using BirA ligase and tetramers assembled by addition of Streptavidin-PE (BD Biosciences) as previously described19. In mice, 107 splenocytes or cells from kidneys were digested with 5 mg ml−1 collagenase D (Roche Diagnostics, Indianapolis, Indiana, USA) and 100 mg ml−1 DNase I (Roche Diagnostics) in HBBS (Sigma-Aldrich) for 30 min at 37 °C, then filtered, erythrocytes lysed and the CD45+ leukocyte population isolated by MACS using mouse CD45 microbeads (Miltenyi Biotec); they were then surface stained with Pacific Blue-labelled anti-mouse CD4 (BD), antigen-presenting cell (APC)-Cy7-labelled anti-mouse CD8 (BioLegend) and 10 nM PE-labelled tetramer. Cells were then incubated with a Live/Dead fixable Near IR Dead Cell Stain (Thermo Scientific), permeabilized using a Foxp3 Fix/Perm Buffer Set (BioLegend) and stained with Alexa Fluor 647-labelled anti-mouse Foxp3 antibody (FJK16 s). To determine Vα2 and Vβ6 usage, cells were stained with PerCP/Cy5.5 anti-mouse Vα2 (B20.1, Biolegend) and antigen-presenting cell labelled anti-mouse Vβ6 (RR4-7, Biolegend). For each mouse a minimum of 100 cells were analysed. The tetramer+ gate was set on the basis of the CD8+ population. In humans, 3 × 107 white blood cells were surface stained with BV510-labelled anti-human CD3 (BioLegend), Pacific Blue-labelled anti-human CD4 (BioLegend), PE-Cy7-labelled anti-human CD127 (BioLegend), FITC-labelled anti-human CD25 (BioLegend) and 10 nM PE-labelled tetramer. Then, cells were incubated with a Live/Dead fixable Near IR Dead Cell Stain (Life Technologies), permeabilized using a Foxp3 Fix/Perm Buffer Set (BioLegend) and stained with Alexa Fluor 647-labelled anti-human Foxp3 antibody (150D). The tetramer+ gate was set on the basis of the CD3+CD4− population. As validation controls, we found that HLA-DR1-α3 tetramer+ cells did not bind to HLA-DR1-CLIP tetramers (data not shown). The human α3 peptide (GWISLWKGFSF), the mouse α3 peptide (DWVSLWKGFSF) and control OVA peptide (ISQAVHAAHAEINEAGR) were synthesized at >95% purity, confirmed by high-performance liquid chromatography (Mimotopes). Recombinant murine α3(IV)NC1 was generated using a baculovirus system21 and recombinant human α3(IV)NC1 expressed in HEK 293 cells22. The murine α3(IV)NC1 peptide library, which consists of 28 20-amino-acid long peptides overlapping by 12 amino acids, was synthesized as a PepSet (Mimotopes). To measure peptide specific recall responses, IFN-γ and IL-17A ELISPOTs and [3H]thymidine proliferation assays were used (Mabtech for human ELISPOTs and BD Biosciences for mouse ELISPOTs). To measure pro-inflammatory responses of HLA-DR15-α3 tetramer+ CD4+ T cells in patients with Goodpasture disease, HLA-DR15-α3 tetramer+ CD4+ T cells were enumerated then isolated from peripheral blood mononuclear cells of patients with Goodpasture disease (frozen at the time of presentation) by magnetic bead separation (Miltenyi Biotec) then co-cultured at a frequency of 400 HLA-DR15-α3 tetramer+ CD4+ T cells per well with 2 × 106 HLA-DR15-α3 tetramer-depleted mitomycin C-treated white blood cells and stimulated with either no antigens, α3 (10 μg ml−1) or whole recombinant human α3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% male AB serum, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin) (Sigma-Aldrich). Cells were cultured for 18 h at 37 °C, 5% CO and the data expressed as numbers of IFN-γ or IL-17A spots per well. To measure pro-inflammatory responses of HLA-DR15-α3 tetramer+ CD4+ T cells in DR15+ transgenic mice, HLA-DR15-α3 tetramer+ CD4+ T cells were enumerated then isolated from pooled spleen and lymph node cells of DR15+ transgenic mice, immunized with mouse α3 10 days previously by magnetic bead separation. They were then co-cultured at a frequency of 400 HLA-DR15-α3 tetramer+ CD4+ T cells per well with 106 HLA-DR15-α3 tetramer-depleted mitomycin C-treated white blood cells and stimulated with either no antigens, mouse α3 (10 μg ml−1), human α3 (10 μg ml−1), whole recombinant mα3(IV)NC1 (10 μg ml−1) or whole recombinant hα3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin). Cells were cultured for 18 h at 37 °C, 5% CO and the data expressed as numbers of IFN-γ or IL-17A spots per well. To determine the immunogenic portions of α3(IV)NC1, mice were immunized subcutaneously with peptide pools (containing α3 amino acids 1–92, 81–164, or 153–233; 10 μg per peptide per mouse), the individual peptide or in some experiments mα3 at 10 μg per mouse in Freund’s complete adjuvant (Sigma-Aldrich). Draining lymph node cells were harvested 10 days after immunization and stimulated in vitro (5 × 105 cells per well) with no antigen, peptide (10 μg ml−1) or whole α3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml streptomycin). For [3H]thymidine proliferation assays, cells were cultured in triplicate for 72 h with [3H]thymidine added to culture for the last 16 h. To measure human α3 - or mouse α3 -specific responses in CD4+ T cells from naive transgenic mice or blood of healthy humans, we used a modification of a previously published protocol23. One million CD4+ T cells were cultured with 106 mitomycin-treated CD4-depleted splenocytes for 8 days in 96-well plates with or without 100 μg ml−1 of human α3 or mouse α3 . T cells were depleted from mouse cultures by sorting out CD4+CD25+ and in humans by sorting out CD4+CD25hiCD127lo cells using antibodies and a cell sorter. Cytokine secretion was detected in the cultured supernatants by cytometric bead array (BD Biosciences) or ELISA (R&D Systems). To determine proliferation, magnetically separated CD4+ T cells were labelled with CellTrace Violet (CTV; Thermo Scientific) before culture. To measure the expansion of T cells, mice were immunized with 100 μg of α3 emulsified in Freund’s complete adjuvant, then boosted 7 days later in Freund’s incomplete adjuvant. Draining lymph node cells were stained with the HLA-DR15-α3 tetramer, CD3, CD4, CXCR5, PD-1, CD8 and Live/Dead Viability dye. To determine the potency of HLA-DR1-α3 tetramer+ T cells, 106 cells per well of CD4+CD25− T effectors isolated by CD4+ magnetic beads and CD25− cell sorting from naive DR15+DR1+ mice were co-cultured with CD4+CD25+ T cells with or without depletion of HLA-DR1-α3 tetramer+ T cells from DR1+ mice at different concentrations: 0, 12.5 × 103, 25 × 103, 50 × 103 and 100 × 103 cells per well in the presence of 106 CD4-depleted mitomycin C-treated spleen and lymph node cells from DR15+DR1+mice in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin) containing 100 μg ml−1 of mouse α3 . To determine proliferation, the CD4+CD25− T effector cells were labelled with CTV before culture. Cells were cultured in triplicate for 8 days in 96-well plates. HLA transgenic mice, on an Fcgr2b−/− background, were immunized with 100 μg of α3 or mα3 subcutaneously on days 0, 7 and 14, first in Freund’s complete, and then in Freund’s incomplete, adjuvant. Mice were killed on day 42. Albuminuria was assessed in urine collected during the last 24 h by ELISA (Bethyl Laboratories) and expressed as milligrams per micromole of urine creatinine. Blood urea nitrogen and urine creatinine were measured using an autoanalyser at Monash Health. Glomerular necrosis and crescent formation were assessed on periodic acid-Schiff (PAS)-stained sections; fibrin deposition using anti-murine fibrinogen antibody (R-4025) and DAB (Sigma); CD4+ T cells, macrophages and neutrophils were detected using anti-CD4 (GK1.5), anti-CD68 (FA/11) and anti-Gr-1 (RB6-8C5) antibodies. The investigators were not blinded to allocation during experiments and outcome assessment, except in histological and immunohistochemical assessment of kidney sections. To deplete regulatory T cells, mice were injected intraperitoneally with 1 mg of an anti-CD25 monoclonal antibody (clone PC61) or rat IgG (control) 2 days before induction of disease. In these experiments, mice were randomly assigned to receive control or anti-CD25 antibodies. Individual DR15-α3 -specific CD4+ T cells were sorted into wells of a 96-well plate. Multiplex single-cell reverse transcription and PCR amplification of TCR CDR3α and CDR3β regions were performed using a panel of TRBV- and TRAV-specific oligonucleotides, as described24, 25. Briefly, mRNA was reverse transcribed in 2.5 μl using a Superscript III VILO cDNA Synthesis Kit (Thermo Fisher Scientific, Waltham, Massachusetts, USA) (containing 1× Vilo reaction mix, 1× superscript RT, 0.1% Triton X-100), and incubated at 25 °C for 10 min, 42 °C for 120 min and 85 °C for 5 min. The entire volume was then used in a 25 μl first-round PCR reaction with 1.5 U Taq DNA polymerase, 1× PCR buffer, 1.5 mM MgCl , 0.25 mM dNTPs and a mix of 25 mouse TRAV or 40 human TRAV external sense primers and a TRAC external antisense primer, along with 19 mouse TRBV or 28 human TRBV external sense primers and a TRBC external antisense primer (each at 5 pmol μl−1), using standard PCR conditions. For the second-round nested PCR, a 2.5 μl aliquot of the first-round PCR product was used in separate TRBV- and TRAV-specific PCRs, using the same reaction mix described above; however, a set of 25 mouse TRAV or 40 human TRAV internal sense primers and a TRAC internal antisense primer, or a set of 19 mouse TRBV or 28 human TRBV internal sense primers and a TRBV internal antisense primer, were used. Second-round PCR products were visualized on a gel and positive reactions were purified with ExoSAP-IT reagent. Purified products were used as template in sequencing reactions with internal TRAC or TRBC antisense primers, as described. TCR gene segments were assigned using the IMGT (International ImMunoGeneTics) database26. In mouse experiments, three mice were pooled per HLA and the number of sequences obtained were as follows. For TRAV: DR15, n = 81; DR1 n = 84; for TRBV: DR15, n = 100; DR1 n = 87; for TRAJ: DR15, n = 81; DR1 n = 84; and for TCR beta joining (TRBJ): DR15, n = 100; DR1 n = 87. Red-blood-cell-lysed splenocytes from DR1+ and DRB15+DR1+ mice were sorted on the basis of surface expression of CD4 and CD25 and being either DR1-α3 tetramer positive or negative into three groups: (1) CD4+CD25−HLA-DR1-α3 tetramer− T cells; (2) CD4+CD25+HLA-DR1-α3 tetramer− T cells; and (3) CD4+CD25+HLA-DR1-α3 tetramer+ T cells. A minimum of 1,000 cells were sorted. Immediately after sorting, the RNA was isolated and complementary DNA (cDNA) generated using a Cells to Ct Kit (Ambion) followed by a preamplification reaction using Taqman Pre Amp Master Mix (Applied Biosystems), which preamplified the following cDNAs: Il2ra, Foxp3, Ctla4, Tnfrsf18, Il7r, Sell, Pdcd1, Entpd1, Cd44, Tgfb3, Itgae, Ccr6, Lag3, Lgals1, Ikzf2, Tnfrsf25, Nrp1, Il10. The preamplified cDNA was used for RT–PCR reactions in duplicate using Taqman probes for the aforementioned genes. Each gene was expressed relative to 18S, logarithmically transformed and presented as a heat map. The Epstein-Barr-virus-transformed human B lymphoblastoid cell lines IHW09013 (SCHU, DR15-DR51-DQ6) and IHW09004 (JESTHOM, DR1-DQ5) were maintained in RPMI (Invitrogen) supplemented with 10% FCS, 50 IU ml−1 penicillin and 50 μg ml−1 streptomycin. Confirmatory tissue typing of these cells was performed by the Victorian Transplantation and Immunogenetics Service. The B-cell hybridoma LB3.1 (anti-DR) was grown in RPMI-1640 with 5% FCS at 37 °C and secreted antibody purified using protein A sepharose (BioRad). HLA-DR-presented peptides were isolated from naive DR15+Fcgr2b+/+ or DR1+Fcgr2b+/+ mice. Spleens and lymph nodes (pooled from five mice in each group) or frozen pellets of human B lymphoblastoid cell lines (triplicate samples of 109 cells) were cryogenically milled and solubilized as previously described12, 27, cleared by ultracentrifugation and MHC peptide complexes purified using LB3.1 coupled to protein A (GE Healthcare). Bound HLA complexes were eluted from each column by acidification with 10% acetic acid. The eluted mixture of peptides and HLA heavy chains was fractionated by reversed-phase high-performance liquid chromatography as previously described10. Peptide-containing fractions were analysed by nano-liquid chromatography–tandem mass spectrometry (nano-LC–MS/MS) using a ThermoFisher Q-Exactive Plus mass spectrometer (ThermoFisher Scientific, Bremen, Germany) operated as described previously10. LC–MS/MS data were searched against mouse or human proteomes (Uniprot/Swissprot v2016_11) using ProteinPilot software (SCIEX) and resulting peptide identities subjected to strict bioinformatic criteria including the use of a decoy database to calculate the false discovery rate28. A 5% false discovery rate cut-off was applied, and the filtered data set was further analysed manually to exclude redundant peptides and known contaminants as previously described29. The mass spectrometry data have been deposited in the ProteomeXchange Consortium via the PRIDE30 partner repository with the data set identifier PXD005935. Minimal core sequences found within nested sets of peptides with either N- or C-terminal extensions were extracted and aligned using MEME (http://meme.nbcr.net/meme/), where motif width was set to 9–15 and motif distribution to ‘one per sequence’31. Graphical representation of the motif was generated using IceLogo32. Crystal trials were set up at 20 °C using the hanging drop vapour diffusion method. Crystals of HLA-DR15-α3 were grown in 25% PEG 3350, 0.2 M KNO and 0.1 M Bis-Tris-propane (pH 7.5), and crystals of HLA-DR1-α3 were grown in 23% PEG 3350, 0.1 M KNO , and 0.1 M Bis-Tris-propane (pH 7.0). Crystals were washed with mother liquor supplemented with 20% ethylene glycol and flash frozen in liquid nitrogen before data collection. Data were collected using the MX1 (ref. 33) and MX2 beamlines at the Australian Synchrotron, and processed with iMosflm and Scala from the CCP4 program suite34. The structures were solved by molecular replacement in PHASER35 and refined by iterative rounds of model building using COOT36 and restrained refinement using Phenix37 (see Extended Data Table 2 for data collection and refinement statistics). No statistical methods were used to predetermine sample size. For normally distributed data, an unpaired two-tailed t-test (when comparing two groups). For non-normally distributed data, non-parametric tests (Mann–Whitney U-test for two groups or a Kruskal–Wallis test with Dunn’s multiple comparison) were used. Statistical analyses, except for TCR usage, was by GraphPad Prism (GraphPad Software). For each TCR type/region (TRAV, TRBV, TRAJ, TRBJ), we compared the TCR distribution (frequencies of different TCRs) between DR15 and DR1 using Fisher’s exact test. This was applied both to mice and to human samples. The P values associated with those TCR distributions are indicated above the pie-charts. To correct for multiple testing for individual TCRs, we used Holm’s method. *P < 0.05, **P < 0.01, ***P < 0.001. The data that support the findings of this study are available from the corresponding authors upon request. Self-peptide repertoires have been deposited in the Proteomics Identifications Database archive with the accession code PXD005935. Structural information has been deposited in the Protein Data Bank under accession numbers 5V4M and 5V4N.


News Article | May 1, 2017
Site: www.eurekalert.org

Paris, France - 1 May 2017: The risk of heart transplant rejection can be reduced by desensitising patient antibodies, according to research presented today at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure.1 The breakthrough comes on the 50th anniversary of heart transplantation. Before heart transplantation the serum of heart transplant candidates is tested for levels of anti-human leukocyte antigen (HLA) which could bind to donor HLA antigens and cause rejection of the organ. At the time of transplantation, a virtual crossmatch is conducted to determine if the patient's anti-HLA antibodies are directed against the donor's specific HLA antigen -- if yes, they are called "donor specific anti-HLA antibody" (DSA). "Most centres do not perform heart transplantation in patients with a high DSA level since the risk of antibody-mediated rejection is high, particularly hyper-acute rejection," said lead author Dr Guillaume Coutance, a cardiologist at Pitié-Salpêtrière Hospital in Paris, France. "Patients then have to wait for a donor with different HLA antigens." To reduce the chance of rejection in these patients at high immunological risk, in 2009 Pitié-Salpêtrière Hospital began a desensitisation programme. The current study analysed the impact of the programme on survival after heart transplantations performed during 2009 to 2015. The type of desensitisation patients receive depends on their DSA level, which is measured by mean fluorescence intensity (MFI). An MFI between 500 and 1000 is considered "low DSA" and an MFI above 1000 is considered "high DSA". All patients receive anti-thymocyte globulins and conventional immunosuppressive therapy (calcineurin inhibitors, mycophenolate mofetil, and corticosteroids). On top of this, patients with low DSA levels receive intravenous immunoglobulins. Patients with high DSA levels are treated with plasmapheresis before and after transplantation, followed by intravenous immunoglobulins after the complete cycle of plasmapheresis. The study included 523 patients who were 50 years old on average and 77% were men. Nearly half (46%) of patients had no DSA, 17% had low DSA, and 37% had high DSA levels. Patients were followed-up for an average of 3.7 years and survival was compared between the three groups. Compared to patients with no or low DSA, those with high DSA were more often younger, female, and had a ventricular assist device. The length of survival after transplantation was similar between the three groups, even after adjustment for age, sex, and having a ventricular assist device before transplantation. Survival at one year and at the end of follow-up was 79% and 73% for those with no DSA, 80% and 72% in patients with low DSA, and 84% and 76% in patients with high DSA levels, respectively (p=0.85). Antibody-mediated rejections were more common in patients with high DSA levels (27% versus 6% in patients with no DSA). These rejections occurred early (a median of 28 days after transplantation) in patients with high DSA levels but they had no impact on survival and could be treated. Patients with high DSA levels had more bleeding complications due to perioperative plasmapheresis. Dr Coutance said: "By desensitising patient's antibodies, those with high immunological risk experience similar survival to patients without DSA. Pre- and post-operative plasmapheresis results in a dramatic drop in DSA levels, which reduces the risk of hyper-acute rejections and early antibody-mediated rejections. Intravenous immunoglobulins will neutralise DSA for weeks." "Despite this regimen, antibody-mediated rejections were frequent but they were not associated with poor outcomes," added Dr Coutance. "Two factors might explain these good results: early diagnosis of rejection with repetitive routine biopsies, and aggressive treatment of rejections with plasmapheresis and intravenous immunoglobulins even in subclinical rejections. The increased bleeding risk is explained by the loss of coagulation factors during plasmapheresis which is important but does not seem to impact survival." He concluded: "This desensitisation programme could shorten waiting times and increase access to transplantation for patients at high immunological risk. However, it will probably not increase the number of transplantations since donor shortage is the limiting factor."


DUBLIN--(BUSINESS WIRE)--Research and Markets has announced the addition of the "Global HLA Typing Transplant Market 2017-2021" report to their offering. The global HLA typing transplant market to grow at a CAGR of 9.20% during the period 2017-2021. The report, Global HLA Typing Transplant Market 2017-2021, has been prepared based on an in-depth market analysis with inputs from industry experts. The report covers the market landscape and its growth prospects over the coming years. The report also includes a discussion of the key vendors operating in this market. One trend in the market is new government initiatives for HLA typing. The growing concerns about hepatitis and HIV are leading the government to develop few standards and strategies to reduce the number of communicable diseases through transplantation. Quality measurement in government-introduced programs lead to increased adoption of bone marrow and umbilical cord transplantation. According to the report, one driver in the market is growing incidence of organ failure. The demand for tissue and organs such as bone marrow, heart, liver, kidney, and lungs is very high worldwide. The increasing rate of alcohol consumption, unhealthy lifestyles and food habits, and drug intake are the leading causes of organ failure. In addition, the rise in older adult population results in increased demand for organs for transplantation. According to a combined study conducted by the Department of Internal Medicine, Division of Hepatology, Loyola University Medical Center; Department of Preventive Health Sciences, Stritch School of Medicine, Loyola University Chicago; and Division of Gastroenterology and Hepatology, University of Michigan Health System, in 2015, liver cirrhosis is one of the major factors of death in the US. For more information about this report visit http://www.researchandmarkets.com/research/3rgnwf/global_hla_typing


News Article | April 27, 2017
Site: globenewswire.com

                   Paris, France - 27 avril 2017 - Le Directoire de Diaxonhit (Alternext : ALEHT, FR0004054427), groupe français leader sur le marché du diagnostic in vitro de spécialités dans les domaines de la transplantation, des maladies infectieuses et de l'oncologie, s'est réuni le 26 avril 2017 et a arrêté les comptes consolidés au 31 décembre 2016. Ces comptes ont été vérifiés par le Conseil de Surveillance2. La transition engagée dès l'été 2016 a entrainé un certain nombre de charges financières et exceptionnelles qui sont notamment liées au plan de réorientation et au plan de réduction de la dilution mis en oeuvre, pour un montant global d'environ 1 M€. Ces facteurs expliquent le résultat net en retrait à -7,9 M€, incluant tous les amortissements liés à l'acquisition d'Ingen, et à -9,6 M€ pro forma, incluant tous les frais financiers et amortissements liés aux acquisitions d'Ingen et de Capforce Plus. Les ventes annuelles de produits de diagnostic in vitro s'inscrivent dans la fourchette annoncée en janvier 2017. Elles s'élèvent ainsi à 27,6 M€ contre 28,9 M€ en 2015, et reflètent le retard dans la disponibilité des nouveaux tests NGS pour le typage HLA et le ralentissement des commandes de tests transplantation à cause des contraintes budgétaires des laboratoires hospitaliers, partiellement compensés par la bonne progression des autres secteurs du diagnostic et du contrôle qualité. Par ailleurs, les produits de R&D thérapeutique se sont élevés à 0,1 M€, en diminution par rapport à 2015 où la Société avait reçu un paiement d'étape non-récurrent d'Allergan de 0,4 M€. Sur une base pro forma, intégrant les résultats 2016 de la société Capforce Plus et de ses filiales comme si elles avaient été acquises le 1er janvier 2016, le chiffre d'affaires annuel s'élève à 44,1 M€, et le montant des revenus annuels à 45 M€. La réduction du coût d'achat des marchandises est directement liée à la baisse des ventes de produits de diagnostic in vitro. Toutefois ce coût d'achat reste affecté par la poursuite du renchérissement du dollar US. Compte-tenu des caractéristiques des contrats d'achat à terme de dollars US détenus par Diaxonhit, le taux de change moyen des dollars achetés en 2016 s'est établi à 1,1463 dollars US par euro contre 1,2173 en 2015. A taux de change constant entre 2015 et 2016, le coût d'achat des marchandises aurait ainsi été inférieur d'environ 0,9 M€. Il est rappelé que les actifs commerciaux réévalués consécutivement à l'acquisition d'IBS font l'objet d'un amortissement sur 10 ans, soit 1 286 K€ au 31 décembre 2016. Ils sont inclus dans les frais marketing et commerciaux. De même, depuis le début de la commercialisation de BJI Inoplex, un actif R&D relatif à ce test et également réévalué consécutivement à l'acquisition d'IBS, fait l'objet d'un amortissement sur 10 ans, soit 98 K€ au 31 décembre 2016, inclus dans les frais de R&D. L'écart d'acquisition restant fait aussi l'objet d'un amortissement sur 10 ans qui vient en déduction du résultat opérationnel et représente, au 31 décembre 2016, une charge de 308 K€. L'ensemble de ces amortissements représente une charge sans effet sur la trésorerie de la Société. Au 31 décembre 2015, Diaxonhit disposait d'une trésorerie de 11,7 M€. Compte-tenu de financements reçus de 0,5 M€ nets des charges d'intérêts et remboursements intervenus sur les obligations, les emprunts et les avances remboursables de la Société, et d'une consommation de trésorerie opérationnelle de 3,3 M€, la trésorerie du Groupe s'élève à 7,9 M€ au 31 décembre 2016. Diaxonhit détient la licence exclusive du test AlloMap® pour l'Europe. En janvier 2016, Diaxonhit et CareDx Inc. ont finalisé avec succès le transfert du test d'expression génomique AlloMap pour la surveillance régulière et non invasive du rejet cellulaire aigu chez les greffés cardiaques, au Laboratoire Central d'Immunologie des Hôpitaux Universitaires de Strasbourg (HUS) en France. Ce transfert a été réalisé en plusieurs étapes qui ont démontré que les résultats des tests AlloMap effectués par le laboratoire des HUS sont les mêmes que ceux qui ont été obtenus par le laboratoire principal de CareDx aux États-Unis. C'est une étape importante pour Diaxonhit et CareDx, tout en étant le premier transfert de ce type pour un test moléculaire développé et déjà commercialisé aux USA. En mai 2016, Diaxonhit et les HUS ont inauguré le centre de traitement des tests AlloMap. Ce centre répond à toutes les exigences de qualité nécessaires pour assurer la précision et la reproductibilité des résultats rendus aux prescripteurs. La Société lui fournit les éléments du test produits par CareDx et lui met également à disposition les instruments nécessaires à la réalisation du test. Diaxonhit fournit aussi aux centres de transplantation cardiaque européens un kit pour réaliser la préparation des échantillons de sang et leur expédition. Dans le cadre de cette étude, dont les résultats sont attendus au cours de l'année 2017, 1 700 prélèvements à l'aiguille fine ont été effectués sur des nodules thyroïdiens découverts chez les 1 581 patients recrutés dans 17 centres cliniques européens (10 en France, 4 en Italie et 3 en Espagne) spécialisés dans le diagnostic et le suivi du cancer de la thyroïde. Avec ces caractéristiques, l'étude CITHY est la plus grosse étude de ce type et une première en Europe qui va également permettre de mieux caractériser les pratiques européennes de suivi des patients présentant un ou plusieurs nodules de la thyroïde. Une nouvelle étude prospective en vie réelle a été réalisée à l'hôpital Raymond-Poincaré (AP-HP) de Garches et à l'hôpital Joseph-Ducuing de Toulouse. Elle a porté sur l'utilisation en routine de BJI InoPlex, avec 361 tests réalisés sur 314 patients plus représentatifs de la population ciblée dans les centres de deuxième ligne. Pour les 80 patients avec une infection chronique à staphylocoque, la performance de BJI InoPlex est améliorée par rapport à celle observée dans l'étude de validation du test. Par ailleurs, les résultats du test BJI InoPlex et de la mise en culture de ponctions articulaires réalisées avant chirurgie, qui avaient été obtenus dans le cadre de l'étude initiale de validation, ont fait l'objet d'une analyse complémentaire en excluant les 72 patients pour lesquels aucune ponction n'avait été réalisée ou pour lesquels le résultat de BJI InoPlex était indéterminé. Cette nouvelle analyse montre d'une part que les résultats de culture sur ponctions articulaires réalisées avant intervention chirurgicale ne sont pas aussi fiables qu'il est généralement admis. Ils montrent aussi clairement que cette fiabilité peut être améliorée en combinant la microbiologie classique à BJI InoPlex. Pendant l'année 2016, DIAXONHIT collaborait avec la société de biotechnologie InnaVirVax dans le cadre d'un consortium ayant pour objectif la mise au point de VAC-3S, un vaccin thérapeutique pour traiter les malades atteints du Sida, et le développement d'un test diagnostique compagnon du vaccin, dont le prototype avait été finalisé en cours d'année.                   InnaVirVax vient d'annoncer à la Société que les résultats de sa dernière étude clinique étaient médiocres. Sur cette base, InnaVirVax a pris la décision d'interrompre définitivement le développement de VAC-3S, et en a notifié Bpifrance et les membres du consortium Prothevih. En conséquence, le développement du test compagnon de VAC-3S est également arrêté par Diaxonhit. La Société évalue actuellement les conséquences de cet arrêt, et en particulier l'utilité de poursuivre le développement du test indépendamment du vaccin thérapeutique.                     Afin de réduire la dilution future des actionnaires de Diaxonhit, quatre transactions spécifiques ont été réalisées en deux temps.                   Au cours de l'exercice 2016, la société a réalisé tout d'abord des amortissements en numéraire d'obligations convertibles émises en juin 2014 (OCA), pour un total de 383 K€. D'autre-part, elle a procédé au rachat en numéraire de 6.158.000 bons de souscription qui avaient également été émis en juin 2014 (BSA), pour 537 K€. Ce dernier montant a constitué une charge financière exceptionnelle sur l'exercice 2016.                   Depuis le 1er janvier 2017, et notamment dans le cadre de la finalisation de l'acquisition de Capforce Plus, Diaxonhit a procédé à deux nouveaux amortissements en numéraire d'OCA pour un montant total de 525 K€, puis racheté 5.953.470 BSA.  Cette restructuration globale a entrainé l'émission de 3.453.012 actions nouvelles.                   Sur la base d'un amortissement par émission d'actions au cours de 0,22€ par actions, les amortissements effectués en numéraire en 2016 et depuis le début de l'année 2017, se seraient traduits par l'émission de 4.127.093 actions supplémentaires. Cumulé aux transactions effectuées sur les BSA, c'est un total de 12.785.551 actions qui ne seront plus émises, soit environ 7% du capital actuel.                     Fort de ses 120 collaborateurs, le nouveau groupe Diaxonhit, acteur intégré français du diagnostic in vitro, intervient de la recherche à la commercialisation de produits diagnostiques de spécialités et désormais également de produits pour la recherche dans le domaine des sciences de la vie. D'autre-part, son expansion continue à s'appuyer à la fois sur la croissance de ses activités commerciales de distribution et sur le développement de produits propriétaires et innovants à forte valeur ajoutée.         Diaxonhit possède un portefeuille étendu et diversifié de produits propriétaires dans quatre spécialités : la transplantation, les maladies infectieuses, les sciences du vivant et le cancer.                   Dans le domaine de la transplantation, le groupe commercialise des milieux de transport et de préservation des greffons de cornée ainsi qu'un dispositif breveté, Iglide(TM), pour en faciliter la mise en oeuvre chirurgicale. Il commercialise également Allomap, un test moléculaire pour le suivi des transplantés cardiaques, dont il détient la licence exclusive pour l'Europe.                   Dans le domaine des maladies infectieuses, le groupe commercialise plusieurs produits propriétaires et notamment TQS pour l'identification du statut immunitaire vis-à-vis du tétanos, BJI Inoplex pour le diagnostic des infections ostéo-articulaires sur prothèse, ainsi que la gamme de biologie moléculaire Eurobioplex (EBX) qui comprend un ensemble de tests permettant d'identifier de nombreux agents pathogènes et d'en évaluer la quantité présente dans l'organisme des patients infectés.                   Dans le domaine des sciences de la vie, le groupe développe un ensemble de produits destinés à la R&D, en particulier auprès d'organismes publics de recherche et de l'industrie pharmaceutique. Il commercialise notamment des milieux de culture cellulaires, des réactifs de biologie moléculaire ainsi que des anticorps propriétaires. Doté d'un laboratoire et d'une forte expertise industrielle, le groupe propose un service de production à façon dédié aux sociétés de biotechnologie ou pharmaceutiques.                   Par ailleurs, Diaxonhit développe d'autres produits sur la base de sa plateforme de biologie moléculaire, en particulier Dx15 pour le diagnostic du cancer de la thyroïde. A travers ses filiales commerciales, Eurobio et Ingen, le groupe renforce aujourd'hui sa position de 1er distributeur indépendant français de diagnostics in vitro sur son territoire.                   Dans ce cadre, il commercialise des tests de diagnostic de spécialité auprès des laboratoires d'analyses de biologie médicale hospitaliers et privés. Il est ainsi le leader en France du marché des tests HLA pour la transplantation. Il commercialise également en exclusivité des tests et des solutions automatisées issus de partenaires industriels étrangers (américains, coréens, européens.) dans les domaines des maladies infectieuses, de l'auto-immunité et des contrôles qualité. Il propose aussi toute une gamme de réactifs et d'instruments dédiés aux laboratoires des sciences de la vie.                   S'appuyant sur ses ingénieurs et spécialistes produits, le groupe assure également un service client haut-de-gamme, avec assistance téléphonique, support technique et service après-vente pour une importante base de plus de 400 instruments installés dans les laboratoires de ses clients. Diaxonhit (Alternext, FR0004054427, ALEHT) est un acteur majeur dans le domaine du diagnostic in vitro de spécialités et des sciences de la vie. Il intervient de la recherche à la commercialisation de tests diagnostiques dans les domaines de la transplantation, des maladies infectieuses et de l'oncologie, ainsi que de produits pour la recherche dans le domaine des sciences du vivant. Il est notamment le leader en France de la commercialisation des tests HLA. Avec ses nombreux partenariats et sa forte présence hospitalière, Diaxonhit dispose de son propre réseau étendu de distribution et d'un portefeuille de produits propriétaires parmi lesquels Tétanos Quick Stick®, BJI Inoplex®, et la gamme de biologie moléculaire EBX (Dengue, Chickungunya, Zika, Hépatite delta, etc.) dans le domaine des maladies infectieuses. Dans le domaine des sciences de la vie, le groupe développe un ensemble de produits destinés à la R&D, en particulier auprès d'organismes publics de recherche et de l'industrie pharmaceutique. Il commercialise notamment des milieux de culture cellulaires, des réactifs de biologie moléculaire ainsi que des anticorps propriétaires, et propose un service de production à façon dédié aux sociétés de biotechnologie ou pharmaceutiques. Diaxonhit produit et commercialise également des milieux de transport et de préservation des greffons de cornée ainsi qu'un dispositif breveté, Iglide(TM), pour en faciliter la mise en oeuvre chirurgicale. La Société est membre du GIE européen DiaMondial. Ce communiqué comporte des éléments non factuels, notamment et de façon non exclusive, certaines affirmations concernant des résultats à venir et d'autres événements futurs. Ces affirmations sont fondées sur la vision actuelle et les hypothèses de la Direction de la Société. Elles incorporent des risques et des incertitudes connues et inconnues qui pourraient se traduire par des différences significatives au titre des résultats, de la rentabilité et des événements prévus. En outre, Diaxonhit, ses actionnaires et ses affiliés, administrateurs, dirigeants, conseils et salariés respectifs n'ont pas vérifié l'exactitude des, et ne font aucune déclaration ou garantie sur, les informations statistiques ou les informations prévisionnelles contenues dans le présent communiqué qui proviennent ou sont dérivées de sources tierces ou de publications de l'industrie; ces données statistiques et informations prévisionnelles ne sont utilisées dans ce communiqué qu'à des fins d'information. Enfin, le présent communiqué peut être rédigé en langue française et en langue anglaise. En cas de différences entre les deux textes, la version française prévaudra.

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