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Murata K.,Research Center for Hepatitis and Immunology | Sugiyama M.,Research Center for Hepatitis and Immunology | Kimura T.,Institute of Immunology Co. | Yoshio S.,Osaka University | And 11 more authors.
Journal of Gastroenterology | Year: 2014

Background: Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes. Methods: The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data. Results: We found that BDCA-4+ plasmacytoid and BDCA-3+ myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10 -10), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %). Conclusions: Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype. © 2013 The Author(s). Source


Santak M.,Institute of Immunology Co.
Periodicum Biologorum | Year: 2012

Influenza viruses have been with mankind for at least 300 years, with epidemics occurring every few years and pandemics every few decades. They replicate extremely rapidly in the host therefore demanding a fast and effective antiviral response. Despite the availability of seasonal trivalent vaccines and antivirals, which are effective for most recipients, influenza remains serious disease. The reason for that is a grand capacity of the influenza virus to adapt to new environmental conditions and evolutionary pressure. Vaccination remains the main protective measure against influenza for general population. The first vaccine was administered in the 1940s and ever since the influenza vaccine has provided tremendous relief against influenza infections. However, time has revealed the ultimate limit of the vaccine and the call for its reinvention has now come. The purpose of this review is to give a brief but comprehensive overview of the currently used prophylactic and therapeutic approaches against influenza and the new most promising developments in this field. Source


Patent
University of Tokyo, Aichi Medical University and Institute Of Immunology Co. | Date: 2012-10-03

It is an object of the present invention to provide a monoclonal antibody, which is suitable for the quantitative analysis of asparagine synthetase in a cell. The present invention provides a monoclonal antibody which specifically recognizes asparagine synthetase that is present in a cell.


Sajevic T.,Jozef Stefan Institute | Leonardi A.,Jozef Stefan Institute | Kovacic L.,Jozef Stefan Institute | Lang-Balija M.,Institute of Immunology Co. | And 6 more authors.
Biochimie | Year: 2013

Hemorrhage is the most potent manifestation of envenomation by Vipera ammodytes ammodytes (V. a. ammodytes) venom in man. A detailed description of the venom components contributing to this effect is thus medically very important. We have characterized a novel component, termed here VaH3, as a potently hemorrhagic snake venom metalloproteinase (SVMP). Its proteolytic activity and overall stability depend on the presence of Zn2+ and Ca2+ ions. The molecular mass of this slightly acidic molecule, determined by MALDI/TOF analysis, is 104 kDa. Chemical reduction and S-carbamoylmethylation result in a single monomer of 53.7 kDa. N-deglycosylation decreased this mass by 4.6 kDa. The complete amino acid sequence of VaH3 was determined by protein and cDNA sequencing, showing that each of the identical glycoprotein subunits comprise a metalloproteinase, a disintegrin-like domain and a cysteine-rich domain, VaH3 belongs to the P-IIIc class of SVMPs. It shows strong sequence similarity to vascular endothelial cell apoptosis-inducing reprolysins. Anti-ammodytagin antibodies strongly cross-reacted with VaH3 and completely neutralized its hemorrhagic activity in rat, despite the fact that the two hemorrhagic P-III SVMPs from V. a. ammodytes venom do not share a very high degree of amino acid sequence identity. In spite of its narrow proteolytic specificity, VaH3 rapidly cleaved some basal membrane and extracellular matrix proteins, such as collagen IV, fibronectin and nidogen. Moreover, it also hydrolyzed plasma proteins involved in blood coagulation. It is an effective α-fibrinogenase that cleaves prothrombin and factor X without activating them. The degradation of these proteins likely contributes to the hemorrhagic activity of VaH3. A three-dimensional model of VaH3 was built to help explain structure-function relationships in ADAM/ADAMTS, a family of proteins having significant therapeutic potential and substantial sequence similarity to VaH3. © 2013 Elsevier Masson SAS. All rights reserved. Source


Halassy B.,Institute of Immunology Co. | Brgles M.,Institute of Immunology Co. | Habjanec L.,Institute of Immunology Co. | Balija M.L.,Institute of Immunology Co. | And 4 more authors.
Comparative Biochemistry and Physiology - C Toxicology and Pharmacology | Year: 2011

Vipera ammodytes is the most venomous European snake, whose venom has been used as antigen for immunization of antivenom-producing animals. Same as venom of any other snake, it is a complex mixture of proteins, peptides and other compounds which biochemical and pharmacological variability has been demonstrated at interspecies and intraspecies level. In this work we demonstrated intraspecific variability between 8 venom production batches using both the conventional and the new methodology. Moreover, in contrast to the literature on different venoms' variability, for the first time we were able to select those biochemical differences that are related to and give information on the venom's toxicity and immunogenicity. We have shown that methods quantifying ammodytoxin (the most toxic compound identified so far in the Vipera ammodytes ammodytes venom) content of the venom clearly distinguish between high and low immunogenic venoms. © 2010 Elsevier Inc. Source

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