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https://www.readbyqxmd.com/read/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#1
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
May 18, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28515281/cxcl4-exposure-potentiates-tlr-driven-polarization-of-human-monocyte-derived-dendritic-cells-and-increases-stimulation-of-t-cells
#2
Sandra C Silva-Cardoso, Alsya J Affandi, Lotte Spel, Marta Cossu, Joel A G van Roon, Marianne Boes, Timothy R D J Radstake
Chemokines have been shown to play immune-modulatory functions unrelated to steering cell migration. CXCL4 is a chemokine abundantly produced by activated platelets and immune cells. Increased levels of circulating CXCL4 are associated with immune-mediated conditions, including systemic sclerosis. Considering the central role of dendritic cells (DCs) in immune activation, in this article we addressed the effect of CXCL4 on the phenotype and function of monocyte-derived DCs (moDCs). To this end, we compared innate and adaptive immune responses of moDCs with those that were differentiated in the presence of CXCL4...
May 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28512240/sting-activation-reverses-lymphoma-mediated-resistance-to-antibody-immunotherapy
#3
Lekh N Dahal, Lang Dou, Khiyam Hussain, Rena Liu, Alexander Earley, Kerry L Cox, Salome Murinello, Ian Tracy, Francesco Forconi, Andrew J Steele, Patrick Duriez, Diego Gomez-Nicola, Jessica L Teeling, Martin J Glennie, Mark S Cragg, Stephen A Beers
Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28505515/rhob-induces-the-production-of-proinflammatory-cytokines-in-tlr-triggered-macrophages
#4
Shuyuan Liu, Lisong Huang, Zhusen Lin, Yuanqin Hu, Ruifeng Chen, Liqiu Wang, Yi Shan
Toll-like receptors (TLRs) are the primary sensors detecting conserved molecular patterns on microorganisms, thus acting as important components of innate immunity against invading pathogens. Many positive and negative regulators of TLR-triggered signaling have been identified. The Rho GTPase RhoB plays a key role in cell migration, division and polarity; however, the function and regulatory mechanisms of RhoB in TLR ligand-triggered innate immune responses remain to be investigated. Here, we report that the expression of RhoB is induced by TLR agonists (lipopolysaccharide (LPS), CpG, poly(I:C)) in macrophages...
May 12, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28502294/-resiquimod-r848-has-more-stronger-immune-adjuvantivity-than-other-tested-tlr-agonists
#5
Yuan Shen, Menghua Zeng, Feng Qiu, Hua Tang
Objective To compare and characterize the Th1 immune responses induced by the most commonly used commercial Toll-like receptor (TLR) agonists through in vivo and ex vivo experiments. Methods The concentrations of IL-12 were tested by ELISA after mouse dendritic cells (DCs) in vitro were stimulated by one of tested TLR agonists, including poly(I:C), monophosphoryl lipid A (MPLA), resiquimod (R848), cytosine polyguanine-C (CpG-C). The changes in percentage and phenotype of DCs, NK cells and effector T cells in the draining lymph nodes were analyzed by flow cytometry after BALB/c mice were immunized with ovalbumin (OVA) mixed with selected TLR agonist...
May 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28502093/the-tlr4-trif-pathway-can-protect-against-the-development-of-experimental-allergic-asthma
#6
Karim H Shalaby, Saba Al-Heialy, Kimitake Tsuchiya, Soroor Farahnak, Toby K McGovern, Paul-Andre Risse, Woong-Kyung Suh, Salman T Qureshi, James G Martin
The Toll-like Receptor (TLR) adaptor proteins Myeloid Differentiating Factor 88 (MyD88) and Toll, interleukin-1 Receptor and Resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF) comprise the two principal limbs of the TLR signaling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ICOS+ T cells by nasal application of Protollin(™) , a mucosal adjuvant composed of TLR2 and 4 agonists. Wild-type (wt), Trif -/- or Myd88 -/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges...
May 14, 2017: Immunology
https://www.readbyqxmd.com/read/28495399/evaluation-of-toll-like-receptor-gene-family-variants-as-prognostic-biomarkers-in-rheumatoid-arthritis
#7
Silvia Torices, Lorena Alvarez-Rodríguez, Ignacio Varela, Pedro Muñoz, Alejandro Balsa, M López-Hoyos, Víctor Martinez-Taboada, Jose L Fernández-Luna
Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main feature is persistent joint inflammation. Toll-like receptors (TLRs) play critical roles in the activation of innate and adaptive immune responses, and influence the activity of NFκB, a key player in chronic inflammation. We aimed at investigating the association of TLR allelic variants with susceptibility and severity of RA through a systematic, high-throughput, analysis of TLR genes. All coding exons and flanking regions of nine members of the TLR family (TLR1-9) were analyzed in 66 patients with RA and 30 healthy controls by next generation sequencing...
May 7, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28495370/an-optimized-method-for-enumerating-cns-derived-memory-b-cells-during-viral-induced-inflammation
#8
Krista D DiSano, Stephen A Stohlman, Cornelia C Bergmann
BACKGROUND: CNS inflammation resulting from infection, injury, or neurodegeneration leads to accumulation of diverse B cell subsets. Although antibody secreting cells (ASC) within the inflamed CNS have been extensively examined, memory B cell (Bmem) characterization has been limited as they do not secrete antibody without stimulation. Moreover, unlike human Bmem, reliable surface markers for murine Bmem remain elusive. NEW METHOD: Using a viral encephalomyelitis model we developed a modified limiting dilution in vitro stimulation assay to convert CNS-derived virus specific Bmem into ASC...
May 8, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28483682/intrahepatic-cd206-macrophages-contribute-to-inflammation-in-advanced-viral-related-liver-disease
#9
Alfonso Tan-Garcia, Lu-En Wai, Dahai Zheng, Erica Ceccarello, Juandy Jo, Nasirah Banu, Atefeh Khakpoor, Adeline Chia, Christine Y L Tham, Anthony T Tan, Michelle Hong, Choong Tat Keng, Laura Rivino, Kai Chah Tan, Kang Hoe Lee, Seng Gee Lim, Evan W Newell, Norman Pavelka, Jinmiao Chen, Florent Ginhoux, Qingfeng Chen, Antonio Bertoletti, Charles-Antoine Dutertre
BACKGROUND & AIMS: Liver inflammation is central to the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. METHODS: Intrahepatic CD14(+) myeloid cells from healthy donors (n=19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n=15) were subjected to detailed phenotypic, molecular and functional characterisation...
May 5, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28483250/monophosphoryl-lipid-a-enhances-nontypeable-haemophilus-influenzae-specific-mucosal-and-systemic-immune-responses-by-intranasal-immunization
#10
Taro Iwasaki, Takashi Hirano, Satoru Kodama, Yoshinori Kadowaki, Munehito Moriyama, Toshiaki Kawano, Masashi Suzuki
OBJECTIVE: Acute otitis media (AOM) is one of the most common infectious diseases in children. Nontypeable Haemophilus influenzae (NTHi) is Gram-negative bacteria that are considered major pathogens of AOM and respiratory tract infections. In this study, we used monophosphoryl lipid A (MPL), a toll-like receptor (TLR) 4 agonist, as an adjuvant to induce mucosal immune responses against NTHi to enhance bacterial clearance from the nasopharynx. METHODS: Mice were administered 10 μg outer membrane protein (OMP) from NTHi and 0, 10, or 20 μg MPL intranasally once a week for 3 weeks...
June 2017: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/28479111/co-utilization-of-a-tlr5-agonist-and-nano-formulation-of-hiv-1-vaccine-candidate-leads-to-increased-vaccine-immunogenicity-and-decreased-immunogenic-dose-a-preliminary-study
#11
Hajar Rostami, Masoumeh Ebtekar, Mehdi Shafiee Ardestani, Mohammad Hossein Yazdi, Mehdi Mahdavi
Vaccines currently available for AIDS show poor efficiency, demonstrating the need for new strategies to increase their immunogenicity. In this study, the HIV-1P24-Nef peptide was used as a model vaccine, followed by utilization of a novel strategy to increase its immunogenicity. There is a growing interest in using TLR agonists for vaccine formulations. Such molecules bind to their receptors on immune cells, especially the cell surface of antigen presenting cells, thereby activating these cells and inflammatory responses...
May 4, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28458620/mesenchymal-stromal-cells-and-toll-like-receptor-priming-a-critical-review
#12
REVIEW
Mehdi Najar, Mohammad Krayem, Nathalie Meuleman, Dominique Bron, Laurence Lagneaux
Mesenchymal Stromal Cells (MSCs) are potential cellular candidates for several immunotherapy purposes. Their multilineage potential and immunomodulatory properties make them interesting tools for the treatment of various immunological diseases. However, depending on the local microenvironment, diverse biological functions of MSCs can be modulated. Indeed, during infections such as obtained following TLR-agonist engagement (called as TLR priming), the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs can present critical changes, which could further affect their therapeutic potential...
April 2017: Immune Network
https://www.readbyqxmd.com/read/28456734/thermosensitive-gel-based-formulation-for-intra-tumoral-delivery-of-toll-like-receptor-7-8-dual-agonist-medi9197
#13
Amir Fakhari, Sean Nugent, James Elvecrog, John Vasilakos, Marta Corcoran, Ashenafi Tilahun, Kristen Siebenaler, Jenny Sun, J Anand Subramony, Alexander Schwarz
Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a, imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intra-tumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel...
April 26, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28448526/human-alkaline-phosphatase-dephosphorylates-microbial-products-and-is-elevated-in-preterm-neonates-with-a-history-of-late-onset-sepsis
#14
Matthew Pettengill, Juan D Matute, Megan Tresenriter, Julie Hibbert, David Burgner, Peter Richmond, José Luis Millán, Al Ozonoff, Tobias Strunk, Andrew Currie, Ofer Levy
BACKGROUND: A host defense function for Alkaline phosphatases (ALPs) is suggested by the contribution of intestinal ALP to detoxifying bacterial lipopolysaccharide (endotoxin) in animal models in vivo and the elevation of ALP activity following treatment of human cells with inflammatory stimuli in vitro. However the activity of ALP in human plasma (primarily tissue-nonspecific ALP; TNAP) on lipopolysaccharide and other microbial products has not been assessed, nor has its expression been studied in preterm newborns, a vulnerable population at high risk of sepsis...
2017: PloS One
https://www.readbyqxmd.com/read/28445506/phenotype-function-and-differentiation-potential-of-human-monocyte-subsets
#15
Lisa B Boyette, Camila Macedo, Kevin Hadi, Beth D Elinoff, John T Walters, Bala Ramaswami, Geetha Chalasani, Juan M Taboas, Fadi G Lakkis, Diana M Metes
Human monocytes have been grouped into classical (CD14++CD16-), non-classical (CD14dimCD16++), and intermediate (CD14++CD16+) subsets. Documentation of normal function and variation in this complement of subtypes, particularly their differentiation potential to dendritic cells (DC) or macrophages, remains incomplete. We therefore phenotyped monocytes from peripheral blood of healthy subjects and performed functional studies on high-speed sorted subsets. Subset frequencies were found to be tightly controlled over time and across individuals...
2017: PloS One
https://www.readbyqxmd.com/read/28432455/dual-activation-of-toll-like-receptors-7-and-9-impairs-the-efficacy-of-antitumor-vaccines-in-murine-models-of-metastatic-breast-cancer
#16
Mariela A Moreno Ayala, María Florencia Gottardo, María Soledad Gori, Alejandro Javier Nicola Candia, Carla Caruso, Andrea De Laurentiis, Mercedes Imsen, Slobodanka Klein, Elisa Bal de Kier Joffé, Gabriela Salamone, Maria G Castro, Adriana Seilicovich, Marianela Candolfi
PURPOSE: Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. METHODS: DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas...
April 21, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28432147/cutting-edge-a-dual-tlr2-and-tlr7-ligand-induces-highly-potent-humoral-and-cell-mediated-immune-responses
#17
Alice Gutjahr, Laura Papagno, Francesco Nicoli, Alain Lamoureux, Fabienne Vernejoul, Thierry Lioux, Emma Gostick, David A Price, Gérard Tiraby, Eric Perouzel, Victor Appay, Bernard Verrier, Stéphane Paul
TLR agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. The aim of this study was to evaluate the immunostimulatory properties of a novel compound incorporating covalently linked moieties designed to stimulate both TLR2 and TLR7. This dual TLR2/TLR7 agonist induced the maturation of dendritic cells and primed substantial populations of cytolytic and highly polyfunctional effector CD8(+) T cells in vitro, and safely potentiated the immunogenic properties of a nanoparticulate Ag in vivo, eliciting humoral responses with a balanced TH1/TH2 profile in mice...
April 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28429728/a-formulated-tlr7-8-agonist-is-a-flexible-highly-potent-and-effective-adjuvant-for-pandemic-influenza-vaccines
#18
Neal Van Hoeven, Christopher B Fox, Brian Granger, Tara Evers, Sharvari W Joshi, Ghislain I Nana, Sarah C Evans, Susan Lin, Hong Liang, Li Liang, Rie Nakajima, Philip L Felgner, Richard A Bowen, Nicole Marlenee, Airn Hartwig, Susan L Baldwin, Rhea N Coler, Mark Tomai, James Elvecrog, Steven G Reed, Darrick Carter
Since 1997, highly pathogenic avian influenza viruses of the H5N1 subtype have been transmitted from avian hosts to humans. The severity of H5N1 infection in humans, as well as the sporadic nature of H5N1 outbreaks, both geographically and temporally, make generation of an effective vaccine a global public health priority. An effective H5N1 vaccine must ultimately provide protection against viruses from diverse clades. Toll-like receptor (TLR) agonist adjuvant formulations have a demonstrated ability to broaden H5N1 vaccine responses in pre-clinical models...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28410380/interleukin-10-and-prostaglandin-e2-have-complementary-but-distinct-suppressive-effects-on-toll-like-receptor-mediated-dendritic-cell-activation-in-ovarian-carcinoma
#19
Eva Brencicova, Ann L Jagger, Hayley G Evans, Mirella Georgouli, Alex Laios, Steve Attard Montalto, Gautam Mehra, Jo Spencer, Ahmed A Ahmed, Shanti Raju-Kankipati, Leonie S Taams, Sandra S Diebold
Dendritic cells (DC) have the potential to instigate a tumour-specific immune response, but their ability to prime naïve lymphocytes depends on their activation status. Thus, for tumour immunotherapy to be effective, the provision of appropriate DC activation stimuli such as Toll-like receptor (TLR) agonists is crucial in order to overcome immunosuppression associated with the tumour microenvironment. To address this, we investigated how ovarian carcinoma (OC)-associated ascites impedes activation of DC by TLR agonists...
2017: PloS One
https://www.readbyqxmd.com/read/28407632/hypothermic-neuronal-rescue-from-infection-sensitised-hypoxic-ischaemic-brain-injury-is-pathogen-dependent
#20
Mari Falck, Damjan Osredkar, Elke Maes, Torun Flatebø, Thomas Ragnar Wood, Hemmen Sabir, Marianne Thoresen
Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, early-onset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2...
April 14, 2017: Developmental Neuroscience
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