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https://www.readbyqxmd.com/read/27919753/advax-a-delta-inulin-microparticle-potentiates-in-built-adjuvant-property-of-co-administered-vaccines
#1
Masayuki Hayashi, Taiki Aoshi, Yasunari Haseda, Kouji Kobiyama, Edward Wijaya, Noriyuki Nakatsu, Yoshinobu Igarashi, Daron M Standley, Hiroshi Yamada, Yoshikazu Honda-Okubo, Hiromitsu Hara, Takashi Saito, Toshiyuki Takai, Cevayir Coban, Nikolai Petrovsky, Ken J Ishii
Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV), a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR) 7 knockout mice which are unable to respond to RNA contained in WV antigen...
December 1, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27891600/human-pdcs-display-sex-specific-differences-in-type-i-interferon-subtypes-and-interferon-%C3%AE-%C3%AE-receptor-expression
#2
Susanne Ziegler, Claudia Beisel, Kathrin Sutter, Morgane Griesbeck, Heike Hildebrandt, Sven Hagen, Ulf Dittmer, Marcus Altfeld
The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-α, in response to toll-like receptor (TLR) 7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex-specific differential expression of IFN-Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFNα-subtypes...
November 28, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27837108/characterization-and-transcriptomic-analysis-of-porcine-blood-conventional-and-plasmacytoid-dendritic-cells-reveals-striking-species-specific-differences
#3
Gael Auray, Irene Keller, Sylvie Python, Markus Gerber, Remy Bruggmann, Nicolas Ruggli, Artur Summerfield
Porcine dendritic cells (DCs) are relatively well characterized, but a clear-cut identification of all DC subsets combined with full transcriptional profiling was lacking, preventing an unbiased insight into the functional specializations of DC subsets. Using a large panel of Abs in multicolor flow cytometry, cell sorting, and RNA sequencing we identified and characterized the porcine equivalent of conventional DCs (cDC) 1 and cDC2 as well as plasmacytoid DCs (pDCs) in the peripheral blood of pigs. We demonstrate that cDC1 are CD135(+)CD14(-)CD172a(low)CADM1(+)wCD11R1(+) cells, cDC2 are CD135(+)CD14(-)CD172a(+)CADM1(+)CD115(+)wCD11R1(+)CD1(+) cells and pDCs are CD4(+)CD135(+)CD172a(+)CD123(+)CD303(+) cells...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27809682/human-immunodeficiency-virus-1-impairs-ifn-alpha-production-induced-by-tlr-7-agonist-in-plasmacytoid-dendritic-cells
#4
Ashwini Dhamanage, Madhuri Thakar, Ramesh Paranjape
Plasmacytoid dendritic cells (pDCs) play an important role in innate immune response against viruses, mainly through interferon-α (IFN-α) secretion. Impaired IFN-α secretion has been observed in patients with acute human immunodeficiency virus type 1 (HIV-1) infection and the reasons for this impairment are still obscure. To know the grounds behind this situation, HIV-1 viral copy numbers similar to those found in primary HIV-1 infection were used to stimulate peripheral blood mononuclear cells (PBMCs) and pDCs in this study...
November 3, 2016: Viral Immunology
https://www.readbyqxmd.com/read/27780938/toll-like-receptor-agonists-partially-restore-the-production-of-pro-inflammatory-cytokines-and-type-i-interferon-in-s%C3%A3-zary-syndrome
#5
Kelly C G Manfrere, Marina P Torrealba, Denis R Miyashiro, Luanda M S Oliveira, Gabriel C de Carvalho, Josenilson F Lima, Anna Claudia C C Branco, Nátalli Z Pereira, Juliana Pereira, José A Sanches, Maria N Sato
Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists...
October 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27696782/human-endogenous-retroviral-genetic-element-with-immune-suppressive-activity-in-both-human-autoimmune-diseases-and-experimental-arthritis
#6
Magdalena Janina Laskaj, Anne Troldborg, Ellen-Margrethe Hauge, Shervin Bahrami, Kristian Stengaard-Pedersen
OBJECTIVES: Human Endogenous Retroviruses (HERVs) are remnants of past retroviral infections in the human genome and have been implicated in different aspects of human biology. The aim of this study was to identify HERVs which are associated with the pathogenesis of Rheumatoid diseases represented by Systemic Lupus Erythematosus (SLE). METHODS: The study subjects included 45 female patients with SLE and 50 geographically and age matched healthy. Real-time RT-PCR analysis was used to examine the transcription levels of 11 genes with coding capacity for complete envelope protein in these individuals...
October 1, 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27693020/novel-lipopeptides-of-esat-6-induce-strong-protective-immunity-against-mycobacterium-tuberculosis-routes-of-immunization-and-tlr-agonists-critically-impact-vaccine-s-efficacy
#7
Nancy Gupta, Satish Vedi, Dennis Y Kunimoto, Babita Agrawal, Rakesh Kumar
Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic...
September 29, 2016: Vaccine
https://www.readbyqxmd.com/read/27680570/anti-pd-1-inhibits-foxp3-treg-cell-conversion-and-unleashes-intratumoural-effector-t-cells-thereby-enhancing-the-efficacy-of-a-cancer-vaccine-in-a-mouse-model
#8
Lydia Dyck, Mieszko M Wilk, Mathilde Raverdeau, Alicja Misiak, Louis Boon, Kingston H G Mills
The co-inhibitory molecule PD-1 suppresses T cell responses and has been targeted in the treatment of cancer. Here, we examined the role of PD-1 in regulating the balance between regulatory and effector T cells and whether blocking PD-1 could enhance tumour vaccine-induced protective immunity. A significantly higher proportion of tumour-resident T cells expressed PD-1 and Foxp3 compared with T cells in the tumour circulation or draining lymph nodes, and this correlated with a lower frequency of IFN-γ- and TNF-secreting CD8 T cells...
September 28, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27672125/contrasting-expression-pattern-of-rna-sensing-receptors-tlr7-rig-i-and-mda5-in-interferon-positive-and-interferon-negative-patients-with-primary-sj%C3%A3-gren-s-syndrome
#9
Naomi I Maria, Eline C Steenwijk, Arne S IJpma, Cornelia G van Helden-Meeuwsen, Petra Vogelsang, Wouter Beumer, Zana Brkic, Paul L A van Daele, P Martin van Hagen, Peter J van der Spek, Hemmo A Drexhage, Marjan A Versnel
OBJECTIVE: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS. METHODS: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature...
September 26, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27630164/transcriptional-repression-of-ifn-regulatory-factor-7-by-myc-is-critical-for-type-i-ifn-production-in-human-plasmacytoid-dendritic-cells
#10
Tae Whan Kim, Seunghee Hong, Yin Lin, Elise Murat, HyeMee Joo, Taeil Kim, Virginia Pascual, Yong-Jun Liu
Type I IFNs are crucial mediators of human innate and adaptive immunity and are massively produced from plasmacytoid dendritic cells (pDCs). IFN regulatory factor (IRF)7 is a critical regulator of type I IFN production when pathogens are detected by TLR 7/9 in pDC. However, hyperactivation of pDC can cause life-threatening autoimmune diseases. To avoid the deleterious effects of aberrant pDC activation, tight regulation of IRF7 is required. Nonetheless, the detailed mechanisms of how IRF7 transcription is regulated in pDC are still elusive...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27624667/skin-scarification-with-plasmodium-falciparum-peptide-vaccine-using-synthetic-tlr-agonists-as-adjuvants-elicits-malaria-sporozoite-neutralizing-immunity
#11
Robert A Mitchell, Rita Altszuler, Ute Frevert, Elizabeth H Nardin
Malaria eradication will require a combination of vector control, chemotherapy and an easily administered vaccine. Sterile immunity can be elicited in humans by immunization with sporozoites, the infective stage injected by bite of the mosquito vector, however, whole parasite vaccines present formidable logistical challenges for production, storage and administration. The "gold standard" for infectious disease eradiation, the Smallpox Eradication Programme, utilized mass immunization using the skin scarification (SS) route...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27609294/toll-like-receptor-tlr-7-and-tlr9-agonists-enhance-interferon-ifn-beta-1a-s-immunoregulatory-effects-on-b-cells-in-patients-with-relapsing-remitting-multiple-sclerosis-rrms
#12
Yazhong Tao, Xin Zhang, Silva Markovic-Plese
We report that B cells from patients with RRMS have decreased endogenous IFN-β secretion and deficient IFN receptor (IFNAR)1/2 and TLR7 gene expression in comparison to healthy controls (HCs), which may contribute to disregulation of cytokine secretion by B cells. We propose that TLR7 and TLR9 stimulation with loxorubin (LOX) and CpG, in combination with exogenous IFN-β may effectively reconstitute endogenous IFN-β production deficit and induce the secretion of immunoregulatory cytokines by B cells. Both LOX/IFN-β and CpG/IFN-β in-vitro treatments of B cells from RRMS patients induced higher endogenous IFN-β gene expression in comparison to the exogenous IFN-β alone...
September 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27607184/tryptophan-metabolism-along-the-kynurenine-pathway-downstream-of-toll-like-receptor-stimulation-in-peripheral-monocytes
#13
Funda Orhan, Maria Bhat, Kristian Sandberg, Sara Ståhl, Fredrik Piehl, Camilla Svensson, Sophie Erhardt, Lilly Schwieler
Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defense against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of the present study is to investigate if stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analyzed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan...
September 8, 2016: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/27583777/thermo-responsive-polymer-nanoparticles-co-deliver-rsv-f-trimers-with-a-tlr-7-8-adjuvant
#14
Joseph R Francica, Geoffrey M Lynn, Richard Laga, Michael Gordon Joyce, Tracy J Ruckwardt, Kaitlyn M Moribito, Man Chen, Rajoshi Chaudhuri, Baoshan Zhang, Mallika Sastry, Kiyoon Ko, Misook Choe, Michal Pechar, Ivelin S Georgiev, Lisa A Kueltzo, Leonard W Seymour, John R Mascola, Peter D Kwong, Barney S Graham, Robert A Seder
Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV) and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here we show that nanoparticle-forming thermo-responsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity...
September 1, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27583440/il-28b-genetic-variants-determine-the-extent-of-monocyte-induced-activation-of-nk-cells-in-hepatitis-c
#15
Benjamin Krämer, Claudia Finnemann, Beatriz Sastre, Philipp Lutz, Andreas Glässner, Franziska Wolter, Felix Goeser, Pavlos Kokordelis, Dominik Kaczmarek, Hans-Dieter Nischalke, Christian P Strassburg, Ulrich Spengler, Jacob Nattermann
BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both...
2016: PloS One
https://www.readbyqxmd.com/read/27543351/degradation-of-acetalated-dextran-can-be-broadly-tuned-based-on-cyclic-acetal-coverage-and-molecular-weight
#16
Naihan Chen, Michael A Collier, Matthew D Gallovic, Graham C Collins, Carla C Sanchez, Elizabeth Q Fernandes, Eric M Bachelder, Kristy M Ainslie
Microparticles (MPs) derived from acid-sensitive biopolymers enable rapid degradation and cargo release under acidic conditions, such as at tumor microenvironments, within lysosomal/phagosomal compartments inside phagocytic cells, or at sites of inflammation. One such acid-sensitive biopolymer, acetalated dextran (Ace-DEX), has tunable degradation rates and pH-neutral degradation byproducts consisting of dextran, acetone, and ethanol. By studying the degradation profiles of Ace-DEX MPs with varying cyclic acetal coverage (CAC) and dextran molecular weight (MW), we concluded that MPs composed of low CAC or high MW polymer degraded the fastest at both pH 7...
October 15, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27513093/novel-pyrimidine-toll-like-receptor-7-and-8-dual-agonists-to-treat-hepatitis-b-virus
#17
David McGowan, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Serge Pieters, Annick Scholliers, Tine Thoné, Bertrand Van Schoubroeck, Dorien De Pooter, Wendy Mostmans, Mourad Daoubi Khamlichi, Werner Embrechts, Deborah Dhuyvetter, Ilham Smyej, Eric Arnoult, Samuël Demin, Herman Borghys, Gregory Fanning, Jaromir Vlach, Pierre Raboisson
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented...
September 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27373163/nucleic-acid-targeting-pathways-promote-inflammation-in-obesity-related-insulin-resistance
#18
Xavier S Revelo, Magar Ghazarian, Melissa Hui Yen Chng, Helen Luck, Justin H Kim, Kejing Zeng, Sally Y Shi, Sue Tsai, Helena Lei, Justin Kenkel, Chih Long Liu, Stephanie Tangsombatvisit, Hubert Tsui, Corneliu Sima, Changting Xiao, Lei Shen, Xiaoying Li, Tianru Jin, Gary F Lewis, Minna Woo, Paul J Utz, Michael Glogauer, Edgar Engleman, Shawn Winer, Daniel A Winer
Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens...
July 19, 2016: Cell Reports
https://www.readbyqxmd.com/read/27279374/a-novel-r848-conjugated-inactivated-influenza-virus-vaccine-is-efficacious-and-safe-in-a-neonate-nonhuman-primate-model
#19
Beth C Holbrook, Jong R Kim, Lance K Blevins, Matthew J Jorgensen, Nancy D Kock, Ralph B D'Agostino, S Tyler Aycock, Mallinath B Hadimani, S Bruce King, Griffith D Parks, Martha A Alexander-Miller
Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. In this study, we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist R848-conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design because it provides multiple antigenic targets allowing for elicitation of a broad immune response...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27258042/dual-role-of-the-tyrosine-kinase-syk-in-regulation-of-toll-like-receptor-signaling-in-plasmacytoid-dendritic-cells
#20
Besma Aouar, Denisa Kovarova, Sebastien Letard, Albert Font-Haro, Jonathan Florentin, Jan Weber, David Durantel, Laurence Chaperot, Joel Plumas, Katerina Trejbalova, Jiri Hejnar, Jacques A Nunès, Daniel Olive, Patrice Dubreuil, Ivan Hirsch, Ruzena Stranska
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs...
2016: PloS One
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