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TLR agonist

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https://www.readbyqxmd.com/read/28110170/tailoring-polymeric-hybrid-micelles-with-lymph-node-targeting-ability-to-improve-the-potency-of-cancer-vaccines
#1
Qin Zeng, Hanmei Li, Hao Jiang, Jiao Yu, Ying Wang, Huan Ke, Tao Gong, Zhirong Zhang, Xun Sun
It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines and particles sized between 10 and 100 nm with a neutral or negative surface charge are preferred for lymphatic transfer after subcutaneous or intradermal injection. However their limited uptake by antigen presenting cells (APCs) and inadequate retention within LNs undoubtedly restrains their strength on activating T cell immunity. Here, we address this issue by tailoring the physicochemical properties of polymeric hybrid micelles (HMs), which are self-assembled from two amphiphilic diblock copolymers, poly-(ethylene glycol) phosphorethanolamine (PEG-PE) and polyethylenimine-stearic acid conjugate (PSA) via hydrophobic and electrostatic interactions...
January 11, 2017: Biomaterials
https://www.readbyqxmd.com/read/28095323/pattern-recognitions-receptors-in-immunodeficiency-disorders
#2
Esameil Mortaz, Ian M Adcock, Payam Tabarsi, Ilad Alavi Darazam, Masoud Movassaghi, Johan Garssen, Hamidreza Jamaati, Aliakbar Velayati
Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs)...
January 14, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28093114/in-vitro-effects-of-the-toll-like-receptor-agonists-monophosphoryl-lipid-a-and-cpg-rich-oligonucleotides-on-cytokine-production-by-equine-cells
#3
A Ziegler, V Gerber, E Marti
Insect bite hypersensitivity (IBH) is an equine allergic dermatitis to Culicoides spp. antigens. Attempts at using allergen-specific immunotherapy (AIT) as a treatment for IBH have so far proven unsuccessful. Toll-like receptor (TLR) agonists can promote a shift in the immune response from the allergy-promoting T helper cell 2 (Th2) response towards a Th1 and/or regulatory response. The aim of this study was to evaluate two immunomodulatory TLR agonists in vitro as potential vaccine adjuvants for a more efficacious AIT in IBH...
January 2017: Veterinary Journal
https://www.readbyqxmd.com/read/28093098/tlr-induced-immunomodulatory-cytokine-expression-by-human-gingival-stem-progenitor-cells
#4
Mohamed K Mekhemar, Sabine Adam-Klages, Dietrich Kabelitz, Christof E Dörfer, Karim M Fawzy El-Sayed
During therapeutic application, mesenchymal stem cells (MSCs) may interact with their environment via their expressed toll-like-receptors (TLRs) leading to pro- or anti-inflammatory immune responses. The present study aimed to describe the gingival margin-derived stem/progenitor cells' (G-MSCs) TLR-induced immune regulatory response to specific TLR agonists. Gingival cells were obtained, immunomagnetically sorted via anti-STRO-1 antibodies and seeded out to achieve colony forming units (CFUs). G-MSCs were investigated for stem cell characteristics and TLR expression...
January 10, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28089548/nanoformulation-of-synergistic-tlr-ligands-to-enhance-vaccination-against-entamoeba-histolytica
#5
Mayuresh M Abhyankar, Zannatun Noor, Mark A Tomai, James Elvecrog, Christopher B Fox, William A Petri
Diarrheal infectious diseases represent a major cause of global morbidity and mortality. There is an urgent need for vaccines against diarrheal pathogens, especially parasites. Modern subunit vaccines rely on combining a highly purified antigen with an adjuvant to increase their efficacy. In the present study, we evaluated the ability of a nanoliposome adjuvant system to trigger a strong mucosal immune response to the Entamoeba histolytica Gal/GalNAc lectin LecA antigen. CBA/J mice were immunized with alum, emulsion or liposome based formulations containing synthetic TLR agonists...
January 12, 2017: Vaccine
https://www.readbyqxmd.com/read/28089340/activation-of-nk-cell-cytotoxicity-by-aerosolized-cpg-odn-poly-i-c-against-lung-melanoma-metastases-is-mediated-by-alveolar-macrophages
#6
Michele Sommariva, Valentino Le Noci, Chiara Storti, Francesca Bianchi, Elda Tagliabue, Andrea Balsari, Lucia Sfondrini
Controversies remain about NK cells direct responsiveness to Toll-like receptor (TLR) agonists or dependence on macrophages. In a melanoma lung metastasis model, aerosolized TLR9 and TLR3 agonists have been reported to induce antitumor immunity through NK cells activation. In the current study, we demonstrated that in vitro TLR9/TLR3 stimulation induced IFN-γ secretion by NK cells, but an increase in their cytotoxicity was detected only after NK cells co-culture with in vitro TLR9/TLR3 agonists pretreated alveolar macrophages...
January 5, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28072760/pentoxifylline-inhibits-tlr-and-inflammasome-mediated-in-vitro-inflammatory-cytokine-production-in-human-blood-with-greater-efficacy-and-potency-in-newborns
#7
Esther M Speer, David J Dowling, Lukasz S Ozog, Jianjin Xu, Jie Yang, Geetika Kennady, Ofer Levy
BACKGROUND: Toll-like receptor (TLR)-mediated inflammation may contribute to neonatal sepsis, for which pentoxifylline (PTX), a phosphodiesterase inhibitor that raises intracellular cAMP, is a candidate adjunctive therapy. We characterized the anti-inflammatory effects of PTX towards TLR-mediated production of inflammatory (TNF, IL-1ß) and pro-resolution (IL-6, IL- 10) cytokines in human newborn and adult blood. METHODS: Newborn cord and adult blood were treated with PTX (50 - 400 μM) before, during or after stimulation with LPS (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/ATP (inflammasome activation)...
January 10, 2017: Pediatric Research
https://www.readbyqxmd.com/read/28069966/inherited-human-irak-1-deficiency-selectively-impairs-tlr-signaling-in-fibroblasts
#8
Erika Della Mina, Alessandro Borghesi, Hao Zhou, Salim Bougarn, Sabri Boughorbel, Laura Israel, Ilaria Meloni, Maya Chrabieh, Yun Ling, Yuval Itan, Alessandra Renieri, Iolanda Mazzucchelli, Sabrina Basso, Piero Pavone, Raffaele Falsaperla, Roberto Ciccone, Rosa Maria Cerbo, Mauro Stronati, Capucine Picard, Orsetta Zuffardi, Laurent Abel, Damien Chaussabel, Nico Marr, Xiaoxia Li, Jean-Laurent Casanova, Anne Puel
Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear...
January 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28054376/toll-like-receptor-tlr-7-expression-in-mycosis-fungoides-and-psoriasis-a-case-control-study
#9
A M El Tawdy, I M Amin, R M Abdel Hay, A S Hassan, Z S Gad, L A Rashed
BACKGROUND: Toll-like receptors (TLRs) have been implicated in various dermatological diseases. TLR agonists have the capacity to potently activate the innate immune cells of patients with advanced, refractory, cutaneous T-cell lymphoma (CTCL). AIM: To detect TLR7 gene expression in mycosis fungoides (MF) (a neoplastic skin condition) and to compare it with psoriasis (an inflammatory skin condition) in an attempt to clarify the pathogenic role played by TLR7 in both conditions...
January 5, 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/28052863/double-stranded-rna-up-regulates-the-expression-of-inflammatory-mediators-in-human-aortic-valve-cells-through-the-tlr3-trif-non-canonical-nf-%C3%AE%C2%BAb-pathway
#10
Qiong Zhan, Rui Song, Fei Li, Lihua Ao, Qingchun Zeng, Dingli Xu, David A Fullerton, Xianzhong Meng
BACKGROUND: Calcific aortic valve disease (CAVD) is a chronic inflammatory condition and the inflammatory responses of aortic valve interstitial cells (AVICs) play a critical role in the disease progression. Double-stranded RNA (dsRNA) released from damaged or stressed cells is pro-inflammatory and may contribute to the mechanism of chronic inflammation observed in diseased aortic valves. The objective of this study is to determine the effect of dsRNA on AVIC inflammatory responses and the underlying mechanism...
January 4, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28052637/future-anti-hbv-strategies
#11
REVIEW
Edward J Gane
Although current oral antivirals can maintain viral suppression and reduce the risk of liver-related complications, lifelong therapy is associated with high cost, risk of breakthrough and potential toxicity. There is a need to develop a finite course of treatment which can provide sustained off-treatment virological and clinical response. The likely marker of such a clinical HBV CURE would be HBsAg clearance, but in addition cccDNA elimination would be required to prevent future reactivation (ie complete HBV cure)...
January 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28036266/combining-vasculature-disrupting-agent-and-toll-like-receptor-7-8-agonist-for-cancer-therapy
#12
Anushree Seth, Hyunseung Lee, Mi Young Cho, Cheongsoo Park, Sovannarith Korm, Joo-Yong Lee, Inpyo Choi, Yong Taik Lim, Kwan Soo Hong
This study evaluates the effect of combination of two different treatment regimens for solid tumor therapy: vasculature targeting agent and immune-stimulation. Poly lactide-co-glycolide (PLGA) nanoparticles were synthesized for intracellular delivery of toll-like receptor (TLR) 7/8 agonist-gardiquimod. Spherical and mono-disperse gardiquimod encapsulated PLGA nanoparticles (Gardi-PLGA), approximately 194 nm in size were formulated. Gardi-PLGA induced immune-stimulation, and vasculature disrupting agent (VDA)-5,6-Dimethylxanthenone-4-acetic acid (DMXAA) was used in combination to assessing the influence on bone marrow derived dendritic cells (BMDCs) and B16-F10 melanoma cells...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035464/the-lipoxin-a4-agonist-bml-111-attenuates-acute-hepatic-dysfunction-induced-by-cecal-ligation-and-puncture-in-rats
#13
Ghada S El-Tanbouly, Mohammed S El-Awady, Nermeen A Megahed, Hassan A El-Kashef, Hatem A Salem
Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP...
December 29, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28018345/increased-toll-like-receptors-activity-and-tlr-ligands-in-patients-with-autoimmune-thyroid-diseases
#14
Shiqiao Peng, Chenyan Li, Xinyi Wang, Xin Liu, Cheng Han, Ting Jin, Shanshan Liu, Xiaowen Zhang, Hanyi Zhang, Xue He, Xiaochen Xie, Xiaohui Yu, Chuyuan Wang, Ling Shan, Chenling Fan, Zhongyan Shan, Weiping Teng
OBJECTIVE: Autoimmune thyroid disease (AITD) is an organ-specific disorder due to the interplay between environmental and genetic factors. Toll-like receptors (TLRs) are pattern recognition receptors expressed abundantly on monocytes. There is a paucity of data on TLR expression in AITD. The aim of this study was to examine TLR expression, activation, ligands, and downstream signaling adaptors in peripheral blood mononuclear cells (PBMCs) extracted from untreated AITD patients and healthy controls...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28003376/selective-irak4-inhibition-attenuates-disease-in-murine-lupus-models-and-demonstrates-steroid-sparing-activity
#15
Shailesh Dudhgaonkar, Sourabh Ranade, Jignesh Nagar, Siva Subramani, Durga Shiv Prasad, Preethi Karunanithi, Ratika Srivastava, Kamala Venkatesh, Sabariya Selvam, Prasad Krishnamurthy, T Thanga Mariappan, Ajay Saxena, Li Fan, Dawn K Stetsko, Deborah A Holloway, Xin Li, Jun Zhu, Wen-Pin Yang, Stefan Ruepp, Satheesh Nair, Joseph Santella, John Duncia, John Hynes, Kim W McIntyre, Julie A Carman
The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway...
December 21, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27999742/reprogramming-of-tlr7-signaling-enhances-antitumor-nk-and-cytotoxic-t-cell-responses
#16
Christian Hotz, Marina Treinies, Ines Mottas, Laurin C Rötzer, Anne Oberson, Lorenzo Spagnuolo, Maurizio Perdicchio, Thibaud Spinetti, Tina Herbst, Carole Bourquin
Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly(I:C) that mimics virally induced immune activation...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27990284/a-structure-function-approach-to-optimizing-tlr4-ligands-for-human-vaccines
#17
Darrick Carter, Christopher B Fox, Tracey A Day, Jeffrey A Guderian, Hong Liang, Tom Rolf, Julie Vergara, Zachary K Sagawa, Greg Ireton, Mark T Orr, Anthony Desbien, Malcolm S Duthie, Rhea N Coler, Steven G Reed
Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll-like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions...
November 2016: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/27987148/generation-of-immunostimulating-130-nm-protamine-rna-nanoparticles
#18
Marina Tusup, Steve Pascolo
Nanoparticles of defined size can be easily obtained by simply mixing Protamine, a pharmaceutical drug that is used to neutralize heparin after surgery, and RNA in the form of oligonucleotides or messenger RNA. Depending on the concentrations of the two reagents and their salt contents, homogenous nanoparticles with a mean diameter of 50 to more than 1000 nm can spontaneously be generated. RNA is a danger signal because it is an agonist of for example TLR-3, -7, and -8; therefore, Protamine-RNA nanoparticles are immunostimulating...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27979367/synthesis-and-immunological-evaluation-of-a-low-molecular-weight-saccharide-with-tlr-4-agonist-activity
#19
Vikram Basava, Heather Romlein, Constantine Bitsaktsis, Cecilia H Marzabadi
The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27956526/tlr10-is-a-b-cell-intrinsic-suppressor-of-adaptive-immune-responses
#20
Nicholas J Hess, Song Jiang, Xinyan Li, Yue Guan, Richard I Tapping
Toll-like receptors play a central role in the initiation of adaptive immune responses with several TLR agonists acting as known B cell mitogens. Despite thousands of publications on TLRs, the function of TLR10 remains unknown. We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction. When challenged with either a T independent or T dependent Ag, TLR10 transgenic mice exhibit diminished Ab responses. Adoptive transfer of splenic B cells into B cell-deficient mice revealed that the suppressive effects on Ag-specific humoral immune responses are entirely B cell intrinsic...
January 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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