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Dong Gao, Yongguang Cai, Yanyuan Chen, Wang Li, Chih-Chang Wei, Xiaoling Luo, Yuhuan Wang
Toll-like receptor (TLR) 7/8 agonists have been applied in combination with chemo-, radio- or immunotherapy for lymphoma, and used as topical drugs for the treatment of viral skin lesions and skin tumors. In the present study, the role of an adenine analog, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine [termed Gao Dong (GD)], a novel TLR7 agonist, in the activation of cytokine-induced killer/natural killer (CIK/NK) cells was determined. The results of the present study indicated that GD was able to activate CIK/NK cells...
April 2018: Oncology Letters
Jaya Talreja, Lobelia Samavati
Post viral infection bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. Despite much efforts put into the discovery of mechanisms of post viral-bacterial infections and their complications in recent years, the molecular mechanisms underlying the increased susceptibility to bacterial infection remain poorly understood. In this study, we focused on the pathways regulating immune responses in murine macrophages and modeled post viral-bacterial infections through pretreatment of bone marrow-derived macrophages (BMDMs) with a toll-like receptor (TLR) 7/8 ligand (R848) and subsequent challenge with TLR2/4 agonists to mimic bacterial infection...
2018: Frontiers in Immunology
Johannes Falke, Christina A Hulsbergen-van de Kaa, Roberto Maj, Egbert Oosterwijk, Johannes Alfred Witjes
OBJECTIVES: To evaluate and compare the pharmacokinetic and pharmacodynamic properties of 2 investigational Toll-like receptor 7 agonists, TMX-101, and TMX-202 after intravenous and intravesical administration in a rat model. TLR-7 agonists are successfully used as topical treatment for various (pre)malignant skin lesions and are now under investigation as intravesical therapy for non-muscle-invasive bladder cancer. METHODS: Rats received an intravesical instillation with TMX-101, TMX-202, or vehicle...
February 27, 2018: Urologic Oncology
Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A Kucaba, Katherine A Murphy, Britnie R James, David M Ferguson, Thomas S Griffith, Jayanth Panyam
Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds...
February 17, 2018: Biomaterials
Eva Villamón, Javier González-Fernández, Esperanza Such, José Vicente Cervera, Daniel Gozalbo, M Luisa Gil
Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML. Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL)...
2018: Cancer Cell International
Marlena M Westcott, Elene A Clemens, Beth C Holbrook, S Bruce King, Martha A Alexander-Miller
Inactivated influenza vaccines are not approved for use in infants less than 6 months of age due to poor immunogenicity in that population. While the live attenuated influenza vaccine has the potential to be more immunogenic, it is not an option for infants and other vulnerable populations, including the elderly and immunocompromised individuals due to safety concerns. In an effort to improve the immunogenicity of the inactivated vaccine for use in vulnerable populations, we have used an approach of chemically crosslinking the Toll-like receptor (TLR) 7/8 agonist R848 directly to virus particles...
February 2, 2018: Vaccine
Serge Pieters, David McGowan, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Werner Embrechts, Annick Scholliers, Wendy Mostmans, Kris Van Dijck, Bertrand Van Schoubroeck, Tine Thoné, Dorien De Pooter, Gregory Fanning, Mari Luz Rosauro, Mourad Daoubi Khamlichi, Ioannis Houpis, Eric Arnoult, Tim H M Jonckers, Pierre Raboisson
The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.
January 16, 2018: Bioorganic & Medicinal Chemistry Letters
Elisabetta Moscarella, Akihito Tanaka, Alfonso Ielasi, Bernardo Cortese, Sebastian Coscarelli, Maria Carmen De Angelis, Davide Piraino, Azeem Latib, Giulietta Grigis, Renatomaria Bianchi, Dario Buccheri, Paolo Calabrò, Maurizio Tespili, Pedro Silva Orrego, Antonio Colombo, Attilio Varricchio
OBJECTIVES: to compare the 1-year outcome between bioresorbable vascular scaffold (BVS), everolimus-eluting stent (EES), and drug-eluting balloon (DEB) for in-stent restenosis (ISR) treatment. BACKGROUND: BVS has been proposed as alternative for ISR treatment. To date a direct comparison between BVS and DES or DEB for ISR treatment is lacking. METHODS: We retrospectively analyzed all ISR lesions treated with BVS, DEB, and EES from January 2012 to December 2014...
January 22, 2018: Catheterization and Cardiovascular Interventions
Frances E Pearson, Karshing Chang, Yoshihito Minoda, Ingrid M Leal Rojas, Oscar L Haigh, Ghazal Daraj, Kirsteen M Tullett, Kristen J Radford
Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141+ and CD1c+ myeloid and CD123+ plasmacytoid dendritic cells (DC) develop from human cord blood CD34+ cells in immunodeficient mice. CD141+ DC are the human equivalents of murine CD8+ /CD103+ DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte (CTL) responses, making them attractive targets to exploit for the development of new cancer immunotherapies...
January 18, 2018: Immunology and Cell Biology
Yi Chen, Tingyu Song, Yong-Le Xiao, Xiaoping Wan, Luyi Yang, Jinghai Li, Guangzhi Zeng, Pengfei Fang, Ze-Zhou Wang, Rong Gao
In order to develop a novel effective immunomodulator to enhance pig resistance against post-weaning multi systemic wasting syndrome (PMWS), a recombinant plasmid co-expressing pig interleukin-2 (IL-2) and fusion interleukin-4/6 (IL-4/6) genes, designated VRIL4/6-2, was constructed and encapsulated in chitosan (CS) nanoparticles prepared by the ionotropic gelation method. Then 21-day old piglets were divided into two groups and intramuscularly injected respectively with VPIL4/6-2-CS and saline along with the porcine circovirus-2 (PCV-2) vaccine...
December 29, 2017: Research in Veterinary Science
Sai Mao, Mingshu Wang, Xumin Ou, Di Sun, Anchun Cheng, Dekang Zhu, Shun Chen, Renyong Jia, Mafeng Liu, Kunfeng Sun, Qiao Yang, Ying Wu, Xinxin Zhao, Xiaoyue Chen
Duck hepatitis A virus 1 (DHAV-1) infection in mature ducks has previously been proposed as a small-animal model for human hepatitis A. However, basic research on the outcome of DHAV-1 infection in mature ducks is limited. Here, we examined the course of viremia, the characteristics of antibody responses, and the profiles of plasma cytokines in mature ducks infected with DHAV-1. During the course of infection, the viremia was detectable soon after infection and persisted for 196 days, however, the ducks presented as clinically asymptomatic...
2017: Frontiers in Immunology
Jérôme Widmer, Cédric Thauvin, Inès Mottas, Van Nga Nguyen, Florence Delie, Eric Allémann, Carole Bourquin
Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles...
January 15, 2018: International Journal of Pharmaceutics
Peter Larson, Tamara A Kucaba, Zhengming Xiong, Michael Olin, Thomas S Griffith, David M Ferguson
A series of N1-modified imidazoquinolines were synthesized and screened for Toll-like receptors (TLR) 7 and 8 activities to identify recognition elements that confer high affinity binding and selectivity. These receptors are key targets in the development of immunomodulatory agents that signal the NF-κB mediated transcription of pro-inflammatory chemokines and cytokines. Results are presented showing both TLR7/8 activations are highly correlated to N1-substitution, with TLR8 selectivity achieved through inclusion of an ethyl-, propyl-, or butylamino group at this position...
November 9, 2017: ACS Medicinal Chemistry Letters
Anargyros Bakopoulos, Alkistis Kapelouzou, Diamantis I Tsilimigras, Michalis Katsimpoulas, Dimitrios Schizas, Chrysostomos Aravanis, Evaggelos Balafas, Manolis Mavroidis, Kitty Pavlakis, Anastasios Machairas, Theodore Liakakos
BACKGROUND: Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system and appear as a severity index of the clinical course...
2017: PloS One
Jurjen M Ruben, Gina Stella García-Romo, Eytan Breman, Sandra van der Kooij, Anke Redeker, Ramon Arens, Cees van Kooten
Plasmacytoid dendritic cells (pDCs) are antigen presenting cells specialized in viral recognition through Toll-like receptor (TLR)7 and TLR9, and produce vast amounts of interferon alpha upon ligation of these TLRs. We had previously demonstrated a strong influx of pDCs in the tubulointerstitium of renal biopsies at the time of acute rejection. However, the role of human pDCs in mediating acute or chronic allograft rejection remains elusive. pDCs are thought to have a limited capacity to ingest apoptotic cells, critical for inducing CD4+ T cell activation via indirect antigen presentation and subsequent activation of antibody producing B cells...
October 20, 2017: Kidney International
Satheesha Avunje, Sung-Ju Jung
The stimulation of immune genes by polyinosinic:polycytidylic acid (poly (I:C)) and imiquimod in olive flounder (Paralichthys olivaceus) and their role in control of viral haemorrhagic septicaemia virus (VHSV) infection were examined. Poly (I:C) (100 μg/fish) treated olive flounder had very low mortality (5%) post VHSV infection, while the imiquimod treated group had 65% and 85% mortality at a dose of 100 μg/fish and 50 μg/fish, respectively. Though the imiquimod treated group had high mortality, it was lower than the untreated group, which had 90% mortality...
October 18, 2017: Fish & Shellfish Immunology
Susana Figueroa-Lozano, Rivca L Valk-Weeber, Sander S van Leeuwen, Lubbert Dijkhuizen, Paul de Vos
SCOPE: Bovine lactoferrin (bLF) is an ingredient of food supplements and infant formulas given its antimicrobial and antiviral properties. We modified bLF enzymatically to alter its N-glycosylation and to isolate the glycan chains. The aims of this study were 1) to evaluate whether such derivates induce responses via Pattern Recognition Receptors (PRRs) namely Toll-like receptors (TLRs) and 2) to relate those responses to their different glycosylation profiles. METHODS AND RESULTS: The unmodified and modified bLF fractions were incubated with reporter cell lines expressing PRRs...
October 3, 2017: Molecular Nutrition & Food Research
José R López-Mínguez, Juan M Nogales-Asensio, Sebastián Romani, Fernando Rivero-Crespo, Victor M Aragón-Extremera, Jesús M Jiménez-Mazuecos, Fernando Carrasco, Juan Francisco Oteo-Domínguez, Francisco Bosa-Ojeda, Joan A Gómez-Hospital
OBJECTIVES: To compare the safety and efficacy of the new cobalt-chromium bioactive stent Titan Optimax(®) (Hexacath, France) with its predecessor, Titan-2(®) . BACKGROUND: The TIOMAX registry includes 784 patients who underwent percutaneous coronary intervention with these stents in 21 Spanish hospitals. METHODS: Analysis of all patients in the registry without exclusion criteria, candidates for revascularization (March-2013/July-2014)...
September 30, 2017: Catheterization and Cardiovascular Interventions
Mahboubeh Ebrahimian, Maryam Hashemi, Mohsen Maleki, Gholamreza Hashemitabar, Khalil Abnous, Mohammad Ramezani, Alireza Haghparast
Strategies to design delivery vehicles are critical in modern vaccine-adjuvant development. Nanoparticles (NPs) encapsulating antigen(s) and adjuvant(s) are promising vehicles to deliver antigen(s) and adjuvant(s) to antigen-presenting cells (APCs), allowing optimal immune responses against a specific pathogen. In this study, we developed a novel adjuvant delivery approach for induction of efficient in vivo immune responses. Polyethylenimine (PEI) was physically conjugated to poly(lactic-co-glycolic) acid (PLGA) to form PLGA/PEI NPs...
2017: Frontiers in Immunology
Carlene Petes, Natalya Odoardi, Katrina Gee
Toll-like receptor (TLR)-7 is an endosomal innate immune sensor capable of detecting single-stranded ribonucleic acid. TLR7-mediated induction of type I interferon and other inflammatory cytokine production is important in antiviral immune responses. Furthermore, altered TLR7 expression levels are implicated in various autoimmune disorders, indicating a key role for this receptor in modulating inflammation. This review is focused on the regulation of TLR7 expression and localization compared to that of the other endosomal TLRs: TLR3, 8, and 9...
2017: Frontiers in Immunology
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