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Muneer G Hasham, Nicoleta Baxan, Daniel J Stuckey, Jane Branca, Bryant Perkins, Oliver Dent, Ted Duffy, Tolani S Hameed, Sarah E Stella, Mohammed Bellahcene, Michael D Schneider, Sian E Harding, Nadia Rosenthal, Susanne Sattler
Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to systemic autoimmunity lacks inducible rodent models. Here, we characterise immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the Toll-like receptor 7/8 (TLR7/8) agonist Resiquimod...
March 1, 2017: Disease Models & Mechanisms
Thibaud Spinetti, Lorenzo Spagnuolo, Inès Mottas, Chiara Secondini, Marina Treinies, Curzio Rüegg, Christian Hotz, Carole Bourquin
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC...
2016: Oncoimmunology
Ethan Poteet, Phoebe Lewis, Changyi Chen, Sam On Ho, Thai Do, SuMing Chiang, Celia Labranche, David Montefiori, Gary Fujii, Qizhi Yao
Human Immunodeficiency Virus (HIV) Virus-Like Particles (VLPs) composed of HIVIIIB Gag and HIVBaL gp120/gp41 envelope are a pseudovirion vaccine capable of presenting antigens in their native conformations. To enhance the immunogenicity of the HIV Env antigen, VLPs were coupled to VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) containing one of four toll-like-receptor (TLR) ligands, each activating a receptor with distinct cellular localization and downstream pathways. C57BL/6 mice were vaccinated by intranasal prime followed by two sub-cheek boosts and their sera immunoglobulin and neutralizing potency were measured over a duration of 3months after vaccination...
November 21, 2016: Vaccine
Yunan Wei, Hao Zhou, Anqi Wang, Lipei Sun, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Qiao Yang, Ying Wu, Kunfeng Sun, Xiaoyue Chen, Anchun Cheng, Shun Chen
The retinoic acid-inducible gene I (RIG-I) and the RIG-I-like receptor (RLR) protein play a critical role in the interferon (IFN) response during RNA virus infection. The tripartite motif containing 25 proteins (TRIM25) was reported to modify caspase activation and RIG-I recruitment domains (CARDs) via ubiquitin. These modifications allow TRIM25 to interact with mitochondrial antiviral signaling molecules (MAVs) and form CARD-CARD tetramers. Goose TRIM25 was cloned from gosling lungs, which possess a 1662 bp open reading flame (ORF)...
2016: BioMed Research International
Latha B Pathangey, Dustin B McCurry, Sandra J Gendler, Ana L Dominguez, Jessica E Gorman, Girish Pathangey, Laurie A Mihalik, Yushe Dang, Mary L Disis, Peter A Cohen
Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor-specific T-cells from peripheral blood. We hypothesized that antigen-driven T-cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by γ-chain cytokine-modulated T-cell hyperexpansion...
February 14, 2017: Oncotarget
Veronika Caisová, Andra Vieru, Zuzana Kumžáková, Simona Glaserová, Hana Husníková, Nikol Vácová, Gabriela Krejčová, Lucie Paďouková, Ivana Jochmanová, Katherine I Wolf, Jindřich Chmelař, Jan Kopecký, Jan Ženka
BACKGROUND: Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19(th) century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. METHODS: B16-F10 murine melanoma model was used...
December 7, 2016: BMC Cancer
Adan Chari Jirmo, Kathleen Daluege, Christine Happle, Melanie Albrecht, Anna-Maria Dittrich, Mandy Busse, Anika Habener, Jelena Skuljec, Gesine Hansen
Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell-driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Xuefeng Wang, Li Li, Jun Wang, Liyang Dong, Yang Shu, Yong Liang, Liang Shi, Chengcheng Xu, Yuepeng Zhou, Yi Wang, Deyu Chen, Chaoming Mao
Helminth-derived products have recently been shown to prevent the development of inflammatory diseases in mouse models. However, most identified immunomodulators from helminthes are mixtures or macromolecules with potentially immunogenic side effects. We previously identified an immunomodulatory peptide called SJMHE1 from the HSP60 protein of Schistosoma japonicum. In this study, we assessed the ability of SJMHE1 to affect murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated by toll-like receptor (TLR) ligands in vitro and its treatment effect on mice with collagen-induced arthritis (CIA)...
March 2017: Journal of Cellular and Molecular Medicine
Gabriela Maria Wiedemann, Severin Johannes Jacobi, Michael Chaloupka, Angelina Krächan, Svetlana Hamm, Stefan Strobl, Roland Baumgartner, Simon Rothenfusser, Peter Duewell, Stefan Endres, Sebastian Kobold
Toll-like receptor 7 (TLR7) agonists are potent immune stimulants able to overcome cancer-associated immune suppression. Due to dose-limiting systemic toxicities, only the topically applied TLR7 agonist (imiquimod) has been approved for therapy of skin tumors. There is a need for TLR7-activating compounds with equivalent efficacy but less toxicity. SC1, a novel small molecule agonist for TLR7, is a potent type-1 interferon inducer, comparable to the reference TLR7 agonist resiquimod, yet with lower induction of proinflammatory cytokines...
July 2016: Oncoimmunology
Matthew D Gallovic, Kevin L Schully, Matthew G Bell, Margaret A Elberson, John R Palmer, Christian A Darko, Eric M Bachelder, Barbara E Wyslouzil, Andrea M Keane-Myers, Kristy M Ainslie
Subunit formulations are regarded as the safest type of vaccine, but they often contain a protein-based antigen that can result in significant challenges, such as preserving antigenicity during formulation and administration. Many studies have demonstrated that encapsulation of protein antigens in polymeric microparticles (MPs) via emulsion techniques results in total IgG antibody titers comparable to alum formulations, however, the antibodies themselves are non-neutralizing. To address this issue, a coaxial electrohydrodynamic spraying (electrospray) technique is used to formulate a microparticulate-based subunit anthrax vaccine under conditions that minimize recombinant protective antigen (rPA) exposure to harsh solvents and high shear stress...
September 5, 2016: Advanced Healthcare Materials
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
Han-Ha Chai, Dajeong Lim, Jae Eun Suk, Bong-Hwan Choi, Yong-Min Cho
In the absence of an experimental bTLR8 structure, recent studies have called attention to the fact that bTLR8 can also be activated by hTLR7/hTLR8 agonist, such as antiviral imidazoquinoline derivatives of resiquimod (R848) and imiquimod (R837) as well as some guanine nucleotide analogs with a scaffold structure related to the nucleic acids of ssRNA virus. In particular, the known small agonists (namely CL075, CL097 and R848) have been targeted to determine distinguishable deciding factors in complex with dimeric bTLR8-ECDs in comparison to ligand-induced activated hTLR8-ECDs...
November 2016: International Journal of Biological Macromolecules
Arunsaravanakumar Annamalai, Saravanan Ramakrishnan, Swati Sachan, B S Anand Kumar, Bal Krishan Sharma, Vimal Kumar, Munuswamy Palanivelu, Berin P Varghese, Ajay Kumar, B C Saravanan, Narayanan Krishnaswamy
The study evaluated the prophylactic potential of resiquimod (R-848), a synthetic TLR7 agonist, against very virulent infectious bursal disease virus (vvIBDV) infection in chicken. Specific pathogen free White Leghorn chicks of three week age were treated with R-848 (50μg/bird, intramuscular) or PBS (n=26/group). Twenty four hour later, half of the birds from each group were challenged with 10(5) ELD50 of vvIBDV and observed for 10days. To understand the effect of R-848, immune response genes such as interferon (IFN)-β, IFN-γ, IL-1β, IL-4, iNOS and TLR7 were analyzed at 24 and 48h post-challenge in PBMCs ex vivo by real-time PCR (n=6/group)...
May 1, 2016: Veterinary Microbiology
William A Nyberg, Alexander Espinosa
Endoplasmic reticulum (ER) stress is a physiological response to protein overload or misfolded proteins in the ER. Certain anti-cancer drugs, e.g. bortezomib and nelfinavir, induce ER stress implying that this could be a successful therapeutic strategy against several forms of cancer. To find novel ER-stress inducers we screened a panel of natural and synthetic Toll-like receptor (TLR) agonists against human keratinocytes and identified the anti-cancer drug imiquimod (IMQ) as a potent inducer of ER stress. Other TLR7 and TLR8 agonists, including resiquimod and gardiquimod, did not induce ER stress, demonstrating that IMQ induces ER stress independently of TLR7 and TLR8...
May 13, 2016: Biochemical and Biophysical Research Communications
Michael C Abt, Charlie G Buffie, Bože Sušac, Simone Becattini, Rebecca A Carter, Ingrid Leiner, James W Keith, David Artis, Lisa C Osborne, Eric G Pamer
Antibiotic administration can disrupt the intestinal microbiota and down-regulate innate immune defenses, compromising colonization resistance against orally acquired bacterial pathogens. Vancomycin-resistant Enterococcus faecium (VRE), a major cause of antibiotic-resistant infections in hospitalized patients, thrives in the intestine when colonization resistance is compromised, achieving extremely high densities that can lead to bloodstream invasion and sepsis. Viral infections, by mechanisms that remain incompletely defined, can stimulate resistance against invading bacterial pathogens...
February 24, 2016: Science Translational Medicine
Paul F McKay, Deborah F L King, Jamie F S Mann, Guillermo Barinaga, Darrick Carter, Robin J Shattock
The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model...
2016: PloS One
Ahmed Nadeem, Nahid Siddiqui, Naif O Al-Harbi, Mohammed M Al-Harbi, Sheikh F Ahmad
Toll-like receptors (TLRs) through innate immune system recognize pathogen associated molecular patterns and play an important role in host defense against bacteria, fungi and viruses. TLR-7 is responsible for sensing single stranded nucleic acids of viruses but its activation has been shown to be protective in mouse models of asthma. The NADPH oxidase (NOX) enzymes family mainly produces reactive oxygen species (ROS) in the lung and is involved in regulation of airway inflammation in response to TLRs activation...
April 2016: International Journal of Biochemistry & Cell Biology
Ronald S Veazey, Asna Siddiqui, Katja Klein, Viviana Buffa, Lucia Fischetti, Lara Doyle-Meyers, Deborah F King, John S Tregoning, Robin J Shattock
Delivering vaccine antigens to mucosal surfaces is potentially very attractive, especially as protection from mucosal infections may be mediated by local immune responses. However, to date mucosal immunization has had limited successes, with issues of both safety and poor immunogenicity. One approach to improve immunogenicity is to develop adjuvants that are effective and safe at mucosal surfaces. Differences in immune responses between mice and men have overstated the value of some experimental adjuvants which have subsequently performed poorly in the clinic...
2015: Human Vaccines & Immunotherapeutics
Nina Salabert, Biliana Todorova, Frédéric Martinon, Raphaël Boisgard, Gerard Zurawski, Sandra Zurawski, Nathalie Dereuddre-Bosquet, Antonio Cosma, Thierry Kortulewski, Jacques Banchereau, Yves Levy, Roger Le Grand, Catherine Chapon
The development of new immunization strategies requires a better understanding of early molecular and cellular events occurring at the site of injection. The skin is particularly rich in immune cells and represents an attractive site for vaccine administration. Here, we specifically targeted vaccine antigens to epidermal Langerhans cells (LCs) using a fusion protein composed of HIV antigens and a monoclonal antibody targeting Langerin. We developed a fluorescence imaging approach to visualize, in vivo, the vaccine-targeted cells...
March 2016: European Journal of Immunology
Anthony D Duong, Michael A Collier, Eric M Bachelder, Barbra E Wyslouzil, Kristy M Ainslie
Resiquimod is a Toll-like receptor (TLR) 7/8 agonist that has previously been used as a vaccine adjuvant, as a topical treatment of viral lesions and skin cancer, and as an antiviral treatment. We report on the combined application of remote loading and electrospray to produce liposomal resiquimod, with the broader goals of improving drug encapsulation efficiency and scalability of liposome production methods. Drug loading in liposomes increased from less than 1% to greater that 3% by mass when remote loading was used, whether the liposomes were generated by thin-film hydration or electrospray methods...
January 4, 2016: Molecular Pharmaceutics
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