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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)...
September 28, 2016: 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
Richard L Salisbury, Courtney E W Sulentic
Transcriptional regulation of the murine immunoglobulin (Ig) heavy chain gene (Igh) involves several regulatory elements including the 3'Igh regulatory region (3'IghRR), which is composed of at least 4 enhancers (hs3A, hs1.2, hs3B, and hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including nuclear factor kappaB/Rel (NF-κB/Rel) proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3'IghRR and hs1...
December 2015: Toxicological Sciences: An Official Journal of the Society of Toxicology
David Killock
No abstract text is available yet for this article.
October 2015: Nature Reviews. Clinical Oncology
Lakshmi Ganapathi, Simon Van Haren, David J Dowling, Ilana Bergelson, Nikunj M Shukla, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu, Sunil A David, Ofer Levy
BACKGROUND: Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848)...
2015: PloS One
Alain H Rook, Joel M Gelfand, Joel C Gelfand, Maria Wysocka, Andrea B Troxel, Bernice Benoit, Christian Surber, Rosalie Elenitsas, Marie A Buchanan, Deborah S Leahy, Rei Watanabe, Ilan R Kirsch, Ellen J Kim, Rachael A Clark
Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease...
September 17, 2015: Blood
Swati Sachan, Saravanan Ramakrishnan, Arunsaravanakumar Annamalai, Bal Krishan Sharma, Hina Malik, B C Saravanan, Lata Jain, Meeta Saxena, Ajay Kumar, Narayanan Krishnaswamy
Resiquimod (R-848), an imidazoquinoline compound, is a potent synthetic Toll-like receptor (TLR) 7 agonist. Although the solitary adjuvant potential of R-848 is well established in mammals, such reports are not available in avian species hitherto. Hence, the adjuvant potential of R-848 was tested in SPF chicken in this study. Two week old chicks were divided into four groups (10 birds/group) viz., control (A), inactivated Newcastle disease virus (NDV) vaccine prepared from velogenic strain (B), commercial oil adjuvanted inactivated NDV vaccine prepared from lentogenic strain (C) and inactivated NDV vaccine prepared from velogenic strain with R-848 (D)...
August 26, 2015: Vaccine
Mohammed A Khedr, Behairy E Behairy, Mohsen E Hussein, Ayman M Marei, Salma A Nage, Haidy M Zakaria
BACKGROUND: Hepatitis C virus (HCV) infection is a major health problem worldwide. Defective dendritic cell (DC) activation of T cells may underlie poor T-cell responsiveness in HCV infection. OBJECTIVE: To evaluate the DCs' functions in chronically infected HCV patients and its correlation with the response to therapy. PATIENTS AND METHODS: This prospective study included 30 chronic hepatitis C (CHC) patients and 30 healthy age-matched and sex-matched controls...
October 2015: European Journal of Gastroenterology & Hepatology
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