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Yu L, Yang F, Li C, Ruan J, Wang J. Poly(amidoamine) Dendrimers as Potential Therapeutic Agents for Conservative Treatment of Irreversible Pulpitis. J Endod 2025:S0099-2399(25)00193-1. [PMID: 40274259 DOI: 10.1016/j.joen.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 04/09/2025] [Accepted: 04/12/2025] [Indexed: 04/26/2025]
Abstract
INTRODUCTION Although cell-free DNA (cfDNA) is involved in several inflammation-related diseases, its role in pulp inflammation remains unclear. The aims of this study were to explore the role of cfDNA in the development of irreversible pulpitis and to identify a potential therapeutic strategy. METHODS Pulpitis plasma samples were collected from patients diagnosed with irreversible pulpitis, and the cfDNA concentration associated with pulpitis was measured using a Quant-iT PicoGreen dsDNA kit. Dental pulp stem cells and Tohoku Hospital Pediatrics -1 macrophages were stimulated with pulpitis plasma, and the expression of inflammatory factors was investigated via real-time reverse transcription PCR and ELISA. Toll-like receptor 9 expression in pulpitis blood-derived cells was analyzed by flow cytometry. Finally, the effects of cationic poly(amidoamine) (PAMAM) on the treatment of inflammation in vitro and in a rat pulpitis model were evaluated. RESULTS We first revealed that pulpitis-derived plasma had elevated cfDNA levels, which caused M1-like macrophage polarization through the toll-like receptor 9 signaling pathway and then induced an inflammatory response in dental pulp stem cells. M1-like macrophage polarization affected the pulp inflammatory microenvironment and could be reversed via a synergistic effect of irrigation and cationic PAMAM for cfDNA scavenging. PAMAM has shown potential for inhibiting inflammatory M1-like macrophage polarization and alleviating pulpitis at the cellular and organism levels. CONCLUSIONS This study elucidated the importance of cfDNA in pulpitis and provides a potential therapeutic strategy. cfDNA scavenging could alleviate the inflammatory response in pulpitis and potentially preserve more vital pulp for teeth with irreversible pulpitis.
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Affiliation(s)
- Lintong Yu
- Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China; Shanghai Research Institute of Stomatology, Shanghai, China
| | - Feng Yang
- Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China; Shanghai Research Institute of Stomatology, Shanghai, China
| | - Chenxi Li
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jing Ruan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jun Wang
- Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China; Shanghai Research Institute of Stomatology, Shanghai, China.
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White CL, Glover MA, Gandhapudi SK, Richards KA, Sant AJ. Flublok Quadrivalent Vaccine Adjuvanted with R-DOTAP Elicits a Robust and Multifunctional CD4 T Cell Response That Is of Greater Magnitude and Functional Diversity Than Conventional Adjuvant Systems. Vaccines (Basel) 2024; 12:281. [PMID: 38543915 PMCID: PMC10975948 DOI: 10.3390/vaccines12030281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/20/2024] [Accepted: 02/29/2024] [Indexed: 04/01/2024] Open
Abstract
It is clear that new approaches are needed to promote broadly protective immunity to viral pathogens, particularly those that are prone to mutation and escape from antibody-mediated immunity. CD4+ T cells, known to target many viral proteins and highly conserved peptide epitopes, can contribute greatly to protective immunity through multiple mechanisms. Despite this potential, CD4+ T cells are often poorly recruited by current vaccine strategies. Here, we have analyzed a promising new adjuvant (R-DOTAP), as well as conventional adjuvant systems AddaVax with or without an added TLR9 agonist CpG, to promote CD4+ T cell responses to the licensed vaccine Flublok containing H1, H3, and HA-B proteins. Our studies, using a preclinical mouse model of vaccination, revealed that the addition of R-DOTAP to Flublok dramatically enhances the magnitude and functionality of CD4+ T cells specific for HA-derived CD4+ T cell epitopes, far outperforming conventional adjuvant systems based on cytokine EliSpot assays and multiparameter flow cytometry. The elicited CD4+ T cells specific for HA-derived epitopes produce IL-2, IFN-γ, IL-4/5, and granzyme B and have multifunctional potential. Hence, R-DOTAP, which has been verified safe by human studies, can offer exciting opportunities as an immune stimulant for next-generation prophylactic recombinant protein-based vaccines.
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Affiliation(s)
- Chantelle L. White
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (C.L.W.); (M.A.G.); (K.A.R.)
| | - Maryah A. Glover
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (C.L.W.); (M.A.G.); (K.A.R.)
| | - Siva K. Gandhapudi
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky School of Medicine, Lexington, KY 40508, USA;
| | - Katherine A. Richards
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (C.L.W.); (M.A.G.); (K.A.R.)
| | - Andrea J. Sant
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (C.L.W.); (M.A.G.); (K.A.R.)
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Chen Z, Yang S, Zhao Z, Feng L, Sheng J, Deng R, Wang B, He Y, Luo D, Chen M, Chen L, Chang K. Smart Tumor Cell-Derived DNA Nano-Tree Assembly for On-Demand Macrophages Reprogramming. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2307188. [PMID: 38145350 PMCID: PMC10933644 DOI: 10.1002/advs.202307188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/07/2023] [Indexed: 12/26/2023]
Abstract
Without coordinated strategies to balance the population and activity of tumor cells and polarized macrophages, antitumor immunotherapy generally offers limited clinical benefits. Inspired by the "eat me" signal, a smart tumor cell-derived proximity anchored non-linear hybridization chain reaction (Panel-HCR) strategy is established for on-demand regulation of tumor-associated macrophages (TAMs). The Panel-HCR is composed of a recognition-then-assembly module and a release-then-regulation module. Upon recognizing tumor cells, a DNA nano-tree is assembled on the tumor cell surface and byproduct strands loaded with CpG oligodeoxynucleotides (CpG-ODNs) are released depending on the tumor cell concentration. The on-demand release of CpG-ODNs can achieve efficient regulation of M2 TAMs into the M1 phenotype. Throughout the recognition-then-assembly process, tumor cell-targeted bioimaging is implemented in single cells, fixed tissues, and living mice. Afterward, the on-demand release of CpG-ODNs regulate the transformation of M2 TAMs into the M1 phenotype by stimulating toll-like receptor 9 to activate the NF-κB pathway and increasing inflammatory cytokines. This release-then-regulation process is verified to induce strong antitumor immune responses both in vitro and in vivo. Altogether, this proposed strategy holds tremendous promise for on-demand antitumor immunotherapy.
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Affiliation(s)
- Zhiguo Chen
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
- Department of Gastroenterology, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Sha Yang
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Zhuyang Zhao
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Liu Feng
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Jing Sheng
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Ruijia Deng
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Binpan Wang
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Yuan He
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Dan Luo
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853‐5701USA
| | - Ming Chen
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Lei Chen
- Department of Gastroenterology, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
| | - Kai Chang
- Department of Clinical Laboratory Medicine, Southwest HospitalArmy Medical University (Third Military Medical University)30 Gaotanyan, Shapingba DistrictChongqing400038China
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Leal Rodríguez C, Shah SA, Rasmussen MA, Thorsen J, Boulund U, Pedersen CET, Castro-Mejía JL, Poulsen CE, Poulsen CS, Deng L, Larsen FAN, Widdowson M, Zhang Y, Sørensen SJ, Moineau S, Petit MA, Chawes B, Bønnelykke K, Nielsen DS, Stokholm J. The infant gut virome is associated with preschool asthma risk independently of bacteria. Nat Med 2024; 30:138-148. [PMID: 38102298 DOI: 10.1038/s41591-023-02685-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 11/07/2023] [Indexed: 12/17/2023]
Abstract
Bacteriophage (also known as phage) communities that inhabit the gut have a major effect on the structure and functioning of bacterial populations, but their roles and association with health and disease in early life remain unknown. Here, we analyze the gut virome of 647 children aged 1 year from the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort, all deeply phenotyped from birth and with longitudinally assessed asthma diagnoses. Specific temperate gut phage taxa were found to be associated with later development of asthma. In particular, the joint abundances of 19 caudoviral families were found to significantly contribute to this association. Combining the asthma-associated virome and bacteriome signatures had additive effects on asthma risk, implying an independent virome-asthma association. Moreover, the virome-associated asthma risk was modulated by the host TLR9 rs187084 gene variant, suggesting a direct interaction between phages and the host immune system. Further studies will elucidate whether phages, alongside bacteria and host genetics, can be used as preclinical biomarkers for asthma.
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Affiliation(s)
- Cristina Leal Rodríguez
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Shiraz A Shah
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Morten Arendt Rasmussen
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
| | - Jonathan Thorsen
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Ulrika Boulund
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Casper-Emil Tingskov Pedersen
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Christina Egeø Poulsen
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Casper Sahl Poulsen
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Ling Deng
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
| | | | - Michael Widdowson
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Yichang Zhang
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
| | - Søren J Sørensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Sylvain Moineau
- Département de Biochimie, de Microbiologie, et de Bio-Informatique, Faculté des Sciences et de Génie, Université Laval, Québec City, QC, Canada
- Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec City, QC, Canada
- Félix d'Hérelle Reference Center for Bacterial Viruses, Université Laval, Québec City, QC, Canada
| | - Marie-Agnès Petit
- Université Paris-Saclay, INRAE, Agroparistech, Micalis Institute, Jouy-en-Josas, France
| | - Bo Chawes
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Klaus Bønnelykke
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark
| | - Dennis S Nielsen
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Stokholm
- Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark.
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
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Bao H, Yan J, Huang J, Deng W, Zhang C, Liu C, Huang A, Zhang Q, Xiong Y, Wang Q, Wu H, Hou L. Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress. J Neuroinflammation 2023; 20:37. [PMID: 36793064 PMCID: PMC9933381 DOI: 10.1186/s12974-023-02724-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.
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Affiliation(s)
- Han Bao
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Jinqi Yan
- grid.452438.c0000 0004 1760 8119Department of Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
| | - Jiancheng Huang
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Wenjuan Deng
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Ce Zhang
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Cong Liu
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Ailing Huang
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Qiao Zhang
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Ying Xiong
- grid.12955.3a0000 0001 2264 7233Department of Anesthesiology, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang’an Rd, Xiamen, 361102 China
| | - Qiang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, West of Yanta Rd, Xi'an, 710061, China.
| | - Huanghui Wu
- Translational Research Institute of Brain and Brain-Like Intelligence, School of Medicine, Shanghai Fourth People's Hospital, Tongji University, Shanghai, 200434, China. .,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, No.1279, Sanmen Rd, Shanghai, 200434, China.
| | - Lichao Hou
- Department of Anesthesiology, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, No. 2000, East of Xiang'an Rd, Xiamen, 361102, China.
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Qu Y, Shen F, Zhang Z, Wang Q, Huang H, Xu Y, Li Q, Zhu X, Sun L. Applications of Functional DNA Materials in Immunomodulatory Therapy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:45079-45095. [PMID: 36171537 DOI: 10.1021/acsami.2c13768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
In recent years, nanoscale or microscale functional materials derived from DNA have shown great potential for immunotherapy as superior delivery carriers. DNA nanostructures with excellent programmability and addressability enable the precise assembly of molecules or nanoparticles. DNA hydrogels have predictable structures and adjustable mechanical strength, thus being advantageous in controllable release of cargos. In addition, utilizing systematic evolution of ligands by exponential enrichment technology, a variety of DNA aptamers have been screened for specific recognition of ions, molecules, and even cells. Moreover, a wide variety of chemical modifications can further enrich the function of DNA. The unique advantages of functional DNA materials make them extremely attractive in immunomodulation. Recently, functional DNA materials-based immunotherapy has shown great potential in fighting against many diseases like cancer, viral infection, and inflammation. Therefore, in this review, we focus on discussing the progress of the applications of functional DNA materials in immunotherapy; before that, we also summarize the characteristics of the functional DNA materials descried above. Finally, we discuss the challenges and future opportunities of functional DNA materials in immunomodulatory therapy.
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Affiliation(s)
- Yanfei Qu
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Fengyun Shen
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ziyi Zhang
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Qi Wang
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Hao Huang
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Yufei Xu
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Qian Li
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xiaoli Zhu
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Lele Sun
- School of Life Sciences, Shanghai University, Shanghai 200444, China
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Latanova A, Starodubova E, Karpov V. Flaviviridae Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation. Viruses 2022; 14:v14081808. [PMID: 36016430 PMCID: PMC9414172 DOI: 10.3390/v14081808] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022] Open
Abstract
Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes.
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Wang Q, Qu Y, Zhang Z, Huang H, Xu Y, Shen F, Wang L, Sun L. Injectable DNA Hydrogel-Based Local Drug Delivery and Immunotherapy. Gels 2022; 8:gels8070400. [PMID: 35877485 PMCID: PMC9320917 DOI: 10.3390/gels8070400] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/13/2022] [Accepted: 06/16/2022] [Indexed: 12/26/2022] Open
Abstract
Regulated drug delivery is an important direction in the field of medicine and healthcare research. In recent years, injectable hydrogels with good biocompatibility and biodegradability have attracted extensive attention due to their promising application in controlled drug release. Among them, DNA hydrogel has shown great potentials in local drug delivery and immunotherapy. DNA hydrogel is a three-dimensional network formed by cross-linking of hydrophilic DNA strands with extremely good biocompatibility. Benefiting from the special properties of DNA, including editable sequence and specificity of hybridization reactions, the mechanical properties and functions of DNA hydrogels can be precisely designed according to specific applications. In addition, other functional materials, including peptides, proteins and synthetic organic polymers can be easily integrated with DNA hydrogels, thereby enriching the functions of the hydrogels. In this review, we first summarize the types and synthesis methods of DNA hydrogels, and then review the recent research progress of injectable DNA hydrogels in local drug delivery, especially in immunotherapy. Finally, we discuss the challenges facing DNA hydrogels and future development directions.
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Affiliation(s)
- Qi Wang
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
| | - Yanfei Qu
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
| | - Ziyi Zhang
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
| | - Hao Huang
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
| | - Yufei Xu
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
| | - Fengyun Shen
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 201240, China
- Correspondence: (F.S.); (L.S.)
| | - Lihua Wang
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China;
| | - Lele Sun
- School of Life Sciences, Shanghai University, Shanghai 200444, China; (Q.W.); (Y.Q.); (Z.Z.); (H.H.); (Y.X.)
- Correspondence: (F.S.); (L.S.)
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9
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Zheng SY, Dong JZ. Role of Toll-Like Receptors and Th Responses in Viral Myocarditis. Front Immunol 2022; 13:843891. [PMID: 35514979 PMCID: PMC9062100 DOI: 10.3389/fimmu.2022.843891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Myocarditis is the common cause of sudden cardiac death, dilated cardiomyopathy (DCM) and heart failure (HF) in young adults. The most common type of myocarditis is viral myocarditis (VMC). Toll-like receptors (TLRs) are vital to identify pathogens in vivo. TLRs promote the differentiation of naive CD4+T cells to T helper (Th) cells, activate the immune response, and participate in the pathogenesis of autoimmune and allergic diseases. Although the pathogenesis of VMC is unclear, autoimmune responses have been confirmed to play a significant role; hence, it could be inferred that VMC is closely related to TLRs and Th responses. Some drugs have been found to improve the prognosis of VMC by regulating the immune response through activated TLRs. In this review, we discuss the role of TLRs and Th responses in VMC.
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Affiliation(s)
- Shi-Yue Zheng
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jian-Zeng Dong
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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10
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Linares R, Francés R, Gutiérrez A, Juanola O. Bacterial Translocation as Inflammatory Driver in Crohn's Disease. Front Cell Dev Biol 2021; 9:703310. [PMID: 34557484 PMCID: PMC8452966 DOI: 10.3389/fcell.2021.703310] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.
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Affiliation(s)
- Raquel Linares
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Ana Gutiérrez
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain.,Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Oriol Juanola
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Faculty of Biomedical Sciences, Universitá della Svizzera Italiana, Lugano, Switzerland
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11
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Sha S, Pearson JA, Peng J, Hu Y, Huang J, Xing Y, Zhang L, Zhu Y, Zhao H, Wong FS, Chen L, Wen L. TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model. Diabetes 2021; 70:504-515. [PMID: 33154070 PMCID: PMC7881860 DOI: 10.2337/db20-0373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 11/01/2020] [Indexed: 12/22/2022]
Abstract
Toll-like receptor 9 (TLR9) is highly expressed in B cells, and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on β-cell autoimmunity is not known. To fill this knowledge gap, we generated NOD mice with a B-cell-specific deficiency of TLR9 (TLR9fl/fl/CD19-Cre+ NOD). The B-cell-specific deletion of TLR9 resulted in near-complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of interleukin-10 (IL-10)-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.
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Affiliation(s)
- Sha Sha
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
| | - James A Pearson
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
| | - Jian Peng
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
| | - Youjia Hu
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
| | - Juan Huang
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
| | - Yanpeng Xing
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Luyao Zhang
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Zhu
- Department of Biostatistics, School of Public Health, Yale University, New Haven, CT
| | - Hongyu Zhao
- Department of Biostatistics, School of Public Health, Yale University, New Haven, CT
| | - F Susan Wong
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, U.K
| | - Li Chen
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China
| | - Li Wen
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
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12
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Shields CW, Wang LLW, Evans MA, Mitragotri S. Materials for Immunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1901633. [PMID: 31250498 DOI: 10.1002/adma.201901633] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/17/2019] [Indexed: 05/20/2023]
Abstract
Breakthroughs in materials engineering have accelerated the progress of immunotherapy in preclinical studies. The interplay of chemistry and materials has resulted in improved loading, targeting, and release of immunomodulatory agents. An overview of the materials that are used to enable or improve the success of immunotherapies in preclinical studies is presented, from immunosuppressive to proinflammatory strategies, with particular emphasis on technologies poised for clinical translation. The materials are organized based on their characteristic length scale, whereby the enabling feature of each technology is organized by the structure of that material. For example, the mechanisms by which i) nanoscale materials can improve targeting and infiltration of immunomodulatory payloads into tissues and cells, ii) microscale materials can facilitate cell-mediated transport and serve as artificial antigen-presenting cells, and iii) macroscale materials can form the basis of artificial microenvironments to promote cell infiltration and reprogramming are discussed. As a step toward establishing a set of design rules for future immunotherapies, materials that intrinsically activate or suppress the immune system are reviewed. Finally, a brief outlook on the trajectory of these systems and how they may be improved to address unsolved challenges in cancer, infectious diseases, and autoimmunity is presented.
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Affiliation(s)
- C Wyatt Shields
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, 02138, USA
| | - Lily Li-Wen Wang
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, 02138, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Michael A Evans
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, 02138, USA
| | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, 02138, USA
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13
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Zhao X, Xiao T, Jin S, Wang J, Wang J, Luo H, Li R, Sun T, Zou J, Li Y. Characterization and immune function of the interferon-β promoter stimulator-1 in the barbel chub, Squaliobarbus curriculus. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 104:103571. [PMID: 31837379 DOI: 10.1016/j.dci.2019.103571] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/29/2019] [Accepted: 12/10/2019] [Indexed: 06/10/2023]
Abstract
To elucidate the immunity-protecting role of the interferon-β promoter stimulator-1 (ScIPS-1) in barbel chub Squaliobarbus curriculus, the full-length cDNA of ScIPS-1 was cloned and expression levels in response to stimulation were investigated. In addition, the function of ScIPS-1 and its domains were analyzed. The full-length cDNA of ScIPS-1 is 2524 bp and encodes 601 aa. The N-terminal caspase activation and recruitment domain, central proline-rich domain, C-terminal transmembrane domain, C2HC-zinc finger, and Cwf21 domains were identified. The mRNA level of ScIPS-1 was the highest in the kidney, whereas the highest protein level was observed in the liver. The ScIPS-1 expressions were significantly up-regulated after lipopolysaccharide and poly I:C treatment. The ScIPS-1 protein level was up-regulated at 12 h in the head kidney and was up-regulated at 12 h and then down-regulated from 12 to 48 h in the liver after grass carp reovirus (GCRV) infection. The CiIFN and CiMx transcription levels were significantly enhanced in pEGFP-C1-IPS-1 and pcDNA3.1-ΔCwf21 overexpressing cells after GCRV infection. The results indicate that ScIPS-1 may function in the immune response against pathogens and provide a basis for achieving resistance to diseases in fish breeding.
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Affiliation(s)
- Xin Zhao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Tiaoyi Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Shengzhen Jin
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Jing'an Wang
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Junya Wang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Hong Luo
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Rui Li
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Tong Sun
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China
| | - Jun Zou
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Yaoguo Li
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, 410128, China.
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14
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Emanet M, Sen Ö, Taşkin IÇ, Çulha M. Synthesis, Functionalization, and Bioapplications of Two-Dimensional Boron Nitride Nanomaterials. Front Bioeng Biotechnol 2019; 7:363. [PMID: 31921797 PMCID: PMC6915082 DOI: 10.3389/fbioe.2019.00363] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/12/2019] [Indexed: 11/23/2022] Open
Abstract
Two-dimensional boron nitride nanostructures (2D-BNNs) have been increasingly investigated for their applications in several scientific and technological areas. This considerable interest is due to their unique physicochemical properties, which include high hydrophobicity, heat and electrical insulation, resistance to oxidation, antioxidation capacity, thermal conductivity, high chemical stability, mechanical strength, and hydrogen storage capacity. They are also used as fillers, antibacterial agents, protective coating agents, lubricants, boron neutron capture therapy agents, nanocarriers for drug delivery, and for the receptor phase in chemosensors. The investigations for their use in medicine and biomedicine are very promising, including cancer therapy and wound healing. In this review, 2D-BNNs synthesis and their surface modification strategies, biocompatibility, and bioapplication studies are discussed. Finally, a perspective for the future use of these novel nanomaterials in the biomedical field is provided.
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Affiliation(s)
| | | | | | - Mustafa Çulha
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
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15
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miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway. Vaccines (Basel) 2019; 7:vaccines7040197. [PMID: 31779082 PMCID: PMC6963666 DOI: 10.3390/vaccines7040197] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/08/2019] [Accepted: 11/11/2019] [Indexed: 01/04/2023] Open
Abstract
The Cytosine–phosphate–guanosine (CpG) motif, which is specifically recognized intracellularly by dendritic cells (DCs), plays a crucial role in regulating the innate immune response. MicroRNAs (miRNAs) can strongly influence the antigen-presenting ability of DCs. In this study, we examine the action of miRNAs on CpG-stimulated and control DCs, as well as their effect on cyclic guanosine monophosphate-adenosine monophosphate (GMP–AMP) synthase (cGAS) and the stimulator of interferon genes (STING) signal pathway. Firstly, we selected miRNAs (miR-29a and miR-378b) based on expression in CpG-stimulated mouse bone marrow-derived dendritic cells (BMDCs). Secondly, we investigated the functions of miR-29a and miR-378b on CpG-stimulated and unstimulated BMDCs. The results showed that miR-29a and miR-378b increased expression of both the immunoregulatory DC surface markers (CD86 and CD40) and the immunosuppressive molecule CD273 by DCs. Thirdly, cytokine detection revealed that both miR-29a and miR-378b enhanced interferon-β (IFN-β) expression while suppressing tumor necrosis factor-α (TNF-α) production. Finally, our results suggest that miR-378b can bind TANK-binding kinase binding protein 1 (TBKBP1) to activate the cGAS/STING signaling pathway. By contrast, miR-29a targeted interferon regulatory factor 7 (IRF7) and promoted the expression of STING. Together, our results provide insight into the molecular mechanism of miRNA induction by CpG to regulate DC function.
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16
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Kang H, Wu W, Yu M, Shapiro J, McElwee KJ. Increased expression of TLR7 and TLR9 in alopecia areata. Exp Dermatol 2019; 29:254-258. [DOI: 10.1111/exd.14043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 08/20/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Hoon Kang
- Department of Dermatology College of Medicine The Catholic University of Korea Seoul Korea
| | - Wen‐Yu Wu
- Department of Dermatology Huashan Hospital Fudan University Shanghai China
| | - Mei Yu
- Department of Dermatology and Skin Science University of British Columbia Vancouver BC Canada
| | - Jerry Shapiro
- The Ronald O. Perelman Department of Dermatology New York University School of Medicine New York NY USA
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17
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Venuti A, Lohse S, Tommasino M, Smola S. Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance. Philos Trans R Soc Lond B Biol Sci 2019; 374:20180287. [PMID: 30955489 PMCID: PMC6501898 DOI: 10.1098/rstb.2018.0287] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2019] [Indexed: 12/19/2022] Open
Abstract
Human papillomaviruses (HPVs) infect the epithelia of skin or mucosa, where they can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. Mucosal high-risk HPVs are causative for cancers of the anogenital region and oropharynx. Clinical data from patients with the rare genetic disorder epidermodysplasia verruciformis (EV) indicate that genus beta-HPVs cooperate with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma. In addition, epidemiological and biological findings indicate that beta-HPV types play a role in UV-mediated skin carcinogenesis also in non-EV individuals. However, the mechanisms used by these cutaneous viruses to promote epithelial carcinogenesis differ significantly from those of mucosal HPVs. Recent studies point to a delicate cross-talk of beta-HPVs with the cell-autonomous immunity of the host keratinocytes and the local immune microenvironment that eventually determines the fate of cutaneous HPV infection and the penetrance of disease. This review gives an overview of the critical interactions of genus beta-HPVs with the local immune system that allow the virus to complete its life cycle, to escape from extrinsic immunity, and eventually to cause chronic inflammation contributing to skin carcinogenesis. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
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Affiliation(s)
- Assunta Venuti
- 1 Infections and Cancer Biology Group, International Agency for Research on Cancer , 150 Cours Albert Thomas, Lyon 69008 , France
| | - Stefan Lohse
- 2 Institute of Virology, Saarland University Medical Center , Kirrbergerstr. Building 47, 66421 Homburg/Saar , Germany
| | - Massimo Tommasino
- 1 Infections and Cancer Biology Group, International Agency for Research on Cancer , 150 Cours Albert Thomas, Lyon 69008 , France
| | - Sigrun Smola
- 2 Institute of Virology, Saarland University Medical Center , Kirrbergerstr. Building 47, 66421 Homburg/Saar , Germany
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18
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De Silva Senapathi U, Abdul-Cader MS, Amarasinghe A, van Marle G, Czub M, Gomis S, Abdul-Careem MF. The In Ovo Delivery of CpG Oligonucleotides Protects against Infectious Bronchitis with the Recruitment of Immune Cells into the Respiratory Tract of Chickens. Viruses 2018; 10:E635. [PMID: 30445707 PMCID: PMC6266937 DOI: 10.3390/v10110635] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 11/11/2018] [Accepted: 11/13/2018] [Indexed: 01/11/2023] Open
Abstract
The in ovo delivery of cytosine-guanosine (CpG) oligodeoxynucleotides (ODNs) protects chickens against many bacterial and viral infections, by activating the toll-like receptor (TLR)21 signaling pathway. Although the delivery of CpG ODNs in ovo at embryo day (ED) 18 has been shown to reduce infectious bronchitis virus (IBV) loads in embryonic chicken lungs pre-hatch, whether in ovo delivered CpG ODNs are capable of protecting chickens against a post-hatch challenge is unknown. Thus, our objectives were to determine the protective effect of the in ovo delivery of CpG ODNs at ED 18 against IBV infection encountered post-hatch and, then, to investigate the mechanisms of protection. We found significantly higher survival rates and reduced IBV infection in the chickens following the pre-treatment of the ED 18 eggs with CpG ODNs. At 3 days post infection (dpi), we found an increased recruitment of macrophages, cluster of differentiation (CD)8α+ and CD4+ T lymphocytes, and an up-regulation of interferon (IFN)-γ mRNA in the respiratory tract of the chickens. Overall, it may be inferred that CpG ODNs, when delivered in ovo, provide protection against IBV infection induced morbidity and mortality with an enhanced immune response.
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Affiliation(s)
- Upasama De Silva Senapathi
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
| | - Mohamed Sarjoon Abdul-Cader
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
| | - Aruna Amarasinghe
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
| | - Guido van Marle
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
| | - Markus Czub
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
| | - Susantha Gomis
- Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B5, Canada.
| | - Mohamed Faizal Abdul-Careem
- Faculty of Veterinary Medicine, University of Calgary, Health Research Innovation Center, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
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19
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Umeki Y, Saito M, Kusamori K, Tsujimura M, Nishimura M, Takahashi Y, Takakura Y, Nishikawa M. Combined encapsulation of a tumor antigen and immune cells using a self-assembling immunostimulatory DNA hydrogel to enhance antigen-specific tumor immunity. J Control Release 2018; 288:189-198. [PMID: 30219278 DOI: 10.1016/j.jconrel.2018.09.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/25/2018] [Accepted: 09/11/2018] [Indexed: 12/24/2022]
Abstract
Our previous study demonstrated that the incorporation of a tumor antigen into a self-assembling DNA hydrogel, comprised of a DNA containing un-methylated cytosine-phosphate-guanine (CpG) dinucleotides (CpG DNA), efficiently induced antigen-specific tumor immunity after intra-tumoral injection into tumor-bearing mice. We hypothesized that the additional incorporation of immune cells, the target for the antigen and immunostimulatory CpG DNA, would increase the antitumor response. To prove this, immune cells were also encapsulated into the CpG DNA hydrogel and delivered along with the antigen. Mouse dendritic DC2.4 cells maintained their form even after incorporation into the DNA hydrogel. The incorporation of mouse macrophage-like J774.1 cells and RAW264.7 cells into CpG DNA hydrogel did not significantly affect their viability. J774.1, RAW264.7, DC2.4, and mouse bone marrow-derived dendritic cells (BMDCs) were efficiently activated when incorporated into the CpG DNA hydrogel. The CpG DNA hydrogel incorporated with both the tumor antigen and BMDCs effectively induced antigen-specific immune responses, and retarded tumor growth following intradermal administration before and after tumor inoculation without severe local and systemic adverse events. These data indicate that the combined delivery of a tumor antigen and immune cells using an immunostimulatory CpG DNA hydrogel is effective in inducing antigen-specific antitumor immunity.
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Affiliation(s)
- Yuka Umeki
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Masaaki Saito
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kosuke Kusamori
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Mari Tsujimura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Moeka Nishimura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
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20
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Diemert DJ, Bottazzi ME, Plieskatt J, Hotez PJ, Bethony JM. Lessons along the Critical Path: Developing Vaccines against Human Helminths. Trends Parasitol 2018; 34:747-758. [PMID: 30064902 DOI: 10.1016/j.pt.2018.07.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 12/16/2022]
Abstract
Helminthic parasites are important targets for vaccine research as they infect an estimated 1 billion people worldwide. Despite significant progress in the discovery of defined antigens as candidates for vaccines, the potential of a helminth vaccine advancing to an investigational product to be tested in humans remains as challenging as it did 50 years ago. Candidate helminth vaccines must still advance along a 'critical path' of preclinical research, vaccine process development (which includes 'chemistry, manufacturing, and controls' or CMC), current good manufacturing practice (cGMP) production of the vaccine, and clinical trials. This path is highly targeted towards meeting the safety, immunogenicity, and efficacy criteria of regulatory bodies such as the US Food and Drug Administration (FDA). For nearly 20 years our product development partnership (PDP), the Texas Children's Hospital Center for Vaccine Development (TCH-CVD), has followed the critical paths of several novel subunit vaccines for the human hookworm Necator americanus and the intestinal trematode Schistosoma mansoni. Herein, we describe the critical lessons learned along this critical path.
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Affiliation(s)
- David J Diemert
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Department of Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Maria Elena Bottazzi
- Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Biology, Baylor University, Waco, TX, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Jordan Plieskatt
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Peter J Hotez
- Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Biology, Baylor University, Waco, TX, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Jeffrey M Bethony
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA.
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21
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Yin P, Liu X, Mansfield AS, Harrington SM, Li Y, Yan Y, Dong H. CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1. Oncotarget 2018; 7:70223-70231. [PMID: 27602959 PMCID: PMC5342548 DOI: 10.18632/oncotarget.11833] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 08/24/2016] [Indexed: 12/29/2022] Open
Abstract
CpG oligodeoxynucleotides, as a ligand of toll-like receptor (TLR)-9, have demonstrated promising antitumor effects in some clinical trials; however, its toxicity and low efficacy as a systemic therapy has limited its therapeutic applications. In order to improve its therapeutic efficacy, we investigated the mechanisms of CpG-induced antitumor immunity in the context of CD8+ T cell responses. We show that IL-12 is required for the expansion of IFN-γ producing tumor-reactive CD8+ T cells capable of rejecting tumors. In addition, CpGs reduced PD-1 expression by effector CD8+ T cells via the IL-12 pathway. The combination of CpG and PD-1 blockade show a synergistic effect in generation of systemic antitumor immunity. Our studies define a critical role of IL-12 in CpG-induced antitumor immunity and provide a rationale for combined therapy with TLR agonists and immune checkpoint blockade in cancer treatment.
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Affiliation(s)
- Peng Yin
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | - Xin Liu
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Yinghua Li
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Yiyi Yan
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Haidong Dong
- Department of Urology, Mayo Clinic, Rochester, MN, USA.,Department of Immunology, Mayo Clinic, Rochester, MN, USA
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22
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Jung H, Kim D, Kang YY, Kim H, Lee JB, Mok H. CpG incorporated DNA microparticles for elevated immune stimulation for antigen presenting cells. RSC Adv 2018; 8:6608-6615. [PMID: 35540407 PMCID: PMC9078369 DOI: 10.1039/c7ra13293j] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/22/2019] [Accepted: 01/30/2018] [Indexed: 11/21/2022] Open
Abstract
As emerging evidence supports the immune stimulating capability of the CpG oligodeoxynucleotides (ODN), CpG-based adjuvants have been widely used. For efficient induction of immune responses, current issues affecting the use of nucleic acid-based adjuvants, e.g. stability in physiological conditions, delivery to immune cells, and successful release within the phagolysosome, should be addressed. Here, we present CpG-based DNA microparticles (DNA-MPs) fabricated by complementary rolling circle amplification (cRCA) as adjuvants for enhancing immune response and production of selective antibody production. Using cRCA method, the sizes of CpG-based DNA-MPs were finely controlled (0.5 and 1 μm) with superior and provided mismatched single stranded form of CpG ODN region for specific cleavage site by DNase II within the phagolysosome. Fabricated CpG-based 1 μm DNA-MPs (DNA-MP-1.0) were successfully internalized into primary macrophages and macrophage cell line (RAW264.7 cells), and elicited superior cytokine production e.g. TNF-α and IL-6, compared to conventional CpG ODNs. After in vivo administration of DNA-MP-1.0 with model antigen ovalbumin (OVA), significantly elevated OVA-specific antibody production was observed. With this in mind, DNA-MP-1.0 could serve as a novel type of adjuvant for the activation of macrophages and the following production of selective antibodies without any noticeable toxicity in vitro and in vivo. As emerging evidence supports the immune stimulating capability of the CpG oligodeoxynucleotides (ODN), CpG-based adjuvants have been widely used.![]()
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Affiliation(s)
- Heejung Jung
- Department of Bioscience and Biotechnology
- Konkuk University
- Seoul 05029
- Republic of Korea
| | - Dajeong Kim
- Department of Chemical Engineering
- University of Seoul
- Seoul 02504
- Republic of Korea
| | - Yoon Young Kang
- Department of Bioscience and Biotechnology
- Konkuk University
- Seoul 05029
- Republic of Korea
| | - Hyejin Kim
- Department of Chemical Engineering
- University of Seoul
- Seoul 02504
- Republic of Korea
| | - Jong Bum Lee
- Department of Chemical Engineering
- University of Seoul
- Seoul 02504
- Republic of Korea
| | - Hyejung Mok
- Department of Bioscience and Biotechnology
- Konkuk University
- Seoul 05029
- Republic of Korea
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23
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Umeki Y, Saito M, Takahashi Y, Takakura Y, Nishikawa M. Retardation of Antigen Release from DNA Hydrogel Using Cholesterol-Modified DNA for Increased Antigen-Specific Immune Response. Adv Healthc Mater 2017; 6. [PMID: 28726304 DOI: 10.1002/adhm.201700355] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 06/15/2017] [Indexed: 12/21/2022]
Abstract
Our previous study indicates that cationization of an antigen is effective for sustained release of both immunostimulatory DNA containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides, or CpG DNA, and antigen from a DNA hydrogel. Another approach to sustained antigen release would increase the applicability and versatility of the system. In this study, a hydrophobic interaction-based sustained release system of ovalbumin (OVA), a model antigen, from immunostimulatory CpG DNA hydrogel is developed by the use of cholesterol-modified DNA and urea-denatured OVA (udOVA). Cholesterol-modified DNA forms a hydrogel, Dgel(chol), and induces IL-6 mRNA expression in mouse skin after intradermal injection, as DNA without cholesterol does. Cholesterol-modified DNA associated with OVA and denaturation of OVA using urea increases the interaction. The release of udOVA from Dgel(chol) is significantly slower than that from DNA hydrogel with no cholesterol, Dgel. Moreover, intratumoral injections of udOVA/Dgel(chol) significantly inhibit the growth of EG7-OVA tumors in mice. These results indicate that sustained release of antigen from Dgel can be achieved by the combination of urea denaturation and cholesterol modification, and retardation of antigen release is effective to induce antigen-specific cancer immunity.
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Affiliation(s)
- Yuka Umeki
- Department of Biopharmaceutics and Drug Metabolism; Graduate School of Pharmaceutical Sciences; Kyoto University; Sakyo-ku Kyoto 606-8501 Japan
| | - Masaaki Saito
- Department of Biopharmaceutics and Drug Metabolism; Graduate School of Pharmaceutical Sciences; Kyoto University; Sakyo-ku Kyoto 606-8501 Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism; Graduate School of Pharmaceutical Sciences; Kyoto University; Sakyo-ku Kyoto 606-8501 Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism; Graduate School of Pharmaceutical Sciences; Kyoto University; Sakyo-ku Kyoto 606-8501 Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism; Graduate School of Pharmaceutical Sciences; Kyoto University; Sakyo-ku Kyoto 606-8501 Japan
- Laboratory of Biopharmaceutics; Faculty of Pharmaceutical Sciences; Tokyo University of Science; Noda Chiba 278-8510 Japan
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24
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Chandler MR, Keene KS, Tuomela JM, Forero-Torres A, Desmond R, Vuopala KS, Harris KW, Merner ND, Selander KS. Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans. PLoS One 2017; 12:e0183832. [PMID: 28886076 PMCID: PMC5590816 DOI: 10.1371/journal.pone.0183832] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/11/2017] [Indexed: 12/11/2022] Open
Abstract
Introduction Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. Methods TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). Results Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. Conclusions Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.
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Affiliation(s)
- Madison R. Chandler
- Harrison School of Pharmacy, Auburn University, Auburn, AL, United States of America
| | - Kimberly S. Keene
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Johanna M. Tuomela
- Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Andres Forero-Torres
- Department of Medicine, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Renee Desmond
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Katri S. Vuopala
- Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland
| | - Kevin W. Harris
- Department of Medicine, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States of America
| | - Nancy D. Merner
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Katri S. Selander
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, United States of America
- * E-mail:
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25
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Chen X, Zhang Q, Luo Y, Gao C, Zhuang X, Xu G, Qiao T. High-dose irradiation in combination with toll-like receptor 9 agonist CpG oligodeoxynucleotide 7909 downregulates PD-L1 expression via the NF-κB signaling pathway in non-small cell lung cancer cells. Onco Targets Ther 2016; 9:6511-6518. [PMID: 27799798 PMCID: PMC5085295 DOI: 10.2147/ott.s116629] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Objectives Irradiation resistance appears as local recurrence and distant metastasis in advanced stages of non-small cell lung cancer (NSCLC). High-dose irradiation combined with immunotherapy improved overall survival and local control of NSCLC. This study explored the underlying molecular mechanism by which the effect of high-dose irradiation plus toll-like receptor 9 (TLR9) agonist CpG oligodeoxynucleotide (CpG ODN) 7909 on NSCLC. Materials and methods NSCLC H460 cells were exposed to constant high-dose irradiation (6.37 Gy) in irradiation (IR) group and the irradiation plus CpG group. Gene expression was assessed using quantitative reverse transcriptase-polymerase chain reaction and Western blot. Knockdown of nuclear factor kappa B (NF-κB) p65 expression was conducted using p65 siRNA. Results Expression of programmed death-ligand 1 (PD-L1) mRNA was significantly decreased in IR combined with CpG ODN 7909 group compared with the control or IR-alone groups (P<0.05). TLR9 expression was also obviously increased in the combination group compared with the control (P<0.05). Moreover, expression of NF-κB p65 was apparently reduced in the combination group compared with the control (P<0.05). However, expression of PD-L1 was significantly decreased after knockdown of p65 in IR group (P<0.05), but increased in the combination group (P<0.05) and slightly increased in CpG ODN-alone group (P<0.05), which was opposite to that without p65 knockdown group. Conclusion This study demonstrated that radiotherapy combined with CpG ODN 7909 was able to downregulate PD-L1 expression through inhibition via the NF-κB signaling pathway.
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Affiliation(s)
- Xue Chen
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
| | - Qi Zhang
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
| | - Youjun Luo
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
| | - Caixia Gao
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
| | - Xibing Zhuang
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
| | - Guoxiong Xu
- Department of Center laboratory, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Tiankui Qiao
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University
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26
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Caro E, Francés R, Zapater P, Pascual S, Bellot P, Such J. Grade of soluble inflammatory response is mainly affected by circulating bacterial DNA concentrations in cirrhosis. Liver Int 2016; 36:1473-80. [PMID: 26991936 DOI: 10.1111/liv.13118] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/08/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. METHODS 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. RESULTS Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). CONCLUSIONS Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.
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Affiliation(s)
- Elena Caro
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain
| | - Rubén Francés
- Departamento de Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Unidad de Farmacología Clínica, Hospital General Universitario de Alicante y Universidad Miguel Hernández, Alicante, Spain
| | - Sonia Pascual
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pablo Bellot
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE, Lerner School of medicine, Case Western Reserve University, Cleveland, OH, US.
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27
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Zhang X, Li N, Meng Y, Zhang R, Bian J, Yao Y, Li J, Deng X. High-Level Expression of Toll-Like Receptors on Dendritic Cells in Adult Patients with Burns on ≥90% of Total Body Surface Area (TBSA). Med Sci Monit 2016; 22:3493-3499. [PMID: 27686145 PMCID: PMC5047034 DOI: 10.12659/msm.897433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background As a serious clinical problem, severe burn injury disturbs the immune system, resulting in progressive suppression of immune response. TLRs are associated with immune system activation, but the effect of TLRs levels on circulating cDCs of severe burn injury patients has not been fully assessed. Material/Methods Ten patients with total body surface area (TBSA) burned >90% admitted to our institution were enrolled in this study. We analyzed TLR2, TLR4, and TLR9 expression on the circulating cDCs by using multicolor flow cytometric analysis in patients at 14 days to 28 days after burn injury according to mortality, and We also assessed Demographics, clinical outcomes, organ function, and inflammatory and acute-phase responses. Results No difference in TBSA, sex, age, or number of operations before the first 14 days after injury were observed between surviving and non-surviving burn patients. The levels of TLR2, TLR4, and TLR9 in circulating cDCs were significantly and consistently elevated in all patients compared to age-matched healthy volunteers, and survivors exhibited higher TLR2 and TLR4 values than non-survivors. Of the survivors, TLR2 and TLR4 levels were higher at 28 days than at 14 days after injury, while the difference in TLR9 levels was not significant. TLR2 levels of non-survivors at 28 days after injury decreased, and the TLR4 and TLR9 levels showed no significant difference. Conclusions TLRs levels in circulating cDCs are highly activated in severe burn injury patients up to 28 days after injury. The low expression of TLR2 in cDCs may be useful as a potential marker predicting the poor prognosis of severe burn patients.
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Affiliation(s)
- Xu Zhang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Na Li
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Yan Meng
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Renjing Zhang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Jinjun Bian
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Ying Yao
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Jinbao Li
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Xiaoming Deng
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
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28
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Dawson E, Leleux JA, Pradhan P, Roy K. Surface-Presentation of CpG and Protein–Antigen on Pathogen-Like Polymer Particles Generate Strong Prophylactic and Therapeutic Antitumor Protection. ACS Biomater Sci Eng 2016; 3:169-178. [DOI: 10.1021/acsbiomaterials.6b00384] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Eileen Dawson
- The University of Texas at Austin, Austin, Texas 78712, United States
| | - Jardin A. Leleux
- The Wallace
H. Coulter Department of Biomedical Engineering at Georgia Tech and
Emory University, The Parker H. Petit Institute for Bioengineering
and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Pallab Pradhan
- The Wallace
H. Coulter Department of Biomedical Engineering at Georgia Tech and
Emory University, The Parker H. Petit Institute for Bioengineering
and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Krishnendu Roy
- The Wallace
H. Coulter Department of Biomedical Engineering at Georgia Tech and
Emory University, The Parker H. Petit Institute for Bioengineering
and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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29
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Burastero SE, Paolucci C, Breda D, Ponti J, Munaro B, Sabbioni E. Chromium (VI)-Induced Immunotoxicity and Intracellular Accumulation in Human Primary Dendritic Cells. Int J Immunopathol Pharmacol 2016; 19:581-91. [PMID: 17026843 DOI: 10.1177/039463200601900314] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Chromium compounds, besides being occupational carcinogens, can also induce allergic contact dermatitis (ACD) and other immunomodulatory effects. In this study we investigate cell viability, uptake and intracellular distribution of chromium in human primary dendritic cells (DCs), either immature (iDCs) or driven to differentiate by a specific maturation stimulus (LPS) (mature DCs, mDCs), when exposed for 48 h to concentrations of soluble radiolabelled Na251CrO4 ranging from 5 to 0.5 μM. The modulation of the expression of membrane markers (CD80, CD86, MHC class II) correlated with the immunological functions of DCs was also measured. After 48 h of exposure the mean IC50 values in 4 donors were 36 and 31 μM in iDCs and mDC respectively, as detected by propidium iodide incorporation. Cellular uptake of chromium was nearly linear with increasing doses. At 48 h post-exposure chromium was accumulated preferentially in the nuclear and cytosolic fractions (44.1 to 66% and 13.1 to 31% of total cellular chromium, respectively). Although a high inter-individual variability was observed, an increase in the expression of CD86 and, to a lower extent, CD80 and MHC class II membrane markers was found in mDCs of single donors. These results highlight the relevance of searching for the biodistribution of trace metals in primary cells of the immune system. Moreover, they suggest that DCs differentiation markers can help in measuring the immunotoxicity of metal
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Affiliation(s)
- S E Burastero
- DIBIT, San Raffaele Scientific Institute, Milan, Italy
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30
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Shang J, Wang X, Wang W, Pan H, Liu S, Li L, Chen L, Xia B. Association between Toll-Like Receptor 9-1237T/C Polymorphism and the Susceptibility of Inflammatory Bowel Diseases: A Meta-Analysis. Yonsei Med J 2016; 57:153-164. [PMID: 26632396 PMCID: PMC4696948 DOI: 10.3349/ymj.2016.57.1.153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 05/13/2015] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The -1237T/C polymorphism of the Toll-like receptor 9 (TLR9) gene has been implicated in the susceptibility of inflammatory bowel diseases (IBDs), but the results remain conflicting. We further investigated this association via meta-analysis. MATERIALS AND METHODS Multiple electronic databases were extensively searched until February, 2015. The strength of association was evaluated by calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS A total of 2987 cases and 2388 controls from eight studies were analyzed. Overall, association was found between TLR9 -1237T/C polymorphism and the risk of IBDs when all the studies were pooled (recessive model, OR: 1.59, 95% CI: 1.02-2.47, p=0.04; homozygote comparison, OR: 1.62, 95% CI: 1.04-2.52, p=0.03; allele model, OR: 1.13, 95% CI: 1.00-1.27, p=0.05). Stratification by ethnicity indicated an association between TLR9 -1237T/C polymorphism and IBDs risk in Caucasians (recessive model, OR: 1.59, 95% CI: 1.02-2.47, p=0.04; homozygote comparison, OR: 1.62, 95% CI: 1.04-2.52, p=0.03; allele model, OR: 1.12, 95% CI: 1.00-1.27, p=0.05). When stratified by disease type, significant correlation were only found in the Crohn's disease subgroup (recessive model, OR: 1.69, 95% CI: 1.05-2.73, p=0.03; homozygote model, OR: 1.74, 95% CI: 1.07-2.82, p=0.02; allele model, OR: 1.15, 95% CI: 1.01-1.32, p=0.04). CONCLUSION The present study suggested that the TLR9 -1237T/C polymorphism might act as a risk factor in the development of IBDs, particularly in Caucasians.
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Affiliation(s)
- Jian Shang
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Xiaobing Wang
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Wei Wang
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Huaqin Pan
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Shi Liu
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Lixia Li
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Liping Chen
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Bing Xia
- Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China
- The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China.
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31
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Iaconelli C, Lemetais G, Kechaou N, Chain F, Bermúdez-Humarán LG, Langella P, Gervais P, Beney L. Drying process strongly affects probiotics viability and functionalities. J Biotechnol 2015; 214:17-26. [PMID: 26325197 DOI: 10.1016/j.jbiotec.2015.08.022] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 06/22/2015] [Accepted: 08/25/2015] [Indexed: 11/19/2022]
Abstract
Probiotic formulations are widely used and are proposed to have a variety of beneficial effects, depending on the probiotic strains present in the product. The impact of drying processes on the viability of probiotics is well documented. However, the impact of these processes on probiotics functionality remains unclear. In this work, we investigated variations in seven different bacterial markers after various desiccation processes. Markers were composed of four different viability evaluation (combining two growth abilities and two cytometric measurements) and in three in vitro functionalities: stimulation of IL-10 and IL-12 production by PBMCs (immunomodulation) and bacterial adhesion to hexadecane. We measured the impact of three drying processes (air-drying, freeze-drying and spray-drying), without the use of protective agents, on three types of probiotic bacteria: Bifidobacterium bifidum, Lactobacillus plantarum and Lactobacillus zeae. Our results show that the bacteria respond differently to the three different drying processes, in terms of viability and functionality. Drying methods produce important variations in bacterial immunomodulation and hydrophobicity, which are correlated. We also show that adherence can be stimulated (air-drying) or inhibited (spray-drying) by drying processes. Results of a multivariate analysis show no direct correlation between bacterial survival and functionality, but do show a correlation between probiotic responses to desiccation-rewetting and the process used to dry the bacteria.
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Affiliation(s)
- Cyril Iaconelli
- UMR Procédés Alimentaires et Microbiologiques, Université de Bourgogne, AgroSup Dijon, 1 Esplanade Erasme, 21000 Dijon, France
| | - Guillaume Lemetais
- Merck Medication Familiale, 18C boulevard Winston Churchill, 21000 Dijon, France
| | - Noura Kechaou
- Institut MICALIS, UMR 1319, Domaine de Vilvert, 78352 Jouy en Josas, France
| | - Florian Chain
- Institut MICALIS, UMR 1319, Domaine de Vilvert, 78352 Jouy en Josas, France
| | | | - Philippe Langella
- Institut MICALIS, UMR 1319, Domaine de Vilvert, 78352 Jouy en Josas, France
| | - Patrick Gervais
- UMR Procédés Alimentaires et Microbiologiques, Université de Bourgogne, AgroSup Dijon, 1 Esplanade Erasme, 21000 Dijon, France
| | - Laurent Beney
- UMR Procédés Alimentaires et Microbiologiques, Université de Bourgogne, AgroSup Dijon, 1 Esplanade Erasme, 21000 Dijon, France.
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Jazwa A, Stoszko M, Tomczyk M, Bukowska-Strakova K, Pichon C, Jozkowicz A, Dulak J. HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses — Effects modified by concomitant VEGF overexpression. Vascul Pharmacol 2015; 71:127-38. [DOI: 10.1016/j.vph.2015.02.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 02/13/2015] [Accepted: 02/24/2015] [Indexed: 12/31/2022]
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Gu X, Wu G, Yao Y, Zeng J, Shi D, Lv T, Luo L, Song Y. Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway. Free Radic Biol Med 2015; 83:149-58. [PMID: 25772007 DOI: 10.1016/j.freeradbiomed.2015.02.034] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 02/14/2015] [Accepted: 02/25/2015] [Indexed: 01/07/2023]
Abstract
An increasing number of studies have focused on the phenomenon that mitochondrial DNA (mtDNA) activates innate immunity responses. However, the specific role of mtDNA in inflammatory lung disease remains elusive. This study was designed to examine the proinflammatory effects of mtDNA in lungs and to investigate the putative mechanisms. C57BL/6 mice were challenged intratracheally with mtDNA with or without pretreatment with chloroquine. Changes in pulmonary histopathology, cytokine concentrations, and phosphorylation levels of p38 MAPK were assayed at four time points. In in vitro experiments, THP-1 macrophages were pretreated or not pretreated with chloroquine, TLR9 siRNA, p38 MAPK siRNA, or SB203580 and then incubated with mtDNA. The levels of cytokines and p-p38 MAPK were detected by ELISA and Western blot, respectively. The intratracheal administration of mtDNA induced infiltration of inflammatory cells, production of proinflammatory cytokines (including IL-1β, IL-6, and TNF-α), and activation of p38 MAPK. The chloroquine pretreatment resulted in an abatement of mtDNA-induced local lung inflammation. In vitro experiments showed that the exposure of THP-1 macrophages to mtDNA also led to a significant upregulation of IL-1β, IL-6, and TNF-α and the activation of p38 MAPK. And these responses were inhibited either by chloroquine and TLR9 siRNA or by SB203580 and p38 MAPK siRNA pretreatment. The intratracheal administration of mtDNA induced a local inflammatory response in the mouse lung that depended on the interactions of mtDNA with TLR9 and may be correlated with infiltrating macrophages that could be activated by mtDNA exposure via the TLR9-p38 MAPK signal transduction pathway.
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Affiliation(s)
- Xiaoling Gu
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Guannan Wu
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Yanwen Yao
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Junli Zeng
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Donghong Shi
- Department of Medical Imaging, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Tangfeng Lv
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China
| | - Liang Luo
- Intensive Care Unit, Wuxi Second Affiliated Hospital, Nanjing Medical University, Wuxi, Jiangsu Province 210004, People's Republic of China
| | - Yong Song
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002, People's Republic of China.
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Primate immune responses to HIV-1 Env formulated in the saponin-based adjuvant AbISCO-100 in the presence or absence of TLR9 co-stimulation. Sci Rep 2015; 5:8925. [PMID: 25762407 PMCID: PMC4356977 DOI: 10.1038/srep08925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/11/2015] [Indexed: 11/08/2022] Open
Abstract
Protein-based vaccines require adjuvants to achieve optimal responses. Toll-like receptor (TLR) 9 agonists were previously shown to improve responses to protein-based vaccines, such as the Hepatitis B virus vaccine formulated in alum. Here, we used CpG-C together with the clinically relevant saponin-based adjuvant AbISCO-100/Matrix-M (AbISCO), to assess if TLR9 co-stimulation would quantitatively or qualitatively modulate HIV-1 envelope glycoprotein (Env)-specific B and T cell responses in rhesus macaques. The macaques were inoculated with soluble Env trimers in AbISCO, with or without the addition of CpG-C, using an interval similar to the Hepatitis B virus vaccine. Following a comprehensive evaluation of antigen-specific responses in multiple immune compartments, we show that the Env-specific circulating IgG, memory B cells and plasma cells displayed similar kinetics and magnitude in the presence or absence of CpG-C and that there was no apparent difference between the two groups in the elicited HIV-1 neutralizing antibody titers or antigen-specific CD4+ T cell responses. Importantly, the control of SHIV viremia was significantly improved in animals from both Env-immunized groups relative to adjuvant alone controls, demonstrating the potential of AbISCO to act as a stand-alone adjuvant for Env-based vaccines.
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Chrząstek K, Borowska D, Kaiser P, Vervelde L. Class B CpG ODN stimulation upregulates expression of TLR21 and IFN-γ in chicken Harderian gland cells. Vet Immunol Immunopathol 2014; 160:293-9. [PMID: 24880703 DOI: 10.1016/j.vetimm.2014.04.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 03/27/2014] [Accepted: 04/28/2014] [Indexed: 12/31/2022]
Abstract
This study aimed to evaluate the response of Harderian gland (HG) cells after in vitro stimulation with class B synthetic oligodeoxyribonucleotides (ODN) containing CpG motifs. This knowledge is of importance for the development of mucosal vaccines for poultry, such as eye-drop or spray vaccines, to determine if class B CpG ODN can act as an vaccine adjuvant or as a prophylactic treatment mainly against respiratory disease viruses. The relative expression of Toll-like receptor 21 (TLR21), interferon (IFN)-γ, interleukin (IL)-1β and IL-10 genes were quantified at 1, 3, 6 and 18 h post-stimulation of HG cells from 5-week-old birds. In addition, it was also investigated if expression of these genes was affected by the age of the birds (differences between 5- and 12-week-old birds), concentrations of ODN or cell preparation method used. Class B CpG ODN induced upregulation of TLR21 and IFN-γ mRNA expression levels at 1h post-stimulation depending on concentration of ODN used but only in HG cells isolated from young birds.
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Affiliation(s)
- Klaudia Chrząstek
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK; Department of Epizootiology and Clinic of Bird and Exotic Animals, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, pl. Grunwadzki 45, Wrocław 50-366, Poland.
| | - Dominika Borowska
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Pete Kaiser
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Lonneke Vervelde
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
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Zhou ZX, Zhang J, Sun L. C7: a CpG oligodeoxynucleotide that induces protective immune response against megalocytivirus in Japanese flounder (Paralichthys olivaceus) via Toll-like receptor 9-mediated signaling pathway. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2014; 44:124-132. [PMID: 24333437 DOI: 10.1016/j.dci.2013.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 12/06/2013] [Accepted: 12/06/2013] [Indexed: 06/03/2023]
Abstract
Megalocytivirus is the causative agent of severe disease outbreaks in farmed fish. Currently there is no effective control against megalocytivirus in aquaculture. Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs are known to possess marked immunostimulatory properties. In this study, we investigated the potentials of ten CpG ODNs as antiviral agents in a model of Japanese flounder (Paralichthys olivaceus). We found that, when administered into flounder, three of the ten CpG ODNs inhibited viral replication in kidney, spleen, and liver. ODN C7, which exhibited the strongest inhibitory activity, was able to promote proliferation of peripheral blood leukocytes and enhance activation of head kidney mononuclear adherent phagocytes. When the expression of toll-like receptor 9 (TLR9) was knocked down in vivo by small interfering RNA, C7-mediated immune response and antiviral activity were significantly blocked. Moreover, when C7 was co-administered with pCN86, a DNA vaccine against megalocytivirus, a significant increase in vaccine-induced protection was observed compared to administration with pCN86 alone. Further analysis showed that compared to fish immunized with pCN86, fish immunized with pCN86 plus C7 exhibited significantly upregulated expression of a wide range of genes involved in innate and adaptive immunity. Taken together, these results indicate that ODN C7 activates TLR9-mediated immune response and possesses antiviral and adjuvant potentials that may be exploited for the control of megalocytivirus infection in farmed flounder.
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Affiliation(s)
- Zhi-xia Zhou
- Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China
| | - Jian Zhang
- Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Sun
- Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China.
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Lv S, Wang J, Dou S, Yang X, Ni X, Sun R, Tian Z, Wei H. Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection. Hepatology 2014; 59:385-94. [PMID: 23907803 DOI: 10.1002/hep.26654] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 07/19/2013] [Indexed: 01/16/2023]
Abstract
UNLABELLED Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-α by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-α production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-α production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. CONCLUSION Endogenous HBV-CpG ODNs from the HBV genome induce IFN-α production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection.
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Affiliation(s)
- Shujuan Lv
- Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China; Department of Microbiology, Anhui Medical University, Hefei, China
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Abstract
The pattern-recognition receptor (PRR) family includes Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and the receptor for advanced glycation end products (RAGE). They recognize various microbial signatures or host-derived danger signals and trigger an immune response. Eosinophils are multifunctional leucocytes involved in the pathogenesis of several inflammatory processes, including parasitic helminth infection, allergic diseases, tissue injury and tumour immunity. Human eosinophils express several PRRs, including TLR1-5, TLR7, TLR9, NOD1, NOD2, Dectin-1 and RAGE. Receptor stimulation induces survival, oxidative burst, activation of the adhesion system and release of cytokines (interleukin-1β, interleukin-6, tumour necrosis factor-α and granulocyte-macrophage colony-stimulating factor), chemokines (interleukin-8 and growth-related oncogene-α) and cytotoxic granule proteins (eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase and major basic protein). It is also evident that eosinophils play an immunomodulatory role by interacting with surrounding cells. The presence of a broad range of PRRs in eosinophils indicates that they are not only involved in defence against parasitic helminths, but also against bacteria, viruses and fungi. From a clinical perspective, eosinophilic PRRs seem to be involved in both allergic and malignant diseases by causing exacerbations and affecting tumour growth, respectively.
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Affiliation(s)
- Anne Månsson Kvarnhammar
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
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Yang M, Yan Y, Fang M, Wan M, Wu X, Zhang X, Zhao T, Wei H, Song D, Wang L, Yu Y. MF59 formulated with CpG ODN as a potent adjuvant of recombinant HSP65-MUC1 for inducing anti-MUC1+ tumor immunity in mice. Int Immunopharmacol 2012; 13:408-16. [PMID: 22595192 PMCID: PMC7106219 DOI: 10.1016/j.intimp.2012.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 04/23/2012] [Accepted: 05/03/2012] [Indexed: 12/31/2022]
Abstract
MF59 is an oil-in-water emulsion adjuvant approved for influenza vaccines for human use in Europe. Due to its Th2 inducing properties, MF59 is seldom tested for cancer vaccines. In this study, MF59 formulated with a C-type CpG oligodeoxynucleotide (YW002) was tested for its Th1 adjuvant activity to induce immune responses to HSP65-MUC1, a recombinant fusion protein incorporating a mycobacterial heat shock protein (HSP65) and mucin 1, cell surface associated (MUC1) derived peptide. Combination of YW002 with MF59 (MF59-YW002) could confer a potent Th1 biasing property to the adjuvant, which enhanced the immunogenicity of HSP65-MUC1 to induce significantly higher levels of specific IgG2c, increased IFN-γ mRNA expression in splenocytes and the generation of antigen-specific cytotoxic T lymphocytes in mice. When prophylactically applied, MF59-YW002 adjuvant containing HSP65-MUC1 inhibited the growth of MUC1+ B16 melanoma and prolonged the survival of tumor-bearing mice. In contrast, adjuvant containing MF59 with HSP65-MUC1 in the absence of YW002, promoted the growth of MUC1+ B16 melanoma in mice. These results suggest that MF59 plus CpG oligodeoxynucleotide might be developed as an efficient adjuvant for tumor vaccines against melanoma, and possibly other tumors.
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Affiliation(s)
- Ming Yang
- Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
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Kanayama M, Morimoto J, Matsui Y, Ikesue M, Danzaki K, Kurotaki D, Ito K, Yoshida T, Uede T. α9β1 integrin-mediated signaling serves as an intrinsic regulator of pathogenic Th17 cell generation. THE JOURNAL OF IMMUNOLOGY 2011; 187:5851-64. [PMID: 22039306 DOI: 10.4049/jimmunol.1101524] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The interaction between matricellular proteins such as tenascin-C (TN-C) and osteopontin (OPN) and integrins has been implicated in the pathology of rheumatoid arthritis in which Th17 cells are recognized as primary pathogenic cells. The differentiation of Th17 cells is tightly regulated by cytokines derived from APCs, receiving various signals including TLR stimuli. In this study, we used a collagen-induced arthritis model and found that increased numbers of α(9) integrin-positive conventional dendritic cells and macrophage were detectable in the draining lymph node (dLN) shortly following first immunization, and these cells produced both TN-C and OPN, ligands for α(9) integrin. α(9) integrin-mediated signaling, induced by TN-C and OPN, promoted the production of Th17-related cytokines by conventional dendritic cells and macrophages in synergy with TLR2 and 4 signaling. This led to the Th17 cell differentiation and arthritis development. Moreover, Th17 cells generated under blocking of α(9) integrin-mediated signaling showed low level of CCR6 expression and impaired migration ability toward CCL20. Thus, we have identified α(9) integrin-mediated signaling by TN-C and OPN as a novel intrinsic regulator of pathogenic Th17 cell generation that contributes to the development of rheumatoid arthritis.
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Affiliation(s)
- Masashi Kanayama
- Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
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Genomic survey of early responses to viruses in Atlantic salmon, Salmo salar L. Mol Immunol 2011; 49:163-74. [DOI: 10.1016/j.molimm.2011.08.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 08/09/2011] [Accepted: 08/09/2011] [Indexed: 11/21/2022]
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Lemke CD, Graham JB, Geary SM, Zamba G, Lubaroff DM, Salem AK. Chitosan is a surprising negative modulator of cytotoxic CD8+ T cell responses elicited by adenovirus cancer vaccines. Mol Pharm 2011; 8:1652-61. [PMID: 21780831 DOI: 10.1021/mp100464y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Adjuvants modulate protective CD8(+) T cell responses generated by cancer vaccines. We have previously shown that immunostimulatory cytosine-phosphodiester-guanine (CpG) oligodeoxynucleotide (ODN) significantly augments tumor protection in mice given adenovirus cancer vaccines. Here, we examined the impact of chitosan, another candidate vaccine adjuvant, on protection conferred by adenovirus cancer vaccines. Unexpectedly, immunization of mice with adenovirus cancer vaccines in combination with chitosan provided little protection against tumor challenge. This directly correlated with the reduced detection of Ag-specific CD8(+) T cells, interferon-γ (IFN-γ) production, and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since the frequency did not change regardless of whether chitosan was delivered. In mammalian cell lines, chitosan did not interfere with adenovirus transgene expression. However, infection of primary murine bone marrow-derived dendritic cells with adenovirus complexed with chitosan significantly reduced viability, transgene expression, and upregulation of major histocompatability (MHC) class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, which could prevent CD8(+) T cell activation from occurring in vivo. These surprising data demonstrate for the first time that chitosan vaccine formulations can negatively impact the induction of CD8(+) T cell responses via its effect on dendritic cells, which is clinically important since consideration of chitosan as an adjuvant for vaccine formulations is growing.
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Affiliation(s)
- Caitlin D Lemke
- College of Pharmacy, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States
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Gutiérrez A, Holler E, Zapater P, Sempere L, Jover R, Pérez-Mateo M, Schoelmerich J, Such J, Wiest R, Francés R. Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn's disease is affected by NOD2/CARD15 genotype. Inflamm Bowel Dis 2011; 17:1641-50. [PMID: 21744420 DOI: 10.1002/ibd.21537] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 09/24/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND Blood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptides are inducible after culture with bacterial products and a linkage has been established between them and NOD2/CARD15. The aim was to test whether defensins and cathelicidin (LL-37) expression and NOD2/CARD15 mutations in blood neutrophils are related to molecular bacterial translocation events in CD patients. METHODS Fifty consecutively admitted CD patients and 15 healthy controls were included. Clinical and analytical characteristics of patients were considered. NOD2/CARD15 genotyping, presence of bacterial-DNA, defensin and cathelicidin gene, and protein levels in neutrophils and serum cytokine levels were studied. RESULTS Twenty patients (40%) presented bacterial-DNA in blood. Eleven were active and 9 were in remission. Bacterial-DNA was not present in controls. NOD2/CARD15 mutations were identified in 25 patients (50%), 15 of which were in remission. Sixty percent of bacterial-DNA(+) and 43% of bacterial-DNA(-) patients showed a NOD2/CARD15 mutation. β-Defensin 2 and LL-37 mRNA and protein levels were upregulated in bacterial-DNA(+) patients. β-Defensin 2 and LL-37 expression correlated with bacterial-DNA concentration only in patients with a wildtype NOD2/CARD15 genotype. Cultured neutrophils of bacterial-DNA(-) patients confirmed the muramyl dipeptide-independent association between DEFB2 and LL-37 with bacterial-DNA concentration in wildtype NOD2/CARD15 patients. Cytokine levels were increased in bacterial-DNA(+) patients and correlated with bacterial-DNA concentration. NOD2/CARD15 genotype did not influence this correlation. CONCLUSIONS β-Defensin 2, LL-37, and proinflammatory cytokines are increased in CD patients with bacterial-DNA in a concentration-dependent manner. NOD2/CARD15 plays a key role in the regulation of this response.
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Affiliation(s)
- Ana Gutiérrez
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
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Kajiyama T, Suzuki Y, Kihara M, Suzuki H, Horikoshi S, Tomino Y. Different pathological roles of toll-like receptor 9 on mucosal B cells and dendritic cells in murine IgA nephropathy. Clin Dev Immunol 2011; 2011:819646. [PMID: 21765852 PMCID: PMC3135126 DOI: 10.1155/2011/819646] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 05/02/2011] [Indexed: 11/24/2022]
Abstract
Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN.
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Affiliation(s)
- Tadahiro Kajiyama
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Masao Kihara
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Satoshi Horikoshi
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Kannaki T, Shanmugam M, Verma P. Toll-like receptors and their role in animal reproduction. Anim Reprod Sci 2011; 125:1-12. [DOI: 10.1016/j.anireprosci.2011.03.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 02/21/2011] [Accepted: 03/14/2011] [Indexed: 01/08/2023]
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Persson CM, Chambers BJ. Plasmacytoid dendritic cell-induced migration and activation of NK cells in vivo. Eur J Immunol 2010; 40:2155-64. [PMID: 20540112 DOI: 10.1002/eji.200940098] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
NK cells are cytotoxic cells of the innate immune system. They have been found to be critical in the defense against infections and also against some tumors. Recent studies have shown that NK cells require signals from accessory cells to induce their recruitment and activation at the site of infection or tumor growth. In this study, we examined whether plasmacytoid DC (pDC) could recruit and activate NK cells in vivo. When CpG-stimulated pDC were injected i.p. to C57BL/6 mice, they efficiently recruited NK cells, a process that was dependent on NK cell CXCR3 and CD62L and in part on CCR5. NK cells isolated from the peritoneum of mice inoculated with TLR7/8 or TLR9-stimulated pDC exhibited greater cytotoxicity against YAC-1 tumor cells than NK cells recovered from mice inoculated with control pDC. The present results are discussed in relation to pDC-induced NK cell migration and activation in vivo.
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Affiliation(s)
- Catrine M Persson
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 2010; 2010:240365. [PMID: 21197425 PMCID: PMC3010626 DOI: 10.1155/2010/240365] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Accepted: 09/15/2010] [Indexed: 12/14/2022] Open
Abstract
On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs) play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR) domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.
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Abstract
Bacterial DNA (bDNA) can activate an innate-immune stimulatory "danger" response via toll-like receptor 9 (TLR9). Mitochondrial DNA (mtDNA) is unique among endogenous molecules in that mitochondria evolved from prokaryotic ancestors. Thus, mtDNA retains molecular motifs similar to bDNA. It is unknown, however, whether mtDNA is released by shock or is capable of eliciting immune responses like bDNA. We hypothesized shock-injured tissues might release mtDNA and that mtDNA might act as a danger-associated molecular pattern (or "alarmin") that can activate neutrophils (PMNs) and contribute to systemic inflammatory response syndrome. Standardized trauma/hemorrhagic shock caused circulation of mtDNA as well as nuclear DNA. Human PMNs were incubated in vitro with purified mtDNA or nuclear DNA, with or without pretreatment by chloroquine (an inhibitor of endosomal receptors like TLR9). Neutrophil activation was assessed as matrix metalloproteinase (MMP) 8 and MMP-9 release as well as p38 and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation. Mitochondrial DNA induced PMN MMP-8/MMP-9 release and p38 phosphorylation but did not activate p44/42. Responses were inhibited by chloroquine. Nuclear DNA did not induce PMN activation. Intravenous injection of disrupted mitochondria (mitochondrial debris) into rats induced p38 MAPK activation and IL-6 and TNF-alpha accumulation in the liver. In summary, mtDNA is released into the circulation by shock. Mitochondrial DNA activates PMN p38 MAPK, probably via TLR9, inducing an inflammatory phenotype. Mitochondrial DNA may act as a danger-associated molecular pattern or alarmin after shock, contributing to the initiation of systemic inflammatory response syndrome.
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Lee S, Yagita H, Sayers TJ, Celis E. Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors. Cancer Immunol Immunother 2010; 59:1073-81. [PMID: 20213120 PMCID: PMC6993141 DOI: 10.1007/s00262-010-0834-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Accepted: 02/10/2010] [Indexed: 10/19/2022]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptosis in various tumor cells by engaging the receptors, DR4 and DR5. Bortezomib (Velcade) is a proteasome inhibitor that has been approved for patients with multiple myeloma. There is some experimental evidence in preclinical models that bortezomib can enhance the susceptibility of tumors to TRAIL-induced apoptosis. In this study, we investigated the effects of TRAIL-induced death using an agonistic antibody to the TRAIL receptor DR5 (alpha-DR5) in combination with bortezomib administered to mice previously injected with breast cancer cells (TUBO). This combination had some beneficial therapeutic effect, which was significantly enhanced by the co-administration of a Toll-like receptor 9 agonist (CpG). In contrast, single agent treatments had little effect on tumor growth. In addition, we evaluated the effect of combination with alpha-DR5, bortezomib, and CpG in the prevention/treatment of spontaneous mammary tumors in Balb-neuT mice. In this model, which is more difficult to treat, we observed dramatic antitumor effects of alpha-DR5, bortezomib and CpG combination therapy. Since such a mouse model more accurately reflects the immunological tolerance that exists in human cancer, our results strongly suggest that these combination strategies could be directly applied to the therapy for cancer patients.
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Affiliation(s)
- Sujin Lee
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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Decrausaz L, Revaz V, Bobst M, Corthésy B, Romero P, Nardelli-Haefliger D. Induction of human papillomavirus oncogene-specific CD8 T-cell effector responses in the genital mucosa of vaccinated mice. Int J Cancer 2010; 126:2469-78. [PMID: 19816937 DOI: 10.1002/ijc.24949] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cervical cancer, the second leading cause of cancer mortality in women worldwide, results from infection with a subset of human papillomaviruses (HPV), HPV-16 being the most prevalent type. The available prophylactic vaccines are an effective strategy to prevent this cancer in the long term. However, they only target 70-80% of all cervical cancers and cannot control existing HPV infections and associated lesions. Therapeutic vaccines are thus necessary for women who cannot benefit from prophylactic vaccination. Induction of protective immune responses in the genital mucosa (GM) may be crucial for efficacy of HPV therapeutic vaccines. We report here that mice that received a single subcutaneous (s.c.) vaccination of an adjuvanted long synthetic HPV16 E7(1-98) polypeptide showed induction of 100% tumor protection against s.c. TC-1 tumors and that tumor regression was mainly provided by CD8 T cells. In vivo cytotoxic assay revealed high E7-specific cytolytic T lymphocytes activity in spleen and in genital draining lymph nodes (LN), and E7-specific CD8 T cells could be detected in GM by tetramer staining. More importantly, high-avidity E7-specific INF-gamma secreting CD8 T cells were induced not only in blood, spleen and LN but also in GM of vaccinated mice, thus providing evidence that a parenteral vaccination may be sufficient to provide regression of genital tumors. In addition, there was no correlation between the responses measured in blood with those measured in GM, highlighting the necessity and relevance to determine the immune responses in the mucosa where HPV-tumors reside.
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Affiliation(s)
- Loane Decrausaz
- Service of Urology and Institute of Microbiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
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