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Li W, Yang X, Wang M, Hu Z, Chen S, Sui X, Chen D, Niu X, Liu J, Xiao Y, Zhou X, Chen G, Gao Y. Development of a Cascade-Targeting Oral Vaccine via Glycoprotein 2 on Intestinal Microfold Cells for Cancer Immunotherapy. NANO LETTERS 2025; 25:5165-5173. [PMID: 39993319 DOI: 10.1021/acs.nanolett.4c06123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
Oral cancer vaccines are convenient and safe, with the presence of gut-associated lymphoid tissue (GALT) involved intestinal Peyer's patch (PPs) containing microfold (M) cells and housing abundant underneath dendritic cells (DCs). Here, we found that the endocytic receptors glycoprotein 2 (GP2) and dectin-1 are respectively expressed on M cells and DCs with high specificity. Then, we discovered a gastrointestinal hydrolysis-resistant D-peptide DGPBP-2(1-8) targeting GP2 by phage display screening and optimization. DGPBP-2(1-8) was conjugated to β-glucan (dectin-1 ligand)-containing yeast capsules (GP2-YCs) to design a cascade-targeting oral vaccine platform, which can help the antigen to efficiently cross intestinal M cells and subsequently be endocytosed by underneath DCs, thus activating CD8+ T cells. More importantly, this oral vaccine can evoke not only cellular but also humoral and mucosal immune responses. Therefore, this cascade-targeting oral vaccine could serve as a novel platform for cancer immunotherapy and infectious disease prevention as well.
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Affiliation(s)
- Wanqiong Li
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Xin Yang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Mengfan Wang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Zheng Hu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Shaomeng Chen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Xinghua Sui
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Danhong Chen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Xiaoshuang Niu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Juan Liu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Youmei Xiao
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Xiuman Zhou
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Guanyu Chen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
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Liu A, Zhang Y, Lin Y, Li X, Wang S, Pu W, Liu X, Jiang Z, Xiao Z. A rat model of adenoid hypertrophy constructed by using ovalbumin and lipopolysaccharides to induce allergy, chronic inflammation, and chronic intermittent hypoxia. Animal Model Exp Med 2025; 8:353-362. [PMID: 38572767 PMCID: PMC11871125 DOI: 10.1002/ame2.12396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 01/18/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Adenoid hypertrophy (AH) is a common pediatric disease that significantly impacts the growth and quality of life of children. However, there is no replicable and valid model for AH. METHODS An AH rat model was developed via comprehensive allergic sensitization, chronic inflammation induction, and chronic intermittent hypoxia (CIH). The modeling process involved three steps: female Sprague-Dawley rats (aged 4-5 weeks) were used for modeling. Allergen sensitization was induced via intraperitoneal administration and intranasal provocation using ovalbumin (OVA); chronic nasal inflammation was induced through intranasal lipopolysaccharide (LPS) administration for sustained nasal irritation; CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber. Postmodel establishment, behaviors, and histological changes in nasopharynx-associated lymphoid tissue (NALT) and nasal mucosa were assessed. Arterial blood gas analysis and quantification of serum and tissue levels of (interleukin) IL-4 and IL-13, OVA-specific immunoglobulin E (sIgE), eosinophil cationic protein (ECP), tumor necrosis factor (TNF-α), IL-17, and transforming growth factor (TGF)-β were conducted for assessment. The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated. RESULTS Rats exhibited notable nasal symptoms and hypoxia after modeling. Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa inflammatory cell infiltration. Elevated IL-4, IL-13, IL-17, OVA-sIgE, ECP, and TNF-α levels and reduced TGF-β levels were observed in the serum and tissue of model-group rats. After a week of treatment, the treatment group exhibited symptom and inflammatory factor improvement. CONCLUSION The model effectively simulates AH symptoms and pathological changes. But it should be further validated for genetic, immunological, and hormonal backgrounds in the currently used and other strains and species.
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Affiliation(s)
- Anqi Liu
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Yixing Zhang
- Department of PediatricsLishui Hospital of Traditional Chinese MedicineLishuiChina
| | - Yan Lin
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xuejun Li
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Shuming Wang
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Wenyan Pu
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xiuxiu Liu
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Zhiyan Jiang
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Zhen Xiao
- Department of PediatricsLonghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
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Sun X, Wu Y, Han C, Zhang N, Chen X, Chen Y. Intestinal epithelial vitamin D receptor defense against inflammatory bowel disease via regulating microfold cells. Immunol Lett 2024; 270:106925. [PMID: 39260525 DOI: 10.1016/j.imlet.2024.106925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 09/13/2024]
Abstract
Vitamin D receptor (VDR) is involved in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism of VDR in IBD is still unclear. Microfold cells (M cells) mediated antigen-sampling pathway is central in developing immune responses to pathogenic and commensal bacteria and related to IBD. We found that Intestinal epithelial cell-specific knockdown of VDR(VDRIEC-KO) increases the susceptibility of mice to experimental colitis induced by sodium dextran sulfate(DSS) by producing more M cells. Knockdown VDR in intestinal epithelial cells increased RANKL-induced microfold cells and promoted the ability of microfold cells to uptake S. Typhimurium (S. T.). Mechanistically, we demonstrated that knockdown VDR promoted the differentiation and maturation of M cells via the Spi-B-dependent pathway. We conclude that M cells may be a potential target of VDR for treating intestinal mucosal barrier dysfunction in IBD.
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Affiliation(s)
- Xiaomeng Sun
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China
| | - Yuxuan Wu
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China
| | - Chenhua Han
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China
| | - Na Zhang
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China
| | - Xin Chen
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China
| | - Yunzi Chen
- Key Laboratory of Immune Microenvironment and Disease, Department of Immunology, Nanjing Medical University, Nanjing 211166, China; Medical Centre for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing 211166, China.
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4
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Onji M, Penninger JM. RANKL and RANK in Cancer Therapy. Physiology (Bethesda) 2023; 38:0. [PMID: 36473204 DOI: 10.1152/physiol.00020.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/RANK in physiology and pathophysiology and discuss underlying principles and strategies to modulate the RANKL/RANK pathway as a therapeutic target in immune-mediated cancer treatment.
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Affiliation(s)
- Masahiro Onji
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Park JI, Cho SW, Kang JH, Park TE. Intestinal Peyer's Patches: Structure, Function, and In Vitro Modeling. Tissue Eng Regen Med 2023; 20:341-353. [PMID: 37079198 PMCID: PMC10117255 DOI: 10.1007/s13770-023-00543-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/21/2023] [Accepted: 04/06/2023] [Indexed: 04/21/2023] Open
Abstract
BACKGOUND Considering the important role of the Peyer's patches (PPs) in gut immune balance, understanding of the detailed mechanisms that control and regulate the antigens in PPs can facilitate the development of immune therapeutic strategies against the gut inflammatory diseases. METHODS In this review, we summarize the unique structure and function of intestinal PPs and current technologies to establish in vitro intestinal PP system focusing on M cell within the follicle-associated epithelium and IgA+ B cell models for studying mucosal immune networks. Furthermore, multidisciplinary approaches to establish more physiologically relevant PP model were proposed. RESULTS PPs are surrounded by follicle-associated epithelium containing microfold (M) cells, which serve as special gateways for luminal antigen transport across the gut epithelium. The transported antigens are processed by immune cells within PPs and then, antigen-specific mucosal immune response or mucosal tolerance is initiated, depending on the response of underlying mucosal immune cells. So far, there is no high fidelity (patho)physiological model of PPs; however, there have been several efforts to recapitulate the key steps of mucosal immunity in PPs such as antigen transport through M cells and mucosal IgA responses. CONCLUSION Current in vitro PP models are not sufficient to recapitulate how mucosal immune system works in PPs. Advanced three-dimensional cell culture technologies would enable to recapitulate the function of PPs, and bridge the gap between animal models and human.
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Affiliation(s)
- Jung In Park
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, 44919, South Korea
| | - Seung Woo Cho
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, 44919, South Korea
| | - Joo H Kang
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, 44919, South Korea
| | - Tae-Eun Park
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, 44919, South Korea.
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Niedzielski A, Chmielik LP, Mielnik-Niedzielska G, Kasprzyk A, Bogusławska J. Adenoid hypertrophy in children: a narrative review of pathogenesis and clinical relevance. BMJ Paediatr Open 2023; 7:10.1136/bmjpo-2022-001710. [PMID: 37045541 PMCID: PMC10106074 DOI: 10.1136/bmjpo-2022-001710] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 03/18/2023] [Indexed: 04/14/2023] Open
Abstract
Adenoids (nasopharyngeal tonsils), being part of Waldeyer's ring, are masses of lymphoid tissues located at the junction of the roof and the posterior wall of the nasopharynx. Adenoids play an important role in the development of the immune system and serve as a defence against infections, being the first organs that come into contact with respiratory and digestive antigens. The causes of adenoid hypertrophy are not fully known. They are most likely associated with aberrant immune reactions, infections, environmental exposures and hormonal or genetic factors. The aim of this review is to summarise the current knowledge of adenoid hypertrophy in children and associated diseases. Adenoid hypertrophy has many clinical manifestations that are frequent in the paediatric population and is accompanied by various comorbidities.
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Affiliation(s)
- Artur Niedzielski
- Department of Pediatric Otolaryngology, Centre of Postgraduate Medical Education, Warszawa, Poland
- Department of Pediatric ENT, The Children's Hospital in Dziekanów Leśny, Dziekanów Leśny, Poland
| | - Lechosław Paweł Chmielik
- Department of Pediatric Otolaryngology, Centre of Postgraduate Medical Education, Warszawa, Poland
- Department of Pediatric ENT, The Children's Hospital in Dziekanów Leśny, Dziekanów Leśny, Poland
| | | | - Anna Kasprzyk
- Department of Pediatric Otolaryngology, Centre of Postgraduate Medical Education, Warszawa, Poland
- Department of Pediatric ENT, The Children's Hospital in Dziekanów Leśny, Dziekanów Leśny, Poland
| | - Joanna Bogusławska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warszawa, Poland
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Horvath D, Temperton N, Mayora-Neto M, Da Costa K, Cantoni D, Horlacher R, Günther A, Brosig A, Morath J, Jakobs B, Groettrup M, Hoschuetzky H, Rohayem J, Ter Meulen J. Novel intranasal vaccine targeting SARS-CoV-2 receptor binding domain to mucosal microfold cells and adjuvanted with TLR3 agonist Riboxxim™ elicits strong antibody and T-cell responses in mice. Sci Rep 2023; 13:4648. [PMID: 36944687 PMCID: PMC10029786 DOI: 10.1038/s41598-023-31198-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/08/2023] [Indexed: 03/23/2023] Open
Abstract
SARS-CoV-2 continues to circulate in the human population necessitating regular booster immunization for its long-term control. Ideally, vaccines should ideally not only protect against symptomatic disease, but also prevent transmission via asymptomatic shedding and cover existing and future variants of the virus. This may ultimately only be possible through induction of potent and long-lasting immune responses in the nasopharyngeal tract, the initial entry site of SARS-CoV-2. To this end, we have designed a vaccine based on recombinantly expressed receptor binding domain (RBD) of SARS-CoV-2, fused to the C-terminus of C. perfringens enterotoxin, which is known to target Claudin-4, a matrix molecule highly expressed on mucosal microfold (M) cells of the nasal and bronchial-associated lymphoid tissues. To further enhance immune responses, the vaccine was adjuvanted with a novel toll-like receptor 3/RIG-I agonist (Riboxxim™), consisting of synthetic short double stranded RNA. Intranasal prime-boost immunization of mice induced robust mucosal and systemic anti-SARS-CoV-2 neutralizing antibody responses against SARS-CoV-2 strains Wuhan-Hu-1, and several variants (B.1.351/beta, B.1.1.7/alpha, B.1.617.2/delta), as well as systemic T-cell responses. A combination vaccine with M-cell targeted recombinant HA1 from an H1N1 G4 influenza strain also induced mucosal and systemic antibodies against influenza. Taken together, the data show that development of an intranasal SARS-CoV-2 vaccine based on recombinant RBD adjuvanted with a TLR3 agonist is feasible, also as a combination vaccine against influenza.
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Affiliation(s)
- Dennis Horvath
- Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
- Centre for the Advanced Study of Collective Behaviour, University of Konstanz, Konstanz, Germany
| | - Nigel Temperton
- Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Canterbury, UK
| | - Martin Mayora-Neto
- Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Canterbury, UK
| | - Kelly Da Costa
- Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Canterbury, UK
| | - Diego Cantoni
- Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Canterbury, UK
| | | | | | | | | | | | - Marcus Groettrup
- Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
| | | | - Jacques Rohayem
- Riboxx Pharmaceuticals, Radebeul, Dresden, Germany and Institute of Virology, Dresden University of Technology, Dresden, Germany
| | - Jan Ter Meulen
- Institute of Virology, Philipps University Marburg, Marburg, Germany.
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8
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Varghese PM, Kishore U, Rajkumari R. Innate and adaptive immune responses against Influenza A Virus: Immune evasion and vaccination strategies. Immunobiology 2022; 227:152279. [DOI: 10.1016/j.imbio.2022.152279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/31/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022]
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9
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Xu H, Cai L, Hufnagel S, Cui Z. Intranasal vaccine: Factors to consider in research and development. Int J Pharm 2021; 609:121180. [PMID: 34637935 DOI: 10.1016/j.ijpharm.2021.121180] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023]
Abstract
Most existing vaccines for human use are administered by needle-based injection. Administering vaccines needle-free intranasally has numerous advantages over by needle-based injection, but there are only a few intranasal vaccines that are currently approved for human use, and all of them are live attenuated influenza virus vaccines. Clearly, there are immunological as well as non-immunological challenges that prevent vaccine developers from choosing the intranasal route of administration. We reviewed current approved intranasal vaccines and pipelines and described the target of intranasal vaccines, i.e. nose and lymphoid tissues in the nasal cavity. We then analyzed factors unique to intranasal vaccines that need to be considered when researching and developing new intranasal vaccines. We concluded that while the choice of vaccine formulations, mucoadhesives, mucosal and epithelial permeation enhancers, and ligands that target M-cells are important, safe and effective intranasal mucosal vaccine adjuvants are needed to successfully develop an intranasal vaccine that is not based on live-attenuated viruses or bacteria. Moreover, more effective intranasal vaccine application devices that can efficiently target a vaccine to lymphoid tissues in the nasal cavity as well as preclinical animal models that can better predict intranasal vaccine performance in clinical trials are needed to increase the success rate of intranasal vaccines in clinical trials.
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Affiliation(s)
- Haiyue Xu
- The University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, United States
| | - Lucy Cai
- University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Stephanie Hufnagel
- The University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, United States
| | - Zhengrong Cui
- The University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, United States.
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10
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Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma. Eur Arch Otorhinolaryngol 2021; 279:1435-1443. [PMID: 34046748 DOI: 10.1007/s00405-021-06894-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/18/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. METHODS This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. RESULTS There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. CONCLUSION The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.
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11
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Alshweiat A, Ambrus R, Csoka II. Intranasal Nanoparticulate Systems as Alternative Route of Drug Delivery. Curr Med Chem 2019; 26:6459-6492. [PMID: 31453778 DOI: 10.2174/0929867326666190827151741] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 06/25/2018] [Accepted: 12/11/2018] [Indexed: 12/18/2022]
Abstract
There is always a need for alternative and efficient methods of drug delivery. The nasal cavity can be considered as a non-invasive and efficient route of administration. It has been used for local, systemic, brain targeting, and vaccination delivery. Although many intranasal products are currently available on the market, the majority is used for local delivery with fewer products available for the other targets. As nanotechnology utilization in drug delivery has rapidly spread out, the nasal delivery has become attractive as a promising approach. Nanoparticulate systems facilitate drug transportation across the mucosal barrier, protect the drug from nasal enzyme degradation, enhance the delivery of vaccines to the lymphoid tissue of the nasal cavity with an adjuvant activity, and offer a way for peptide delivery into the brain and the systemic circulation, in addition to their potential for brain tumor treatment. This review article aims at discussing the potential benefit of the intranasal nanoparticulate systems, including nanosuspensions, lipid and surfactant, and polymer-based nanoparticles as regards productive intranasal delivery. The aim of this review is to focus on the topicalities of nanotechnology applications for intranasal delivery of local, systemic, brain, and vaccination purposes during the last decade, referring to the factors affecting delivery, regulatory aspects, and patient expectations. This review further identifies the benefits of applying the Quality by Design approaches (QbD) in product development. According to the reported studies on nanotechnology-based intranasal delivery, potential attention has been focused on brain targeting and vaccine delivery with promising outcomes. Despite the significant research effort in this field, nanoparticle-based products for intranasal delivery are not available. Thus, further efforts are required to promote the introduction of intranasal nanoparticulate products that can meet the requirements of regulatory affairs with high patient acceptance.
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Affiliation(s)
- Areen Alshweiat
- Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary.,Faculty of Pharmaceutical Science, The Hashemite University, Zarqa, Jordan
| | - Rita Ambrus
- Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary
| | - IIdikó Csoka
- Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary
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12
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Kobayashi N, Takahashi D, Takano S, Kimura S, Hase K. The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases. Front Immunol 2019; 10:2345. [PMID: 31649668 PMCID: PMC6794464 DOI: 10.3389/fimmu.2019.02345] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023] Open
Abstract
Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.
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Affiliation(s)
- Nobuhide Kobayashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,Department of Bacteriology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daisuke Takahashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Takano
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
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13
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Deng H, Dutta P, Liu J. Stochastic modeling of nanoparticle internalization and expulsion through receptor-mediated transcytosis. NANOSCALE 2019; 11:11227-11235. [PMID: 31157808 PMCID: PMC6634982 DOI: 10.1039/c9nr02710f] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Receptor-mediated transcytosis (RMT) is a fundamental mechanism for the transcellular transport of nanoparticles. RMT is a complex process, during which the nanoparticles actively interact with the membrane and the membrane profile undergoes extreme deformations for particle internalization and expulsion. In this work, we developed a stochastic model to study the endocytosis and exocytosis of nanoparticles across soft membranes. The model is based on the combination of a stochastic particle binding model with a membrane model, and accounts for both clathrin-mediated endocytosis for internalization and actin-mediated exocytosis for expulsion. Our results showed that nanoparticles must have certain avidity with enough ligand density and ligand-receptor binding affinity to be taken up, while too high avidity limited the particle release from the cell surface. We further explored the functional roles of actin during exocytosis, which has been a topic under active debate. Our simulations indicated that the membrane compression due to the actin induced tension tended to break the ligand-receptor bonds and to shrink the fusion pore. Therefore, an intermediate tension promoted the fusion pore expansion and nanoparticle release, while high tension prohibits particle release. Our model provides new and critical mechanistic insights into RMT, and represents a powerful platform for aiding the rational design of nanocarriers for controlled drug delivery.
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Affiliation(s)
- Hua Deng
- School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99163, USA.
| | - Prashanta Dutta
- School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99163, USA.
| | - Jin Liu
- School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99163, USA.
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14
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Huh H, Wong S, St Jean J, Slavcev R. Bacteriophage interactions with mammalian tissue: Therapeutic applications. Adv Drug Deliv Rev 2019; 145:4-17. [PMID: 30659855 DOI: 10.1016/j.addr.2019.01.003] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 11/30/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022]
Abstract
The human body is a large reservoir for bacterial viruses known as bacteriophages (phages), which participate in dynamic interactions with their bacterial and human hosts that ultimately affect human health. The current growing interest in human resident phages is paralleled by new uses of phages, including the design of engineered phages for therapeutic applications. Despite the increasing number of clinical trials being conducted, the understanding of the interaction of phages and mammalian cells and tissues is still largely unknown. The presence of phages in compartments within the body previously considered purely sterile, suggests that phages possess a unique capability of bypassing anatomical and physiological barriers characterized by varying degrees of selectivity and permeability. This review will discuss the direct evidence of the accumulation of bacteriophages in various tissues, focusing on the unique capability of phages to traverse relatively impermeable barriers in mammals and its relevance to its current applications in therapy.
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Affiliation(s)
- Haein Huh
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Shirley Wong
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Jesse St Jean
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Roderick Slavcev
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada.
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15
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Date Y, Ebisawa M, Fukuda S, Shima H, Obata Y, Takahashi D, Kato T, Hanazato M, Nakato G, Williams IR, Hase K, Ohno H. NALT M cells are important for immune induction for the common mucosal immune system. Int Immunol 2018; 29:471-478. [PMID: 29186424 DOI: 10.1093/intimm/dxx064] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 11/26/2017] [Indexed: 01/05/2023] Open
Abstract
Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS).
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Affiliation(s)
- Yasuhiro Date
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.,RIKEN Center for Sustainable Resource Science, Kanagawa, Japan
| | - Masashi Ebisawa
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Shinji Fukuda
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan
| | - Hideaki Shima
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Yuuki Obata
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Daisuke Takahashi
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan
| | - Tamotsu Kato
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Misaho Hanazato
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Gaku Nakato
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Ifor R Williams
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Koji Hase
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan
| | - Hiroshi Ohno
- RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.,Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.,Graduate School of Medicine, Chiba University, Chiba, Japan
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16
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Bykov AS, Karaulov AV, Tsomartova DA, Kartashkina NL, Goriachkina VL, Kuznetsov SL, Stonogina DA, Chereshneva YV. M CELLS ARE THE IMPORTANT POST IN THE INITIATION OF IMMUNE RESPONSE IN INTESTINE. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2018. [DOI: 10.15789/2220-7619-2018-3-263-272] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Microfold cells (M cells) are specialized intestinal epithelial cells that initiate mucosal immune responses. These unique phagocytic epithelial cells are specialized for the transfer of a broad range of particulate antigens and microorganisms across the follicle-associated epithelium (FAE) into the gut-associated lymphoid tissue (GALT) by a process termed transcytosis. The molecular basis of antigen uptake by M cells has been gradually identified in the last decade. Active sampling of intestinal antigen initiates regulated immune responses that ensure intestinal homeostasis. The delivery of luminal substances across the intestinal epithelium to the immune system is a critical event in immune surveillance resulting in tolerance to dietary antigens and immunity to pathogens (e.g., bacteria, viruses, and parasites) and their toxins. Several specialized mechanisms transport luminal antigen across the gut epithelium. Discovery of M cell-specific receptors are of great interest, which could act as molecular tags for targeted delivery oral vaccine to M cells. Recent studies demonstrated that M cells utilize several receptors to recognize and transport specific luminal antigens. Vaccination through the mucosal immune system can induce effective systemic immune responses simultaneously with mucosal immunity. How this process is regulated is largely unknown. This review aims to show a new understanding of the factors that influence the development and function of M cells; to show the molecules expressed on M cells which appear to be used as immunosurveillance receptors to sample pathogenic microorganisms in the gut; to note how certain pathogens appear to exploit M cells to inject the host; and, finally, how this knowledge is used to specifically "target" antigens to M cells to attempt to improve the efficacy of mucosal vaccines. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells.
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17
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Chen X, Liu S, Goraya MU, Maarouf M, Huang S, Chen JL. Host Immune Response to Influenza A Virus Infection. Front Immunol 2018; 9:320. [PMID: 29556226 PMCID: PMC5845129 DOI: 10.3389/fimmu.2018.00320] [Citation(s) in RCA: 309] [Impact Index Per Article: 44.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 02/05/2018] [Indexed: 12/25/2022] Open
Abstract
Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.
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Affiliation(s)
- Xiaoyong Chen
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Shasha Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Mohsan Ullah Goraya
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Mohamed Maarouf
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | - Ji-Long Chen
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.,CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
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18
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Intranasal immunization with dry powder vaccines. Eur J Pharm Biopharm 2017; 122:167-175. [PMID: 29122735 DOI: 10.1016/j.ejpb.2017.11.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 10/30/2017] [Accepted: 11/03/2017] [Indexed: 12/22/2022]
Abstract
Vaccination represents a cost-effective weapon for disease prevention and has proven to dramatically reduce the incidences of several diseases that once were responsible for significant mortality and morbidity worldwide. The nasal cavity constitutes the initial stage of the respiratory system and the first contact with inhaled pathogens. The intranasal (IN) route for vaccine administration is an attractive alternative to injection, due to the ease of administration as well as better patient compliance. Many published studies have demonstrated the safety and effectiveness of IN immunization with liquid vaccines. Currently, two liquid IN vaccines are available and both contain live attenuated influenza viruses. FluMist® was approved in 2003 in the United States, and Nasovac® H1N1 vaccine was approved in India in 2010. Preclinical studies showed that IN immunization with dry powder vaccines (DPVs) is feasible. Although there is not a commercially available DPV yet, DPVs have the inherent advantage of being relatively more stable than liquid vaccines. This review focuses on recent developments of DPVs as next-generation IN vaccines.
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19
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Mabbott NA. Immunology of Prion Protein and Prions. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 150:203-240. [PMID: 28838662 DOI: 10.1016/bs.pmbts.2017.06.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Many natural prion diseases are acquired peripherally, such as following the oral consumption of contaminated food or pasture. After peripheral exposure many prion isolates initially accumulate to high levels within the host's secondary lymphoid tissues. The replication of prions within these tissues is essential for their efficient spread to the brain where they ultimately cause neurodegeneration. This chapter describes our current understanding of the critical tissues, cells, and molecules which the prions exploit to mediate their efficient propagation from the site of exposure (such as the intestine) to the brain. Interactions between the immune system and prions are not only restricted to the secondary lymphoid tissues. Therefore, an account of how the activation status of the microglial in the brain can also influence progression of prion disease pathogenesis is provided. Prion disease susceptibility may also be influenced by additional factors such as chronic inflammation, coinfection with other pathogens, and aging. Finally, the potential for immunotherapy to provide a means of safe and effective prophylactic or therapeutic intervention in these currently untreatable diseases is considered.
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Affiliation(s)
- Neil A Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Midlothian, United Kingdom.
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20
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Pulmonary immunity to viruses. Clin Sci (Lond) 2017; 131:1737-1762. [PMID: 28667071 DOI: 10.1042/cs20160259] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 03/31/2017] [Accepted: 04/06/2017] [Indexed: 12/28/2022]
Abstract
Mucosal surfaces, such as the respiratory epithelium, are directly exposed to the external environment and therefore, are highly susceptible to viral infection. As a result, the respiratory tract has evolved a variety of innate and adaptive immune defenses in order to prevent viral infection or promote the rapid destruction of infected cells and facilitate the clearance of the infecting virus. Successful adaptive immune responses often lead to a functional state of immune memory, in which memory lymphocytes and circulating antibodies entirely prevent or lessen the severity of subsequent infections with the same virus. This is also the goal of vaccination, although it is difficult to vaccinate in a way that mimics respiratory infection. Consequently, some vaccines lead to robust systemic immune responses, but relatively poor mucosal immune responses that protect the respiratory tract. In addition, adaptive immunity is not without its drawbacks, as overly robust inflammatory responses may lead to lung damage and impair gas exchange or exacerbate other conditions, such as asthma or chronic obstructive pulmonary disease (COPD). Thus, immune responses to respiratory viral infections must be strong enough to eliminate infection, but also have mechanisms to limit damage and promote tissue repair in order to maintain pulmonary homeostasis. Here, we will discuss the components of the adaptive immune system that defend the host against respiratory viral infections.
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21
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Yang J, Dai L, Yu Q, Yang Q. Histological and anatomical structure of the nasal cavity of Bama minipigs. PLoS One 2017; 12:e0173902. [PMID: 28339502 PMCID: PMC5365122 DOI: 10.1371/journal.pone.0173902] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 02/28/2017] [Indexed: 12/23/2022] Open
Abstract
Objective The nasal mucosa is equipped with abundant lymphatic tissues, serving as the first line of defense against invasion by microorganisms. In this study, we characterized the features of the nasal mucosa of Bama minipigs (Sus scrofa domestica) via histological analysis. Methods Five cross sections (I, II, III, IV, and V) were obtained from the distal end of the nasal cavity toward the pharynx (along the cavity axis) and examined. Specifically, CD3+ T cells, immunoglobulin A (IgA)+ cells, and M cells were detected by immunohistochemistry, while dendritic cells (DCs) were detected by immunofluorescence. The distribution of goblet cells was determined by periodic acid-Schiff (PAS) staining. Results The nasal cavity of Bama minipigs can be divided into three parts: the regio vestibularis (I, II), regio respiratoria (III, IV), and regio olfactoria (V). Lymphoid tissue was present at random locations in the nasal cavity. Abundant lymphoid tissue was located in the roof of the nasopharyngeal meatus and was continuous with the lymphoid tissue of the pharynx. The distribution of CD3+ T cells, IgA+ cells, M cells, and DCs increased distally in the nasal cavity. Conclusions The present work comprises a histological study of the nasal cavity of Bama minipigs, and will be beneficial for understanding the mechanisms of immunity in these animals after nasal vaccination.
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Affiliation(s)
- Jingjing Yang
- Veterinary College, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, PR China
| | - Lei Dai
- Veterinary College, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, PR China
| | - Qinghua Yu
- Veterinary College, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, PR China
| | - Qian Yang
- Veterinary College, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, PR China
- * E-mail:
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22
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Sehgal A, Kobayashi A, Donaldson DS, Mabbott NA. c-Rel is dispensable for the differentiation and functional maturation of M cells in the follicle-associated epithelium. Immunobiology 2016; 222:316-326. [PMID: 27663963 PMCID: PMC5152706 DOI: 10.1016/j.imbio.2016.09.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/30/2016] [Accepted: 09/17/2016] [Indexed: 01/22/2023]
Abstract
M cells reside within the follicle-associated epithelium (FAE) overlying the gut-associated lymphoid tissues. These unique phagocytic epithelial cells enable the mucosal immune system to sample antigens within the lumen of the intestine. The differentiation of M cells from uncommitted precursors in the FAE is dependent on the production of receptor activator of nuclear factor-κB ligand (RANKL) by subepithelial stromal cells. The ligation of a variety of cell surface receptors activates the nuclear factor-κB (NF-κB) family of transcription factors which in-turn induce the transcription of multiple target genes. RANKL-stimulation can stimulate the nuclear translocation of the NF-κB subunit c-Rel. We therefore used c-Rel-deficient mice to determine whether the differentiation and functional maturation of M cells in the Peyer's patches was dependent on c-Rel. Our data show that c-Rel-deficiency does not influence the expression of RANKL or RANK in Peyer's patches, or the induction of M-cell differentiation in the FAE. RANKL-stimulation in the differentiating M cells induces the expression of SpiB which is essential for their subsequent maturation. However, SpiB expression in the FAE was also unaffected in the absence of c-Rel. As a consequence, the functional maturation of M cells was not impaired in the Peyer's patches of c-Rel-deficient mice. Although our data showed that the specific expression of CCL20 and ubiquitin D in the FAE was not impeded in the absence of c-Rel, the expression of ubiquitin D was dramatically reduced in the B cell-follicles of c-Rel-deficient mice. Coincident with this, we also observed that the status of follicular dendritic cells in the B cell-follicles was dramatically reduced in Peyer's patches from c-Rel-deficient mice. Taken together, our data show that c-Rel is dispensable for the RANKL-mediated differentiation and functional maturation of M cells.
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Affiliation(s)
- Anuj Sehgal
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Atsushi Kobayashi
- Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - David S Donaldson
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Neil A Mabbott
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
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23
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Mabbott NA, Kobayashi A, Sehgal A, Bradford BM, Pattison M, Donaldson DS. Aging and the mucosal immune system in the intestine. Biogerontology 2015; 16:133-45. [PMID: 24705962 DOI: 10.1007/s10522-014-9498-z] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 03/24/2014] [Indexed: 02/07/2023]
Abstract
Bacterial and viral infections of the gastrointestinal tract are more common in the elderly and represent a major cause of morbidity and mortality. The mucosal immune system provides the first line of defence against pathogens acquired by ingestion and inhalation, but its function is adversely affected in the elderly. This aging-related decline in the immune function is termed immunosenescence and is associated with diminished abilities to generate protective immunity, reduced vaccine efficacy, increased incidence of cancer, inflammation and autoimmunity, and the impaired ability to generate tolerance to harmless antigens. In this review we describe our current understanding of the effects immunosenescence has on the innate and adaptive arms of the mucosal immune system in the intestine. Current estimates suggest that by the year 2050 up to 40% of the UK population will be over 65 years old, bringing with it important health challenges. A thorough understanding of the mechanisms that contribute to the development of immunosenescence is therefore crucial to help identify novel approaches to improve mucosal immunity in the elderly.
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Affiliation(s)
- Neil A Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK,
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24
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Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
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25
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Kang H, Yan M, Yu Q, Yang Q. Characterization of Nasal Cavity-Associated Lymphoid Tissue in Ducks. Anat Rec (Hoboken) 2014; 297:916-24. [DOI: 10.1002/ar.22888] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 12/30/2013] [Accepted: 01/06/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Haihong Kang
- College of Veterinary Medicine; Nanjing Agricultural University; Nanjing People's Republic of China
| | - Mengfei Yan
- College of Veterinary Medicine; Nanjing Agricultural University; Nanjing People's Republic of China
| | - Qinghua Yu
- College of Veterinary Medicine; Nanjing Agricultural University; Nanjing People's Republic of China
| | - Qian Yang
- College of Veterinary Medicine; Nanjing Agricultural University; Nanjing People's Republic of China
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26
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Tugizov SM, Herrera R, Palefsky JM. Epstein-Barr virus transcytosis through polarized oral epithelial cells. J Virol 2013; 87:8179-8194. [PMID: 23698302 PMCID: PMC3700193 DOI: 10.1128/jvi.00443-13] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 04/29/2013] [Indexed: 01/28/2023] Open
Abstract
Although Epstein-Barr virus (EBV) is an orally transmitted virus, viral transmission through the oropharyngeal mucosal epithelium is not well understood. In this study, we investigated how EBV traverses polarized human oral epithelial cells without causing productive infection. We found that EBV may be transcytosed through oral epithelial cells bidirectionally, from both the apical to the basolateral membranes and the basolateral to the apical membranes. Apical to basolateral EBV transcytosis was substantially reduced by amiloride, an inhibitor of macropinocytosis. Electron microscopy showed that virions were surrounded by apical surface protrusions and that virus was present in subapical vesicles. Inactivation of signaling molecules critical for macropinocytosis, including phosphatidylinositol 3-kinases, myosin light-chain kinase, Ras-related C3 botulinum toxin substrate 1, p21-activated kinase 1, ADP-ribosylation factor 6, and cell division control protein 42 homolog, led to significant reduction in EBV apical to basolateral transcytosis. In contrast, basolateral to apical EBV transcytosis was substantially reduced by nystatin, an inhibitor of caveolin-mediated virus entry. Caveolae were detected in the basolateral membranes of polarized human oral epithelial cells, and virions were detected in caveosome-like endosomes. Methyl β-cyclodextrin, an inhibitor of caveola formation, reduced EBV basolateral entry. EBV virions transcytosed in either direction were able to infect B lymphocytes. Together, these data show that EBV transmigrates across oral epithelial cells by (i) apical to basolateral transcytosis, potentially contributing to initial EBV penetration that leads to systemic infection, and (ii) basolateral to apical transcytosis, which may enable EBV secretion into saliva in EBV-infected individuals.
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Affiliation(s)
- Sharof M Tugizov
- Department of Medicine, University of California San Francisco, San Francisco, California, USA.
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27
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Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 2013; 6:666-77. [PMID: 23695511 PMCID: PMC3686595 DOI: 10.1038/mi.2013.30] [Citation(s) in RCA: 470] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The transcytosis of antigens across the gut epithelium by microfold cells (M cells) is important for the induction of efficient immune responses to some mucosal antigens in Peyer's patches. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells. This review highlights these important advances, with particular emphasis on: the host genes which control the functional maturation of M cells; how this knowledge has led to the rapid advance in our understanding of M-cell biology in the steady state and during aging; molecules expressed on M cells which appear to be used as "immunosurveillance" receptors to sample pathogenic microorganisms in the gut; how certain pathogens appear to exploit M cells to infect the host; and finally how this knowledge has been used to specifically target antigens to M cells to attempt to improve the efficacy of mucosal vaccines.
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Abstract
Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses.
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Almeida* AJ, Florindo HF. Nanocarriers Overcoming the Nasal Barriers: Physiological Considerations and Mechanistic Issues. NANOSTRUCTURED BIOMATERIALS FOR OVERCOMING BIOLOGICAL BARRIERS 2012. [DOI: 10.1039/9781849735292-00117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Makidon PE, Belyakov IM, Blanco LP, Janczak KW, Landers J, Bielinska AU, Groom JV, Baker JR. Nanoemulsion mucosal adjuvant uniquely activates cytokine production by nasal ciliated epithelium and induces dendritic cell trafficking. Eur J Immunol 2012; 42:2073-86. [PMID: 22653620 DOI: 10.1002/eji.201142346] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 04/13/2012] [Accepted: 05/03/2012] [Indexed: 01/08/2023]
Abstract
While the nasal mucosa is a potentially useful site for human immunization, toxin-based nasal adjuvants are generally unsafe and less effective in humans. Safe mucosal adjuvants that activate protective immunity via mucosal administration are highly dependent on barrier antigen sampling by epithelial and DCs. Here, we demonstrate that protein antigens formulated in unique oil-in-water nanoemulsions (NEs) result in distinctive transcellular antigen uptake in ciliated nasal epithelial cells, leading to delivery into nasal associated lymphoid tissue. NE formulation also enhances MHC class II expression in epithelial cells and DC activation/trafficking to regional lymphoid tissues in mice. These materials appear to induce local epithelial cell apoptosis and heterogeneous cytokine production by mucosal epithelial cells and mixed nasal tissues, including G-CSF, GM-CSF, IL-1a, IL-1b, IL-5, IL-6, IL-12, IP-10, KC, MIP-1a, TGF-β, and TSLP. This is the first observation of a nasal adjuvant that activates calreticulin-associated apoptosis of ciliated nasal epithelial cells to generate broad cytokine/chemokine responses in mucosal tissue.
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Affiliation(s)
- Paul E Makidon
- Division of Allergy and Clinical Immunology, Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
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31
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Rautava J, Syrjänen S. Biology of human papillomavirus infections in head and neck carcinogenesis. Head Neck Pathol 2012; 6 Suppl 1:S3-15. [PMID: 22782219 PMCID: PMC3394166 DOI: 10.1007/s12105-012-0367-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 05/08/2012] [Indexed: 12/14/2022]
Abstract
The association between human papillomaviruses (HPV) and oral cancer was initially suggested nearly 30 years ago by us. Today, the research interest of head and neck squamous cell carcinoma (HNSCC) has substantially increased. HPV-associated HNSCC is considered a distinct clinical entity with better prognosis than the classical tobacco and alcohol associated cancers. HPV 16 seems to be the main genotype present in HNSCC and it most probably utilizes the same pathways in epithelial cell transformation as established for genital cancer. High-risk HPV E6 and E7 target the well characterized cellular proteins p53 and Rb, respectively. In addition, several other cellular targets of E6 and E7 have been identified. This review gives an overview on the biology of HPV which aids in dissecting the role of HPV in head and neck carcinogenesis. It also summarizes the possible pathways involved in creating new tools for diagnosis and therapy of HPV-associated HNSCC.
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Affiliation(s)
- Jaana Rautava
- Department of Oral Pathology, Faculty of Medicine, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20880 Turku, Finland ,Department of Pathology, Turku University Hospital, Turku, Finland
| | - Stina Syrjänen
- Department of Oral Pathology, Faculty of Medicine, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20880 Turku, Finland ,Department of Pathology, Turku University Hospital, Turku, Finland
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A step-by-step approach to study the influence of N-acetylation on the adjuvanticity of N,N,N-trimethyl chitosan (TMC) in an intranasal nanoparticulate influenza virus vaccine. Eur J Pharm Sci 2012; 45:467-74. [DOI: 10.1016/j.ejps.2011.10.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 09/20/2011] [Accepted: 10/04/2011] [Indexed: 11/15/2022]
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33
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Amorij JP, Kersten GFA, Saluja V, Tonnis WF, Hinrichs WLJ, Slütter B, Bal SM, Bouwstra JA, Huckriede A, Jiskoot W. Towards tailored vaccine delivery: needs, challenges and perspectives. J Control Release 2012; 161:363-76. [PMID: 22245687 DOI: 10.1016/j.jconrel.2011.12.039] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 12/22/2011] [Accepted: 12/27/2011] [Indexed: 11/30/2022]
Abstract
The ideal vaccine is a simple and stable formulation which can be conveniently administered and provides life-long immunity against a given pathogen. The development of such a vaccine, which should trigger broad and strong B-cell and T-cell responses against antigens of the pathogen in question, is highly dependent on tailored vaccine delivery approaches. This review addresses vaccine delivery in its broadest scope. We discuss the needs and challenges in the area of vaccine delivery, including restrictions posed by specific target populations, potentials of dedicated stable formulations and devices, and the use of adjuvants. Moreover, we address the current status and perspectives of vaccine delivery via several routes of administration, including non- or minimally invasive routes. Finally we suggest possible directions for future vaccine delivery research and development.
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Affiliation(s)
- Jean-Pierre Amorij
- Vaccinology, National Institute for Public Health and Environment, Bilthoven, The Netherlands
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34
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Stanberry LR, Simon JK, Johnson C, Robinson PL, Morry J, Flack MR, Gracon S, Myc A, Hamouda T, Baker JR. Safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W805EC combined with approved seasonal influenza antigens. Vaccine 2011; 30:307-16. [PMID: 22079079 DOI: 10.1016/j.vaccine.2011.10.094] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 10/22/2011] [Accepted: 10/30/2011] [Indexed: 11/18/2022]
Abstract
BACKGROUND Improving the systemic and mucosal immune response following intranasal vaccination could enhance disease protection against respiratory pathogens. We assessed the safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W(80)5EC combined with approved seasonal influenza antigens. METHODS This was a first-in-human Phase I study in 199 healthy adult volunteers randomized to receive a single intranasal administration of 5%, 10%, 15% or 20% W(80)5EC, combined with 4 or 10 μg strain-specific Fluzone(®) HA, compared with intranasal PBS, intranasal Fluzone(®), or 15 ug strain-specific intramuscular Fluzone(®). Safety was evaluated by physical examination, laboratory parameters, symptom diaries, and adverse event reports. Serum HAI titers and nasal wash IgA were assessed at baseline as well as 28 and 60 days after vaccination. RESULTS W(80)5EC adjuvant combined with seasonal influenza antigens was well tolerated without safety concerns or significant adverse events. The highest dose of 20% W(80)5EC combined with 10 μg strain-specific HA elicited clinically meaningful systemic immunity based on increases in serum HAI GMT and ≥ 70% seroprotection for all 3 influenza strains, as well as a rise in antigen-specific IgA in nasal wash specimens. CONCLUSIONS W(80)5EC adjuvant was safe and well tolerated in healthy adult volunteers and elicited both systemic and mucosal immunity following a single intranasal vaccination.
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Affiliation(s)
- L R Stanberry
- Department of Pediatrics, Columbia University, New York, NY, USA
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35
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Tiwari S, Verma SK, Agrawal GP, Vyas SP. Viral protein complexed liposomes for intranasal delivery of hepatitis B surface antigen. Int J Pharm 2011; 413:211-9. [DOI: 10.1016/j.ijpharm.2011.04.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Revised: 04/09/2011] [Accepted: 04/14/2011] [Indexed: 10/18/2022]
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36
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Abstract
The current vaccine market is gaining momentum in the development of alternative administration routes namely intranasal, oral, topical, pulmonary, vaginal, and rectal; the nasal route offers the most promising opportunity for vaccine administration. It can enhance convenience, safety, elicit both local and systemic immune responses; thus potentially provide protection from pathogens at the site of entry. Nasal vaccine innovation comes with both opportunities and challenges. The innovative strategies used by industry and researchers to overcome the hurdles are discussed in this article: these include live-attenuated vaccines, adjuvants, mucoadhesives, particulate delivery systems, virus-like particles, vaccine manufacture, challenges of regulatory authorities, and the nasal vaccine impact on market potential. Critical issues for effective nasal vaccination are the antigen-retention period that enables its interaction with the lymphatic system and choice of an adjuvant that is nontoxic and induces the required immune response. Co-adjuvanting by means of a mucoadhesive technology addresses some of these issues. ChiSys(®), a natural bioadhesive with proven intranasal safety profile, has already demonstrated efficacy for several nasally delivered vaccines including norovirus. With the looming threat of a pandemic, alternatives such as intranasal vaccination will ultimately facilitate greater public compliance and rapid mass global vaccination.
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Affiliation(s)
- Inderjit Jabbal-Gill
- Archimedes Development Ltd., Albert Einstein Centre, Nottingham Science & Technology Park, University Boulevard, Nottingham, UK.
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37
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Influence of particle size on the pathology and efficacy of vaccination in a murine model of inhalational anthrax. J Med Microbiol 2010; 59:1415-1427. [DOI: 10.1099/jmm.0.024117-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Deposition of Bacillus anthracis endospores within either the lungs or nasal passages of A/J mice after aerosol exposure was influenced by different particle sized aerosols and resulted in different infection kinetics. The infection resulting from the inhalation of endospores within a 12 μm particle aerosol was prolonged compared to that from a 1 μm particle aerosol with a mean time-to-death of 161±16.1 h and 101.6±10.4 h, respectively. Inhalation of endospores within 1 μm or 12 μm particle aerosols resulted in a median lethal dose of 2432 and 7656 c.f.u., respectively. Initial involvement of the upper respiratory tract lymph nodes was observed in 75–83 % of mice exposed to either the 1 μm or 12 μm particle inhalational infections. Lung deposition was significantly greater after inhalation of the 1 μm particle aerosol with pronounced involvement of the mediastinal lymph node. Gastrointestinal involvement was observed only in mice exposed to 12 μm particle aerosols where bacteriological and histopathological analysis indicated primary gastritis (17 %), activation of the Peyer's patches (72 %) and colonization and necrosis of the mesenteric lymph nodes (67 %). Terminal disease was characterized by bacteraemia in both inhalational infections with preferential dissemination to spleen, liver, kidneys and thymus. Immunization with 1 μg recombinant protective antigen vaccine was equally efficacious against B. anthracis infections arising from the inhalation of 1 and 12 μm particle aerosols, providing 73–80 % survival under a suboptimum immunization schedule.
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Kumlin U, Olofsson S, Dimock K, Arnberg N. Sialic acid tissue distribution and influenza virus tropism. Influenza Other Respir Viruses 2009; 2:147-54. [PMID: 19453419 PMCID: PMC4941897 DOI: 10.1111/j.1750-2659.2008.00051.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Abstract Avian influenza A viruses exhibit a strong preference for using α2,3‐linked sialic acid as a receptor. Until recently, the presumed lack of this receptor in human airways was believed to constitute an efficient barrier to avian influenza A virus infection of humans. Recent zoonotic outbreaks of avian influenza A virus have triggered researchers to analyse tissue distribution of sialic acid in further detail. Here, we review and extend the current knowledge about sialic acid distribution in human tissues, and discuss viruses with ocular tropism and their preference for α2,3‐linked sialic acid.
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Affiliation(s)
- Urban Kumlin
- Department of Clinical Microbiology, Division of Virology, Umeå University, Umeå, Sweden
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39
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Meier-Trummer CS, Tobler K, Hilbe M, Stewart JP, Hart J, Campbell I, Haig DM, Glauser DL, Ehrensperger F, Ackermann M. Ovine herpesvirus 2 structural proteins in epithelial cells and M-cells of the appendix in rabbits with malignant catarrhal fever. Vet Microbiol 2009; 137:235-42. [DOI: 10.1016/j.vetmic.2009.01.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 01/12/2009] [Accepted: 01/19/2009] [Indexed: 11/16/2022]
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40
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Sharma S, Mukkur T, Benson HA, Chen Y. Pharmaceutical Aspects of Intranasal Delivery of Vaccines Using Particulate Systems. J Pharm Sci 2009; 98:812-43. [DOI: 10.1002/jps.21493] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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41
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Different pathologies but equal levels of responsiveness to the recombinant F1 and V antigen vaccine and ciprofloxacin in a murine model of plague caused by small- and large-particle aerosols. Infect Immun 2009; 77:1315-23. [PMID: 19188359 DOI: 10.1128/iai.01473-08] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Presently there is a significant effort to develop and evaluate vaccines and antibiotics against the potential bioterrorism agent Yersinia pestis. The animal models used to test these countermeasures involve the deposition of small particles within the lung. However, deliberate aerosol release of Y. pestis will generate both small and large inhalable particles. We report in this study that the pathogenesis patterns of plague infections caused by the deposition of 1- and 12-microm-particle aerosols of Y. pestis in the lower and upper respiratory tracts (URTs) of mice are different. The median lethal dose for 12-mum particles was 4.9-fold greater than that for 1-microm particles. The 12-microm-particle infection resulted in the degradation of the nasal mucosa and nasal-associated lymphoid tissue (NALT) plus cervical lymphadenopathy prior to bacteremic dissemination. Lung involvement was limited to secondary pneumonia. In contrast, the 1-microm-particle infection resulted in primary pneumonia; in 40% of mice, the involvement of NALT and cervical lymphadenopathy were observed, indicating entry via both URT lymphoid tissues and lungs. Despite bacterial deposition in the gastrointestinal tract, the involvement of Peyer's patches was not observed in either infection. Although there were major differences in pathogenesis, the recombinant F1 and V antigen vaccine and ciprofloxacin protected against plague infections caused by small- and large-particle aerosols.
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43
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Takano KI, Kojima T, Ogasawara N, Go M, Kikuchi S, Ninomiya T, Kurose M, Koizumi JI, Kamekura R, Murata M, Tanaka S, Chiba H, Himi T, Sawada N. Expression of tight junction proteins in epithelium including Ck20-positive M-like cells of human adenoids in vivo and in vitro. J Mol Histol 2008; 39:265-73. [PMID: 18246436 DOI: 10.1007/s10735-008-9162-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Accepted: 01/16/2008] [Indexed: 11/26/2022]
Abstract
The human adenoid epithelium forms a continuous barrier against a wide variety of exogenous antigens. In this study, to elucidate the structures of the epithelial barrier in the human adenoid, including M-cells, we identified M-cells using an anti-cytokeratin 20 (Ck20) antibody and investigated expression of tight junction proteins in human adenoid epithelium in vivo and in vitro. In human adenoid epithelium and primary cultures, mRNAs of occludin, junctional adhesion molecule-A, ZO-1, and claudin-1, -4, -7, and -8 were detected by reverse transcription-polymerase chain reaction, whereas claudin-2 and -9 were expressed in vitro. In the epithelium in vivo, some Ck20-positive cells were randomly observed and indicated pocket-like structures, whereas Ck7 was positive in almost cells. Transmission electron microscopy revealed that Ck20-associated gold particles could be identified in M-like cells which had short microvilli and harboured the lymphocyte in the pocket-like structure. In primary cultures in vitro, Ck20-positive cells were also detected and had a function to take up fluorescent microparticles. In Ck20-positive cells in vivo and in vitro, expression of occludin, ZO-1, claudin-1 and -7 were observed at cell borders. These results indicate that the epithelial barrier of the human adenoid is stably maintained by expression of tight junction proteins in the epithelium including Ck20-positive M-like cells.
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Affiliation(s)
- Ken-ichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Cutler CW, Teng YTA. Oral mucosal dendritic cells and periodontitis: many sides of the same coin with new twists. Periodontol 2000 2007; 45:35-50. [PMID: 17850447 PMCID: PMC2828688 DOI: 10.1111/j.1600-0757.2007.00222.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Christopher W Cutler
- Department of Periodontics and Implantology, School of Dental Medicine, Stony Brook University, New York, NY, USA
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45
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Fujimura Y, Akisada T, Harada T, Haruma K. Uptake of microparticles into the epithelium of human nasopharyngeal lymphoid tissue. Med Mol Morphol 2006; 39:181-186. [PMID: 17187179 DOI: 10.1007/s00795-006-0335-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2006] [Accepted: 08/14/2006] [Indexed: 10/23/2022]
Abstract
The M cells of nasopharyngeal lymphoid tissue (NALT) have been considered to play an important role for vaccine delivery systems in humans. A number of investigations have reported particle uptake data in NALT of rodents. However, there have been no reports indicating any involvement of the nasopharyngeal lymphoid tissue in human vaccination. In the present study, we investigated whether the epithelium of human adenoid tissues might incorporate fluorescent microparticles using electron and fluorescent microscopy. The dissected adenoid tissues were incubated with various sizes and concentrations of fluorescent microparticles for 120 min at 37 degrees C. Furthermore, the effect of surface coatings of microparticles with cations on the uptake into the epithelium of adenoid tissues was investigated. Transmission electron microscopy revealed that microparticles were taken up by the M cells of human nasopharyngeal lymphoid tissues. The NALT-M cells showed greater uptake of the smallest particles, 0.2 microm in diameter, than those of 0.5, 1.0, or 2.0 microm diameter. It was also revealed that surface coatings with poly-L: -lysin or chitosan resulted in efficient uptake into the NALT. These results indicate that nasal administration of antigenic microparticles, which were coated with cationic materials, probably leads to a useful method of transnasal vaccination against respiratory and intestinal infections in humans.
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Affiliation(s)
- Yoshinori Fujimura
- Department of Internal Medicine, Center for Gastroenterology and Endoscopy, Kawasaki Hospital, Kawasaki Medical School, 2-1-80 Nakasange, Okayama, 700-8505, Japan.
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46
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Abstract
The mucosal lining of the respiratory and digestive systems contains the largest and most complex immune system in the body, but surprisingly little is known of the immune system that serves the oral mucosa. This review focuses on dendritic cells, particularly powerful arbiters of immunity, in response to antigens of microbial or tumor origin, but also of tolerance to self-antigens and commensal microbes. Although first discovered in 1868, the epidermal dendritic Langerhans cells remained enigmatic for over a century, until they were identified as the most peripheral outpost of the immune system. Investigators' ability to isolate, enrich, and culture dendritic cells has led to an explosion in the field. Presented herein is a review of dendritic cell history, ontogeny, function, and phenotype, and the role of different dendritic cell subsets in the oral mucosa and its diseases. Particular emphasis is placed on the mechanisms of recognition and capture of microbes by dendritic cells. Also emphasized is how dendritic cells may regulate immunity/tolerance in response to oral microbes.
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Affiliation(s)
- C W Cutler
- Department of Periodontics, 110 Rockland Hall, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794-8703, USA.
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47
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Suvilehto J, Roivainen M, Seppänen M, Meri S, Hovi T, Carpén O, Pitkäranta A. Rhinovirus/enterovirus RNA in tonsillar tissue of children with tonsillar disease. J Clin Virol 2005; 35:292-7. [PMID: 16280256 DOI: 10.1016/j.jcv.2005.08.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2005] [Revised: 08/19/2005] [Accepted: 08/26/2005] [Indexed: 11/21/2022]
Abstract
BACKGROUND Human rhinoviruses (HRVs) together with the closely related human enteroviruses (HEVs) cause most of the acute respiratory illnesses throughout the year. HRVs have been detected in most parts of the respiratory tract but not in pharyngeal tonsils. OBJECTIVES We aimed to find out whether HRVs were detectable in tonsillar tissue and if their presence correlated to the tonsillar disease. STUDY DESIGN Thirty-three tonsillar samples collected in February-March 2003 from children with no acute respiratory symptoms were studied with HRV in situ hybridization (HRV-ISH). Ten tonsillar samples were further examined in a separate laboratory by two different reverse transcription polymerase chain reaction (RT-PCR) methods designed for detection of HRV/HEV RNA. RESULTS Twenty of the 33 samples (62%) were positive by HRV-ISH. Five positive and five negative HRV-ISH samples were investigated by two different PCR methods. HRV/HEV RNA was detected in 9 of the 10 specimens by a hanging drop-nested PCR. One HRV-ISH negative sample was positive by a conventional non-nested PCR. One of the samples studied by all three methods, from a patient with recurrent tonsillitis, had no detectable HRV/HEV RNA. Positive result in HRV-ISH did not correlate significantly with underlying tonsillar disease, history of respiratory infections or bronchial asthma. Altogether HRV/HEV RNA was detected in 75% of the tonsils with no correlation to patients' operation indication or history of respiratory diseases. CONCLUSIONS In February-March, HRV/HEV RNA was frequently found in tonsillar tissue in children irrespective of the tonsillar pathology. Whether detection of the RNA is a marker of chronic infection or is merely remnant of past infection is not known.
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Affiliation(s)
- Jari Suvilehto
- Department of Otorhinolaryngology, Helsinki University Hospital, Lohja Hospital, Lohjantie 26 A, FI-03100 Nummela, Finland.
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48
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Roth-Walter F, Bohle B, Schöll I, Untersmayr E, Scheiner O, Boltz-Nitulescu G, Gabor F, Brayden DJ, Jensen-Jarolim E. Targeting antigens to murine and human M-cells with Aleuria aurantia lectin-functionalized microparticles. Immunol Lett 2005; 100:182-8. [PMID: 15913790 DOI: 10.1016/j.imlet.2005.03.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2005] [Accepted: 03/30/2005] [Indexed: 10/25/2022]
Abstract
Neuraminidases act as a virulence factors for several pathogens that invade the human body through Peyer's patch M-cells. Because of the structural similarity of Aleuria aurantia lectin (AAL) to neuraminidases, we hypothesized that AAL might also target human M-cells. In an in vitro human M-cell co-culture model significantly more particles were transported across the epithelium when microparticles were functionalized with AAL versus those that were not. Moreover, high concentrations of AAL induced no detectable cytotoxic effects on the related intestinal epithelial cell cultures, epithelial Caco2- and HT29-MTX-E12-cells. Upon incubation with AAL, PBMCs of allergic volunteers proliferated in response to AAL and secreted the cytokines, IL-2, IFN-gamma, IL-10 and IL-5 in a concentration-dependent manner, indicating immune-stimulatory properties of the lectin. We conclude that AAL-coated microparticles may have the potential to target entrapped antigens to human M-cells for oral vaccination.
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Affiliation(s)
- Franziska Roth-Walter
- Center of Physiology and Pathophysiology, Medical University of Vienna, AKH-3Q, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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49
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Meagher CK, Liu H, Moore CP, Phillips TE. Conjunctival M cells selectively bind and translocate Maackia amurensis leukoagglutinin. Exp Eye Res 2005; 80:545-53. [PMID: 15781282 DOI: 10.1016/j.exer.2004.11.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2004] [Revised: 11/01/2004] [Accepted: 11/09/2004] [Indexed: 11/21/2022]
Abstract
Antigen-sampling M cells are found in the follicle-associated epithelium above organized lymphoid tissue in many mucosae. They play a key role in initiating the mucosal immune response and act as a site of entry for opportunistic pathogens. This study investigates the presence of M cells in the Guinea pig conjunctiva. Maackia amurensis leukoagglutinin I and II (MAL-I and MAL-II) were identified as potential conjunctival M cell markers based on a screening of 12 lectins and 5 carbohydrate epitope antibodies on aldehyde-fixed follicles. Biotinylated or fluorescein-conjugated MAL-I was then instilled into conjunctival sacs in vivo for 15-60 min. Specimens were assessed by epi-fluorescence stereomicroscopy, confocal scanning laser microscopy and transmission and scanning electron microscopy (TEM and SEM). Selective labelling of a subset of epithelial cells overlying lymphoid follicles was observed following in vivo exposure to MAL-I. MAL-I labelling was restricted to cells with sparse, irregular microvilli. Cells preferentially labelled with MAL-I were found to internalize the lectin during a 60 min in vivo exposure. MAL-I was transcytosed to basolateral membranes of cells filled with intracellular vesicles during a 45 min in vivo incubation. This study demonstrates that the Guinea pig conjunctiva contains a cell with morphological and functional characteristics of antigen-sampling M cells.
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Affiliation(s)
- Carisa K Meagher
- Division of Biological Sciences, University of Missouri, 3 Tucker Hall, Columbia, MO, USA.
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Roth-Walter F, Schöll I, Untersmayr E, Fuchs R, Boltz-Nitulescu G, Weissenböck A, Scheiner O, Gabor F, Jensen-Jarolim E. M cell targeting with Aleuria aurantia lectin as a novel approach for oral allergen immunotherapy. J Allergy Clin Immunol 2004; 114:1362-8. [PMID: 15577836 DOI: 10.1016/j.jaci.2004.08.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The extent and quality of the immune response to orally applied allergens may critically depend on the precise site of uptake at the intestinal mucosa. OBJECTIVE The aim of this study was to construct allergen vehicles optimized for oral allergen immunotherapy. METHODS By using a murine model, we examined the immunomodulatory effect of birch pollen proteins entrapped in poly(D,L-lactide-co-glycolide) microspheres, which were specifically targeted to enterocytes or to M cells, in an ongoing T h 2 response. BALB/c mice express different carbohydrates on these 2 cell types. To target the sialylic residues on murine enterocytes, we functionalized microspheres with wheat germ agglutinin (WGA) and, to target alpha-L-fucose on M cells, with a lectin from Aleuria aurantia (AAL), the orange peel mushroom. RESULTS Both WGA and AAL functionalization enhanced binding to human Caco2 cells substantially, which express sialylic and, as carcinoma cells, also alpha-L-fucose residues. Different groups of BALB/c mice were first sensitized to birch pollen and subsequently fed with birch pollen-loaded functionalized (WGA microspheres, AAL microspheres) or nonfunctionalized, birch pollen extract-loaded particles. When mice were fed with AAL microspheres, birch pollen-specific IgG2a, but not IgG1 or IgE, increased significantly. As expected, in a 3 H-thymidin assay, their splenocytes proliferated specifically on birch pollen stimulation. Both targeting strategies, using WGA or AAL, induced IL-10 as well as IL-4 production. However, in AAL microsphere-treated mice, IFN-gamma synthesis was significantly increased, which may be responsible for the significant IgG2a production in this group. CONCLUSION Our data indicate that targeting M cells by using AAL-coated allergen vehicles may be a promising strategy for oral allergen immunotherapy.
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