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Del Vecchio G, Nguyen NPN, Ouyang K, Odhiambo CO, Nelson AM, Deng M, Pellegrini M, Agak GW. Functional Dynamics of Dendritic Cells in Response to Cutibacteriumacnes Strains Associated with Healthy and Acne-Prone Skin. J Invest Dermatol 2025:S0022-202X(25)00292-1. [PMID: 40020992 DOI: 10.1016/j.jid.2025.02.132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 03/03/2025]
Affiliation(s)
- Giorgia Del Vecchio
- Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - Nam Phuong N Nguyen
- Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Kelsey Ouyang
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Amanda M Nelson
- Department of Dermatology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Min Deng
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Matteo Pellegrini
- Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - George W Agak
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
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2
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Dudziak D, Heger L, Agace WW, Bakker J, de Gruijl TD, Dress RJ, Dutertre C, Fenton TM, Fransen MF, Ginhoux F, Heyman O, Horev Y, Hornsteiner F, Kandiah V, Kles P, Lubin R, Mizraji G, Prokopi A, Saar O, Sopper S, Stoitzner P, Strandt H, Sykora MM, Toffoli EC, Tripp CH, van Pul K, van de Ven R, Wilensky A, Yona S, Zelle‐Rieser C. Guidelines for preparation and flow cytometry analysis of human nonlymphoid tissue DC. Eur J Immunol 2025; 55:e2250325. [PMID: 39668411 PMCID: PMC11739683 DOI: 10.1002/eji.202250325] [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: 12/09/2022] [Revised: 09/19/2024] [Accepted: 09/25/2024] [Indexed: 12/14/2024]
Abstract
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs, and various nonlymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single-cell suspensions from human nonlymphoid tissues including lung, skin, gingiva, intestine as well as from tumors and tumor-draining lymph nodes with a subsequent analysis of dendritic cells by flow cytometry. Further, prepared single-cell suspensions can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, etc. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
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Affiliation(s)
- Diana Dudziak
- Institute of ImmunologyJena University HospitalFriedrich‐Schiller‐UniversityJenaGermany
- Laboratory of Dendritic Cell BiologyDepartment of DermatologyUniversity Hospital ErlangenErlangenGermany
| | - Lukas Heger
- Laboratory of Dendritic Cell BiologyDepartment of DermatologyUniversity Hospital ErlangenErlangenGermany
- Department of Transfusion Medicine and HemostaseologyUniversity Hospital ErlangenErlangenGermany
| | - William W Agace
- LEO Foundation Skin Immunology Research CenterDepartment of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
- Immunology SectionLund UniversityLundSweden
| | - Joyce Bakker
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Tanja D. de Gruijl
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Regine J. Dress
- Institute of Systems ImmunologyHamburg Center for Translational Immunology (HCTI)University Medical Center Hamburg‐EppendorfHamburgGermany
| | | | | | - Marieke F. Fransen
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Department of Pulmonary DiseasesAmsterdam UMC location Vrije UniversiteitAmsterdamThe Netherlands
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and ResearchSingaporeSingapore
- Department of Immunology and MicrobiologyShanghai Institute of ImmunologyShanghai Jiao Tong University School of MedicineShanghaiChina
- SingHealth Duke‐NUS Academic Medical CentreTranslational Immunology InstituteSingaporeSingapore
- INSERM U1015, Gustave Roussy Cancer CampusVillejuifFrance
| | - Oded Heyman
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Yael Horev
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Florian Hornsteiner
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Vinitha Kandiah
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Paz Kles
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Ruth Lubin
- Faculty of Dental MedicineThe Institute of Biomedical and Oral ResearchHebrew University of JerusalemIsrael
| | - Gabriel Mizraji
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Anastasia Prokopi
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Or Saar
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Sieghart Sopper
- Internal Medicine V, Hematology and OncologyMedical University of InnsbruckInnsbruckAustria
- Tyrolean Cancer Research CenterInnsbruckAustria
| | - Patrizia Stoitzner
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Helen Strandt
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Martina M Sykora
- Internal Medicine V, Hematology and OncologyMedical University of InnsbruckInnsbruckAustria
- Tyrolean Cancer Research CenterInnsbruckAustria
| | - Elisa C. Toffoli
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Christoph H. Tripp
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Kim van Pul
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Rieneke van de Ven
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
- Department of Otolaryngology, Head and Neck SurgeryAmsterdam UMC location Vrije UniversiteitAmsterdamThe Netherlands
| | - Asaf Wilensky
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Simon Yona
- Faculty of Dental MedicineThe Institute of Biomedical and Oral ResearchHebrew University of JerusalemIsrael
| | - Claudia Zelle‐Rieser
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
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3
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Di Raimondo C, Lozzi F, Di Domenico PP, Paganini C, Campione E, Galluzzo M, Bianchi L. Blastic Plasmacytoid Dendritic Cell Neoplasm, from a Dermatological Point of View. Int J Mol Sci 2024; 25:7099. [PMID: 39000208 PMCID: PMC11240932 DOI: 10.3390/ijms25137099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Although disease awareness has increased over time, BPDCN represents a rare disease with an aggressive clinical course and a dismal prognosis. Due to the overlap in clinical and histological features with a large spectrum of inflammatory and neoplastic diseases, BPDCN is difficult to diagnose. Furthermore, given the rarity of the disease, treatment options for BPDCN are limited, sometimes changing by practitioner and hospitals. Treatment options range from conventional chemotherapy to the recently approved biologic agent tagraxofusp and stem cell transplantation. Therefore, a multidisciplinary approach with coordination among dermatologists, pathologists, and hematologists is ultimately imperative to reach the correct diagnosis and management of BPDCN.
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Affiliation(s)
- Cosimo Di Raimondo
- Dermatology Unit, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy (L.B.)
| | - Flavia Lozzi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | | | - Claudia Paganini
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Elena Campione
- Dermatology Unit, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy (L.B.)
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Marco Galluzzo
- Dermatology Unit, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy (L.B.)
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Luca Bianchi
- Dermatology Unit, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy (L.B.)
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
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4
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Trompette A, Ubags ND. Skin barrier immunology from early life to adulthood. Mucosal Immunol 2023; 16:194-207. [PMID: 36868478 DOI: 10.1016/j.mucimm.2023.02.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 03/05/2023]
Abstract
Our skin has a unique barrier function, which is imperative for the body's protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity.
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Affiliation(s)
- Aurélien Trompette
- Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Niki D Ubags
- Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
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5
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Tsao SY. Potential of mRNA vaccines to become versatile cancer vaccines. World J Clin Oncol 2022; 13:663-674. [PMID: 36160466 PMCID: PMC9476609 DOI: 10.5306/wjco.v13.i8.663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/15/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
For centuries, therapeutic cancer vaccines have been developed and tried clinically. Way back in the late 19th century, the Father of Immunotherapy, William Coley had discovered that bacterial toxins were effective for inoperable sarcomas. In the 1970s, the Bacillus Calmette-Guérin (BCG) vaccine was repurposed, e.g., for advanced melanomas. Then, therapeutic cancer vaccines based on tumor-associated antigens (found on the surfaces of cancer cells) were tried clinically but apparently have not made a really significant clinical impact. For repurposed pathogen vaccines, only the BCG vaccine was approved in 1989 for local application to treat nonmuscle-invading bladder cancers. Although the mildly toxic vaccine adjuvants deliberately added to conventional pathogen vaccines are appropriate for seasonal applications, when repurposed for continual oncology usage, toxicity may be problematic. In 2010, even with the approval of sipuleucel-T as the very first cancer vaccine (dendritic cell) developed for designated prostate cancers, it has also not made a really significant clinical impact. Perhaps more "user friendly" cancer vaccines should be explored. As from approximately 30 years ago, the safety and effectiveness of mRNA vaccination for oncology had already been studied, the current coronavirus disease 2019 pandemic, though disastrous, has given such progressively advancing technology a kickstart. For oncology, other virtues of mRNA vaccines seem advantageous, e.g., rapid and versatile development, convenient modular design, and entirely cell-free synthesis, are being progressively recognized. Moreover, mRNAs encoding various oncology antigens for vaccination may also be tested with the combi-nation of relatively non-toxic modalities of oncology treatments, e.g., metformin or metronomic (low-dose, prolonged administration) chemotherapy. Admittedly, robust clinical data obtained through good quality clinical trials are mandatory.
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Affiliation(s)
- Shiu-Ying Tsao
- Department of Oncology, Hong Kong SAR Oncology Centre, Hong Kong SAR 999077, China
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6
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Safina I, Childress LT, Myneni SR, Vang KB, Biris AS. Cell-Biomaterial Constructs for Wound Healing and Skin Regeneration. Drug Metab Rev 2022; 54:63-94. [PMID: 35129408 DOI: 10.1080/03602532.2021.2025387] [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: 11/03/2022]
Abstract
Over the years, conventional skin grafts, such as full-thickness, split-thickness, and pre-sterilized grafts from human or animal sources, have been at the forefront of skin wound care. However, these conventional grafts are associated with major challenges, including supply shortage, rejection by the immune system, and disease transmission following transplantation. Due to recent progress in nanotechnology and material sciences, advanced artificial skin grafts-based on the fundamental concepts of tissue engineering-are quickly evolving for wound healing and regeneration applications, mainly because they can be uniquely tailored to meet the requirements of specific injuries. Despite tremendous progress in tissue engineering, many challenges and uncertainties still face skin grafts in vivo, such as how to effectively coordinate the interaction between engineered biomaterials and the immune system to prevent graft rejection. Furthermore, in-depth studies on skin regeneration at the molecular level are lacking; as a consequence, the development of novel biomaterial-based systems that interact with the skin at the core level has also been slow. This review will discuss 1) the biological aspects of wound healing and skin regeneration, 2) important characteristics and functions of biomaterials for skin regeneration applications, and 3) synthesis and applications of common biomaterials for skin regeneration. Finally, the current challenges and future directions of biomaterial-based skin regeneration will be addressed.
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Affiliation(s)
- Ingrid Safina
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, 2801 S. University Avenue, Little Rock, AR 72204 USA
| | - Luke T Childress
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, 2801 S. University Avenue, Little Rock, AR 72204 USA
| | - Srinivas R Myneni
- Department of Periodontology, Stony Brook University, Stony Brook, NY 11794 USA
| | - Kieng Bao Vang
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, 2801 S. University Avenue, Little Rock, AR 72204 USA
| | - Alexandru S Biris
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, 2801 S. University Avenue, Little Rock, AR 72204 USA
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7
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Heine A, Juranek S, Brossart P. Clinical and immunological effects of mRNA vaccines in malignant diseases. Mol Cancer 2021; 20:52. [PMID: 33722265 PMCID: PMC7957288 DOI: 10.1186/s12943-021-01339-1] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Drug Delivery Systems
- Gene Expression Regulation, Neoplastic
- Gene Transfer Techniques
- Humans
- Immunity
- Immunotherapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Neoplasms/etiology
- Neoplasms/pathology
- Neoplasms/therapy
- RNA Stability
- RNA, Messenger/genetics
- RNA, Messenger/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Vaccines, Synthetic/immunology
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Affiliation(s)
- Annkristin Heine
- Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Stefan Juranek
- Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Peter Brossart
- Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.
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8
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Adam L, Tchitchek N, Todorova B, Rosenbaum P, Joly C, Poux C, Chapon C, Spetz AL, Ustav M, Le Grand R, Martinon F. Innate Molecular and Cellular Signature in the Skin Preceding Long-Lasting T Cell Responses after Electroporated DNA Vaccination. THE JOURNAL OF IMMUNOLOGY 2020; 204:3375-3388. [PMID: 32385135 DOI: 10.4049/jimmunol.1900517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 04/09/2020] [Indexed: 12/21/2022]
Abstract
DNA vaccines delivered with electroporation (EP) have shown promising results in preclinical models and are evaluated in clinical trials. In this study, we aim to characterize early mechanisms occurring in the skin after intradermal injection and EP of the auxoGTUmultiSIV DNA vaccine in nonhuman primates. First, we show that EP acts as an adjuvant by enhancing local inflammation, notably via granulocytes, monocytes/macrophages, and CD1aint-expressing cell recruitment. EP also induced Langerhans cell maturation, illustrated by CD86, CD83, and HLA-DR upregulation and their migration out of the epidermis. Second, we demonstrate the crucial role of the DNA vaccine in soluble factors release, such as MCP-1 or IL-15. Transcriptomic analysis showed that EP played a major role in gene expression changes postvaccination. However, the DNA vaccine is required to strongly upregulate several genes involved in inflammatory responses (e.g., Saa4), cell migration (e.g., Ccl3, Ccl5, or Cxcl10), APC activation (e.g., Cd86), and IFN-inducible genes (e.g., Ifit3, Ifit5, Irf7, Isg15, orMx1), illustrating an antiviral response signature. Also, AIM-2, a cytosolic DNA sensor, appeared to be strongly upregulated only in the presence of the DNA vaccine and trends to positively correlate with several IFN-inducible genes, suggesting the potential role of AIM-2 in vaccine sensing and the subsequent innate response activation leading to strong adaptive T cell responses. Overall, these results demonstrate that a combined stimulation of the immune response, in which EP and the auxoGTUmultiSIV vaccine triggered different components of the innate immunity, led to strong and persistent cellular recall responses.
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Affiliation(s)
- Lucille Adam
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Nicolas Tchitchek
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Biliana Todorova
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Pierre Rosenbaum
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Candie Joly
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Candice Poux
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Catherine Chapon
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Anna-Lena Spetz
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden; and
| | - Mart Ustav
- Institute of Technology, University of Tartu, 50411 Tartu, Estonia
| | - Roger Le Grand
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France
| | - Frédéric Martinon
- Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université Paris-Sud 11, INSERM U1184, 92265 Fontenay-aux-Roses, France;
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9
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Busold S, Nagy NA, Tas SW, van Ree R, de Jong EC, Geijtenbeek TBH. Various Tastes of Sugar: The Potential of Glycosylation in Targeting and Modulating Human Immunity via C-Type Lectin Receptors. Front Immunol 2020; 11:134. [PMID: 32117281 PMCID: PMC7019010 DOI: 10.3389/fimmu.2020.00134] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/20/2020] [Indexed: 12/31/2022] Open
Abstract
C-type lectin receptors (CLRs) are important in several immune regulatory processes. These receptors recognize glycans expressed by host cells or by pathogens. Whereas pathogens are recognized through their glycans, which leads to protective immunity, aberrant cellular glycans are now increasingly recognized as disease-driving factors in cancer, auto-immunity, and allergy. The vast variety of glycan structures translates into a wide spectrum of effects on the immune system ranging from immune suppression to hyper-inflammatory responses. CLRs have distinct expression patterns on antigen presenting cells (APCs) controlling their role in immunity. CLRs can also be exploited to selectively target specific APCs, modulate immune responses and enhance antigen presentation. Here we will discuss the role of glycans and their receptors in immunity as well as potential strategies for immune modulation. A special focus will be given to different dendritic cell subsets as these APCs are crucial orchestrators of immune responses in infections, cancer, auto-immunity and allergies. Furthermore, we will highlight the potential use of nanoscale lipid bi-layer structures (liposomes) in targeted immunotherapy.
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Affiliation(s)
- Stefanie Busold
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Noémi A Nagy
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Sander W Tas
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands.,Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam Rheumatology and Immunology Center, University of Amsterdam, Amsterdam, Netherlands
| | - Ronald van Ree
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands.,Department of Otorhinolaryngology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Esther C de Jong
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Teunis B H Geijtenbeek
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
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10
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A Distinct Pretreatment Immune Gene Signature in Lentigo Maligna Is Associated with Imiquimod Response. J Invest Dermatol 2019; 140:869-877.e16. [PMID: 31580843 DOI: 10.1016/j.jid.2019.07.725] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 07/26/2019] [Accepted: 07/30/2019] [Indexed: 12/24/2022]
Abstract
Lentigo maligna (LM) is a common subtype of in situ melanoma on chronically sun-exposed skin, particularly the head and neck of older patients. Although surgery is the standard treatment, there is associated morbidity, and options such as imiquimod cream or radiotherapy may be used if surgery is refused or inappropriate. Complete response rates following imiquimod treatment are variable in the literature. The aim of this study was to evaluate the host immune response both before and following treatment with imiquimod to better identify likely responders. Paired pre- and post-imiquimod treatment specimens were available for 27 patients. Patients were treated with imiquimod 5 days per week for 12 weeks; at 16 weeks, lesions were excised for histological assessment. Of the 27 patients, 16 were responders and 11 failed to clear the disease. PDL1 protein expression was increased, accompanied by a unique gene signature in lesions from patients that subsequently histologically cleared LM by 16 weeks. This comprised 57 upregulated immune genes in signaling networks for antigen presentation, type I interferon signaling, and T-cell activation. This may represent an early responder group to imiquimod, and this unique gene signature potentially can be used as a biomarker of LM response to imiquimod.
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11
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Hermanrud C, van Capel TMM, Auer M, Karrenbauer V, Deisenhammer F, de Jong EC, Fogdell-Hahn A. Different Interferon Beta Preparations Induce the Same Qualitative Immune Response in Human Skin. J Interferon Cytokine Res 2019; 39:302-313. [PMID: 30848986 DOI: 10.1089/jir.2018.0038] [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] [Indexed: 11/12/2022] Open
Abstract
Interferon beta (IFNβ) is used as a first-line treatment for multiple sclerosis (MS) and is injected intramuscularly or subcutaneously (s.c.). The subcutaneous route is considered more immunogenic as it is associated with increased antidrug antibody-positive patients. The skin contains dendritic cells (DCs) and it is unclear whether these contribute to immunogenicity. To assess the effect of IFNβ on skin-resident cells, IFNβ was injected intradermally (i.d.) ex vivo using a human skin explant model or s.c. in vivo in MS patients. Ex vivo, intradermal IFNβ injections reduced migration and enhanced surface CD86 expression of dermal DCs, and an increased expression of HLA-DR+ was observed in skin biopsies taken after subcutaneous IFNβ injection (in vivo). In both models, IFNβ elevated the expression of several inflammatory cytokines when compared to the control biopsies. Our results show that 3 different IFNβ preparations, normalized in dose and injection site, induce similar immune responses, suggesting that the differences in immunogenicity are likely due to the route and frequency of administration.
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Affiliation(s)
- Christina Hermanrud
- 1 Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Toni M M van Capel
- 2 Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
| | - Michael Auer
- 3 Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Virginija Karrenbauer
- 1 Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Florian Deisenhammer
- 3 Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Esther C de Jong
- 2 Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
| | - Anna Fogdell-Hahn
- 1 Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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12
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Szczepanik M, Majewska-Szczepanik M, Wong FS, Kowalczyk P, Pasare C, Wen L. Regulation of contact sensitivity in non-obese diabetic (NOD) mice by innate immunity. Contact Dermatitis 2018; 79:197-207. [PMID: 29943459 DOI: 10.1111/cod.13046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 04/15/2018] [Accepted: 05/08/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Genetic background influences allergic immune responses to environmental stimuli. Non-obese diabetic (NOD) mice are highly susceptible to environmental stimuli. Little is known about the interaction of autoimmune genetic factors with innate immunity in allergies, especially skin hypersensitivity. OBJECTIVES To study the interplay of innate immunity and autoimmune genetic factors in contact hypersensitivity (CHS) by using various innate immunity-deficient NOD mice. METHODS Toll-like receptor (TLR) 2-deficient, TLR9-deficient and MyD88-deficient NOD mice were used to investigate CHS. The cellular mechanism was determined by flow cytometry in vitro and adoptive cell transfer in vivo. To investigate the role of MyD88 in dendritic cells (DCs) in CHS, we also used CD11cMyD88+ MyD88-/- NOD mice, in which MyD88 is expressed only in CD11c+ cells. RESULTS We found that innate immunity negatively regulates CHS, as innate immunity-deficient NOD mice developed exacerbated CHS accompanied by increased numbers of skin-migrating CD11c+ DCs expressing higher levels of major histocompatibility complex II and CD80. Moreover, MyD88-/- NOD mice had increased numbers of CD11c+ CD207- CD103+ DCs and activated T effector cells in the skin-draining lymph nodes. Strikingly, re-expression of MyD88 in CD11c+ DCs (CD11cMyD88+ MyD88-/- NOD mice) restored hyper-CHS to a normal level in MyD88-/- NOD mice. CONCLUSION Our results suggest that the autoimmune-prone NOD genetic background aggravates CHS regulated by innate immunity, through DCs and T effector cells.
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Affiliation(s)
- Marian Szczepanik
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut.,Department of Medical Biology, Health Science Faculty, Jagiellonian University Medical College, Krakow, Poland
| | - Monika Majewska-Szczepanik
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut.,Department of Medical Biology, Health Science Faculty, Jagiellonian University Medical College, Krakow, Poland
| | - Florence S Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Paulina Kowalczyk
- Department of Medical Biology, Health Science Faculty, Jagiellonian University Medical College, Krakow, Poland
| | - Chandrashekhar Pasare
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Li Wen
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
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13
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Rosenbaum P, Tchitchek N, Joly C, Stimmer L, Hocini H, Dereuddre-Bosquet N, Beignon AS, Chapon C, Levy Y, Le Grand R, Martinon F. Molecular and Cellular Dynamics in the Skin, the Lymph Nodes, and the Blood of the Immune Response to Intradermal Injection of Modified Vaccinia Ankara Vaccine. Front Immunol 2018; 9:870. [PMID: 29922280 PMCID: PMC5996922 DOI: 10.3389/fimmu.2018.00870] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 04/09/2018] [Indexed: 01/05/2023] Open
Abstract
New vaccine design approaches would be greatly facilitated by a better understanding of the early systemic changes, and those that occur at the site of injection, responsible for the installation of a durable and oriented protective response. We performed a detailed characterization of very early infection and host response events following the intradermal administration of the modified vaccinia virus Ankara as a live attenuated vaccine model in non-human primates. Integrated analysis of the data obtained from in vivo imaging, histology, flow cytometry, multiplex cytokine, and transcriptomic analysis using tools derived from systems biology, such as co-expression networks, showed a strong early local and systemic inflammatory response that peaked at 24 h, which was then progressively replaced by an adaptive response during the installation of the host response to the vaccine. Granulocytes, macrophages, and monocytoid cells were massively recruited during the local innate response in association with local productions of GM-CSF, IL-1β, MIP1α, MIP1β, and TNFα. We also observed a rapid and transient granulocyte recruitment and the release of IL-6 and IL-1RA, followed by a persistent phase involving inflammatory monocytes. This systemic inflammation was confirmed by molecular signatures, such as upregulations of IL-6 and TNF pathways and acute phase response signaling. Such comprehensive approaches improve our understanding of the spatiotemporal orchestration of vaccine-elicited immune response, in a live-attenuated vaccine model, and thus contribute to rational vaccine development.
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Affiliation(s)
- Pierre Rosenbaum
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France.,Vaccine Research Institute, Henri Mondor Hospital, Créteil, France
| | - Nicolas Tchitchek
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France
| | - Candie Joly
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France
| | - Lev Stimmer
- CEA - INSERM, MIRCen, UMS27, Fontenay-aux-Roses, France.,INSERM U1169, Kremlin-Bicêtre, France
| | - Hakim Hocini
- Vaccine Research Institute, Henri Mondor Hospital, Créteil, France.,INSERM U955, Henri Mondor Hospital, University of Paris East, Créteil, France
| | - Nathalie Dereuddre-Bosquet
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France
| | - Anne-Sophie Beignon
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France.,Vaccine Research Institute, Henri Mondor Hospital, Créteil, France
| | - Catherine Chapon
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France.,Vaccine Research Institute, Henri Mondor Hospital, Créteil, France
| | - Yves Levy
- Vaccine Research Institute, Henri Mondor Hospital, Créteil, France.,INSERM U955, Henri Mondor Hospital, University of Paris East, Créteil, France
| | - Roger Le Grand
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France.,Vaccine Research Institute, Henri Mondor Hospital, Créteil, France
| | - Frédéric Martinon
- Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, CEA - Université Paris Sud 11 - INSERM U1184, Fontenay-aux-Roses, France.,Vaccine Research Institute, Henri Mondor Hospital, Créteil, France
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14
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Carvalho-Costa TM, Mendes MT, da Silva MV, Rodrigues V, Bruschi Thedei GCM, Oliveira CJF, Thedei G. Light-Emitting Diode at 460 ± 20 nm Increases the Production of IL-12 and IL-6 in Murine Dendritic Cells. Photomed Laser Surg 2017. [DOI: 10.1089/pho.2016.4244] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
| | - Maria Tays Mendes
- Laboratory of Immunology, Federal University of Triângulo Mineiro, Uberaba, Brazil
| | | | - Virmondes Rodrigues
- Laboratory of Immunology, Federal University of Triângulo Mineiro, Uberaba, Brazil
| | | | | | - Geraldo Thedei
- Laboratory of Molecular Biology, University of Uberaba, Uberaba, Brazil
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15
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Korenfeld D, Gorvel L, Munk A, Man J, Schaffer A, Tung T, Mann C, Klechevsky E. A type of human skin dendritic cell marked by CD5 is associated with the development of inflammatory skin disease. JCI Insight 2017; 2:96101. [PMID: 28931765 DOI: 10.1172/jci.insight.96101] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 08/10/2017] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are important in regulating immunity and tolerance and consist of functionally distinct subsets that differentially regulate T lymphocyte function. The underlying basis for this subset specificity is lacking, particularly in humans, where the classification of tissue DCs is currently incomplete. Examination of healthy human epidermal Langerhans cells and dermal skin cells revealed a tissue CD5-expressing DC subtype. The CD5+ DCs were potent inducers of cytotoxic T cells and Th22 cells. The products of these T cells, IL-22 and IFN-γ, play a key role in the pathogenesis of psoriasis. Remarkably, CD5+ DCs were significantly enriched in lesional psoriatic skin compared with distal tissues, suggesting their involvement in the disease. We show that CD5+ DCs can be differentiated from hematopoietic progenitor cells independently of the CD5- DCs. A progenitor population found in human cord blood and in the dermal skin layer, marked as CD34-CD123+CD117dimCD45RA+, was an immediate precursor of these CD11c+CD1c+CD5+ DCs. Overall, our discovery of the CD5-expressing DC subtype suggests that strategies to regulate their composition or function in the skin will represent an innovative approach for the treatment of immune-mediated disorders in and beyond the skin.
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Affiliation(s)
- Daniel Korenfeld
- Department of Pathology and Immunology, Division of Immunobiology
| | - Laurent Gorvel
- Department of Pathology and Immunology, Division of Immunobiology
| | - Adiel Munk
- Department of Pathology and Immunology, Division of Immunobiology
| | - Joshua Man
- Department of Pathology and Immunology, Division of Immunobiology
| | - Andras Schaffer
- Department of Pathology and Immunology, Dermatopathology Center
| | - Thomas Tung
- Department of Surgery, Division of Plastic and Reconstructive Surgery, and
| | - Caroline Mann
- Department of Medicine, Division of Dermatology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Eynav Klechevsky
- Department of Pathology and Immunology, Division of Immunobiology
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16
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Hamuro L, Kijanka G, Kinderman F, Kropshofer H, Bu DX, Zepeda M, Jawa V. Perspectives on Subcutaneous Route of Administration as an Immunogenicity Risk Factor for Therapeutic Proteins. J Pharm Sci 2017; 106:2946-2954. [PMID: 28576695 DOI: 10.1016/j.xphs.2017.05.030] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 04/06/2017] [Accepted: 05/22/2017] [Indexed: 01/19/2023]
Abstract
An increasing number of therapeutic proteins are being developed for delivery through the subcutaneous (SC) route of administration. Relative to intravenous (IV) administration, the SC route offers more convenience to patients, flexibility in dosing, and potential to reduce health care costs. There is a perception that SC administration can pose a higher immunogenicity risk than IV administration for a given protein. To evaluate whether there is a difference in therapeutic protein immunogenicity associated with administration routes, a more detailed understanding of the interactions with the immune system by each route is needed. Few approved therapeutic proteins have available clinical immunogenicity data sets in the public domain that represent both IV and SC administration routes. This has prevented a direct comparison of the 2 routes of administration across a large sample size. Of the 6 marketed products where SC and IV route-related incidences of anti-drug antibody (ADA) were available, 4 were associated with higher immunogenicity incidence with SC. In other cases, there was no apparent difference between the SC and IV routes. Overall, the ADA incidence was low (<15%) with no impact on safety or efficacy. The challenges associated with identifying specific risk factors unique to SC administration are discussed.
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Affiliation(s)
- Lora Hamuro
- Bristol-Myers Squibb, Clinical Pharmacology and Pharmacometrics, Route 206 & Province Line Road, Princeton, New Jersey 08543.
| | - Grzegorz Kijanka
- Leiden University, Faculty of Science, Leiden Academic Centre for Drug Research, Drug Delivery Technology, Einsteinweg 55, 2333 CC Leiden, Netherlands
| | | | - Harald Kropshofer
- F.Hoffman-La Roche Ltd, Pharmaceuticals Division, CH-4070 Basel, Switzerland
| | - De-Xiu Bu
- Pfizer, PDM Immunogenicity Sciences, Andover, Massachusetts 01810
| | - Monica Zepeda
- Halozyme Therapeutics 11388 Sorrento Valley Road, San Diego, California 92121
| | - Vibha Jawa
- Merck Sharp & Dohme Corp., 2000 Galloping Hill Road, K-15 E-410C, Kenilworth, New Jersey 07033
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17
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Abstract
In recent years, numerous studies have demonstrated the outstanding abilities of mRNA to elicit potent immune responses against pathogens, making it a viable new platform for vaccine development (reviewed in Weissman, Expert Rev Vaccines 14:265-281, 2015; Sahin et al., Nat Rev Drug Discov 13:759-780, 2014). The incorporation of modified nucleosides in mRNA has many advantages and is currently undergoing a renaissance in the field of therapeutic protein delivery. Its use in a vaccine against infectious diseases has only begun to be described, but offers advantages for the generation of potent and long-lived antibody responses. FPLC purification and substitution of modified nucleosides in the mRNA make it non-inflammatory and highly translatable (Kariko et al., Immunity 23:165-175, 2005; Kariko et al., Mol Ther 16:1833-1840, 2008; Kariko et al., Nucleic Acids Research 39:e142, 2011) that are crucial features for therapeutic relevance. Formulation of the mRNA in lipid nanoparticles (LNPs) protects it from degradation enabling high levels of protein production for extended periods of time (Pardi et al., J Control Release, 2015). Here, we describe a simple vaccination method using LNP-encapsulated 1-methylpseudouridine-containing FPLC purified mRNA in mice. Furthermore, we describe the evaluation of antigen-specific T and B cell responses elicited by this vaccine format.
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Affiliation(s)
- Norbert Pardi
- Department of Medicine, University of Pennsylvania, 52 Johnson Pavilion, Philadelphia, PA, 19104, USA
| | - Drew Weissman
- Department of Medicine, University of Pennsylvania, 52 Johnson Pavilion, Philadelphia, PA, 19104, USA.
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18
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Nirschl CJ, Anandasabapathy N. Duality at the gate: Skin dendritic cells as mediators of vaccine immunity and tolerance. Hum Vaccin Immunother 2016; 12:104-16. [PMID: 26836327 DOI: 10.1080/21645515.2015.1066050] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Since Edward Jenner's discovery that intentional exposure to cowpox could provide lifelong protection from smallpox, vaccinations have been a major focus of medical research. However, while the protective benefits of many vaccines have been successfully translated into the clinic, the cellular and molecular mechanisms that differentiate effective vaccines from sub-optimal ones are not well understood. Dendritic cells (DCs) are the gatekeepers of the immune system, and are ultimately responsible for the generation of adaptive immunity and lifelong protective memory through interactions with T cells. In addition to lymph node and spleen resident DCs, a number of tissue resident DC populations have been identified at barrier tissues, such as the skin, which migrate to the local lymph node (migDC). These populations have unique characteristics, and play a key role in the function of cutaneous vaccinations by shuttling antigen from the vaccination site to the draining lymph node, rapidly capturing freely draining antigens in the lymph node, and providing key stimuli to T cells. However, while migDCs are responsible for the generation of immunity following exposure to certain pathogens and vaccines, recent work has identified a tolerogenic role for migDCs in the steady state as well as during protein immunization. Here, we examine the roles and functions of skin DC populations in the generation of protective immunity, as well as their role as regulators of the immune system.
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Affiliation(s)
- Christopher J Nirschl
- a Department of Dermatology ; Harvard Skin Disease Research Center; Brigham and Women's Hospital ; Boston , MA USA
| | - Niroshana Anandasabapathy
- a Department of Dermatology ; Harvard Skin Disease Research Center; Brigham and Women's Hospital ; Boston , MA USA
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19
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Gerlach UA, Vrakas G, Sawitzki B, Macedo R, Reddy S, Friend PJ, Giele H, Vaidya A. Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection. Am J Transplant 2016; 16:1892-900. [PMID: 26713513 DOI: 10.1111/ajt.13693] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 11/24/2015] [Accepted: 12/20/2015] [Indexed: 01/25/2023]
Abstract
Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.
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Affiliation(s)
- U A Gerlach
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK.,Department of General, Visceral and Transplantation Surgery, Charité-Universitaetsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - G Vrakas
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
| | - B Sawitzki
- Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - R Macedo
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
| | - S Reddy
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
| | - P J Friend
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
| | - H Giele
- Department of Plastic and Reconstructive Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
| | - A Vaidya
- Department of Transplant Surgery, Oxford University Hospitals and University of Oxford, Oxford, UK
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20
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O'Keeffe M, Mok WH, Radford KJ. Human dendritic cell subsets and function in health and disease. Cell Mol Life Sci 2015; 72:4309-25. [PMID: 26243730 PMCID: PMC11113503 DOI: 10.1007/s00018-015-2005-0] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/15/2015] [Accepted: 07/28/2015] [Indexed: 12/24/2022]
Abstract
The method of choice for the development of new vaccines is to target distinct dendritic cell subsets with antigen in vivo and to harness their function in situ to enhance cell-mediated immunity or induce tolerance to specific antigens. The innate functions of dendritic cells themselves may also be targeted by inhibitors or activators that would target a specific function such as interferon production, potentially important in autoimmune disease and chronic viral infections. Importantly targeting dendritic cells requires detailed knowledge of both the surface phenotype and function of each dendritic cell subset, including how they may respond to different types of vaccine adjuvants, their ability to produce soluble mediators and to process and present antigens and induce priming of naïve T cells. This review summarizes our knowledge of the functional attributes of the human dendritic cell subsets in the steady state and upon activation and their roles in human disease.
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Affiliation(s)
- Meredith O'Keeffe
- Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne, VIC, 3004, Australia
- Department of Immunology, Monash University, Clayton, VIC, 3800, Australia
| | - Wai Hong Mok
- Mater Research Institute, University of Queensland, 37 Kent St, Woolloongabba, QLD, 4012, Australia
| | - Kristen J Radford
- Mater Research Institute, University of Queensland, 37 Kent St, Woolloongabba, QLD, 4012, Australia.
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21
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Geginat J, Nizzoli G, Paroni M, Maglie S, Larghi P, Pascolo S, Abrignani S. Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets. Front Immunol 2015; 6:527. [PMID: 26528289 PMCID: PMC4603245 DOI: 10.3389/fimmu.2015.00527] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 09/28/2015] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4+ and CD8+ T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4+ T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α+ mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α− mDCs preferentially prime CD4+ T cells and promote Th2 or Th17 differentiation. BDCA-3+ mDC2 are the human homologue of CD8α+ mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8+ T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against persistent infections or cancer.
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Affiliation(s)
- Jens Geginat
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Giulia Nizzoli
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Moira Paroni
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Stefano Maglie
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Paola Larghi
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Steve Pascolo
- Department of Dermatology, University Hospital of Zurich , Zurich , Switzerland
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy ; DISCCO, Department of Clinical Sciences and Community Health, University of Milano , Milan , Italy
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22
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The TGF-β superfamily in dendritic cell biology. Cytokine Growth Factor Rev 2015; 26:647-57. [PMID: 26115564 DOI: 10.1016/j.cytogfr.2015.06.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 06/15/2015] [Indexed: 12/18/2022]
Abstract
The TGF-β superfamily consists of a large group of pleiotropic cytokines that are involved in the regulation of many developmental, physiological and pathological processes. Dendritic cells are antigen-presenting cells that play a key role in innate and adaptive immune responses. Dendritic cells have a complex relationship with the TGF-β cytokine superfamily being both source and targets for many of these cytokines. Some TGF-β family members are expressed by dendritic cells and modulate immune responses, for instance through the induction of T cell polarization. Others play a crucial role in the development and function of the different dendritic cell subsets. This review summarizes the current knowledge on the role of TGF-β family cytokines in dendritic cell biology, focusing on TGF-β as well as on other, less characterized, members of these important immune mediators.
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Artyomov MN, Munk A, Gorvel L, Korenfeld D, Cella M, Tung T, Klechevsky E. Modular expression analysis reveals functional conservation between human Langerhans cells and mouse cross-priming dendritic cells. ACTA ACUST UNITED AC 2015; 212:743-57. [PMID: 25918340 PMCID: PMC4419344 DOI: 10.1084/jem.20131675] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 04/01/2015] [Indexed: 12/19/2022]
Abstract
In depth phenotyping and functional analysis of skin dendritic cell subsets suggests that the function of Langerhans cells may not be conserved between mouse and human and supports the idea that human Langernhans cells may be a relevant therapeutic target. Characterization of functionally distinct dendritic cell (DC) subsets in mice has fueled interest in whether analogous counterparts exist in humans. Transcriptional modules of coordinately expressed genes were used for defining shared functions between the species. Comparing modules derived from four human skin DC subsets and modules derived from the Immunological Genome Project database for all mouse DC subsets revealed that human Langerhans cells (LCs) and the mouse XCR1+CD8α+CD103+ DCs shared the class I–mediated antigen processing and cross-presentation transcriptional modules that were not seen in mouse LCs. Furthermore, human LCs were enriched in a transcriptional signature specific to the blood cross-presenting CD141/BDCA-3+ DCs, the proposed equivalent to mouse CD8α+ DCs. Consistent with our analysis, LCs were highly adept at inducing primary CTL responses. Thus, our study suggests that the function of LCs may not be conserved between mouse and human and supports human LCs as an especially relevant therapeutic target.
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Affiliation(s)
- Maxim N Artyomov
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Adiel Munk
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Laurent Gorvel
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Daniel Korenfeld
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Marina Cella
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Thomas Tung
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Eynav Klechevsky
- Department of Pathology and Immunology and Department of Surgery/Plastic and Reconstructive Surgery Center, Washington University School of Medicine, St. Louis, MO 63110
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Summerfield A, Meurens F, Ricklin ME. The immunology of the porcine skin and its value as a model for human skin. Mol Immunol 2014; 66:14-21. [PMID: 25466611 DOI: 10.1016/j.molimm.2014.10.023] [Citation(s) in RCA: 325] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 10/16/2014] [Accepted: 10/27/2014] [Indexed: 01/21/2023]
Abstract
The porcine skin has striking similarities to the human skin in terms of general structure, thickness, hair follicle content, pigmentation, collagen and lipid composition. This has been the basis for numerous studies using the pig as a model for wound healing, transdermal delivery, dermal toxicology, radiation and UVB effects. Considering that the skin also represents an immune organ of utmost importance for health, immune cells present in the skin of the pig will be reviewed. The focus of this review is on dendritic cells, which play a central role in the skin immune system as they serve as sentinels in the skin, which offers a large surface area exposed to the environment. Based on a literature review and original data we propose a classification of porcine dendritic cell subsets in the skin corresponding to the subsets described in the human skin. The equivalent of the human CD141(+) DC subset is CD1a(-)CD4(-)CD172a(-)CADM1(high), that of the CD1c(+) subset is CD1a(+)CD4(-)CD172a(+)CADM1(+/low), and porcine plasmacytoid dendritic cells are CD1a(-)CD4(+)CD172a(+)CADM1(-). CD209 and CD14 could represent markers of inflammatory monocyte-derived cells, either dendritic cells or macrophages. Future studies for example using transriptomic analysis of sorted populations are required to confirm the identity of these cells.
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Affiliation(s)
- Artur Summerfield
- Institute of Virology and Immunology, Sensemattstrasse 293, 3147 Mittelhäusern, Switzerland.
| | - François Meurens
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada
| | - Meret E Ricklin
- Institute of Virology and Immunology, Sensemattstrasse 293, 3147 Mittelhäusern, Switzerland
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Marquet F, Vu Manh TP, Maisonnasse P, Elhmouzi-Younes J, Urien C, Bouguyon E, Jouneau L, Bourge M, Simon G, Ezquerra A, Lecardonnel J, Bonneau M, Dalod M, Schwartz-Cornil I, Bertho N. Pig Skin Includes Dendritic Cell Subsets Transcriptomically Related to Human CD1a and CD14 Dendritic Cells Presenting Different Migrating Behaviors and T Cell Activation Capacities. THE JOURNAL OF IMMUNOLOGY 2014; 193:5883-93. [DOI: 10.4049/jimmunol.1303150] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Boltjes A, van Wijk F. Human dendritic cell functional specialization in steady-state and inflammation. Front Immunol 2014; 5:131. [PMID: 24744755 PMCID: PMC3978316 DOI: 10.3389/fimmu.2014.00131] [Citation(s) in RCA: 138] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 03/14/2014] [Indexed: 12/11/2022] Open
Abstract
Dendritic cells (DC) represent a heterogeneous population of antigen-presenting cells that are crucial in initiating and shaping immune responses. Although all DC are capable of antigen-uptake, processing, and presentation to T cells, DC subtypes differ in their origin, location, migration patterns, and specialized immunological roles. While in recent years, there have been rapid advances in understanding DC subset ontogeny, development, and function in mice, relatively little is known about the heterogeneity and functional specialization of human DC subsets, especially in tissues. In steady-state, DC progenitors deriving from the bone marrow give rise to lymphoid organ-resident DC and to migratory tissue DC that act as tissue sentinels. During inflammation additional DC and monocytes are recruited to the tissues where they are further activated and promote T helper cell subset polarization depending on the environment. In the current review, we will give an overview of the latest developments in human DC research both in steady-state and under inflammatory conditions. In this context, we review recent findings on DC subsets, DC-mediated cross-presentation, monocyte-DC relationships, inflammatory DC development, and DC-instructed T-cell polarization. Finally, we discuss the potential role of human DC in chronic inflammatory diseases.
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Affiliation(s)
- Arjan Boltjes
- Laboratory for Translational Immunology, Department of Pediatric Immunology, University Medical Center Utrecht , Utrecht , Netherlands
| | - Femke van Wijk
- Laboratory for Translational Immunology, Department of Pediatric Immunology, University Medical Center Utrecht , Utrecht , Netherlands
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27
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Belkaid Y, Artis D. Immunity at the barriers. Eur J Immunol 2014; 43:3096-7. [PMID: 24166766 DOI: 10.1002/eji.201344133] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 10/01/2013] [Accepted: 10/21/2013] [Indexed: 01/15/2023]
Affiliation(s)
- Yasmine Belkaid
- Program in Barrier Immunity and Repair, National Institute of Allergy and Infectious Disease, Bethesda, MD, USA; Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, USA
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