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Khan A, Roy P, Ley K. Breaking tolerance: the autoimmune aspect of atherosclerosis. Nat Rev Immunol 2024; 24:670-679. [PMID: 38472321 PMCID: PMC11682649 DOI: 10.1038/s41577-024-01010-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 03/14/2024]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease of the arterial walls and is characterized by the accumulation of lipoproteins that are insufficiently cleared by phagocytes. Following the initiation of atherosclerosis, the pathological progression is accelerated by engagement of the adaptive immune system. Atherosclerosis triggers the breakdown of tolerance to self-components. This loss of tolerance is reflected in defective expression of immune checkpoint molecules, dysfunctional antigen presentation, and aberrations in T cell populations - most notably in regulatory T (Treg) cells - and in the production of autoantibodies. The breakdown of tolerance to self-proteins that is observed in ASCVD may be linked to the conversion of Treg cells to 'exTreg' cells because many Treg cells in ASCVD express T cell receptors that are specific for self-epitopes. Alternatively, or in addition, breakdown of tolerance may trigger the activation of naive T cells, resulting in the clonal expansion of T cell populations with pro-inflammatory and cytotoxic effector phenotypes. In this Perspective, we review the evidence that atherosclerosis is associated with a breakdown of tolerance to self-antigens, discuss possible immunological mechanisms and identify knowledge gaps to map out future research. Rational approaches aimed at re-establishing immune tolerance may become game changers in treating ASCVD and in preventing its downstream sequelae, which include heart attacks and strokes.
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Affiliation(s)
- Amir Khan
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Payel Roy
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Klaus Ley
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA.
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2
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Meulewaeter S, Zhang Y, Wadhwa A, Fox K, Lentacker I, Harder KW, Cullis PR, De Smedt SC, Cheng MHY, Verbeke R. Considerations on the Design of Lipid-based mRNA Vaccines Against Cancer. J Mol Biol 2024; 436:168385. [PMID: 38065276 DOI: 10.1016/j.jmb.2023.168385] [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: 09/15/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 12/26/2023]
Abstract
Throughout the last decades, mRNA vaccines have been developed as a cancer immunotherapeutic and the technology recently gained momentum during the COVID-19 pandemic. Recent promising results obtained from clinical trials investigating lipid-based mRNA vaccines in cancer therapy further highlighted the potential of this therapy. Interestingly, while the technologies being used in authorized mRNA vaccines for the prevention of COVID-19 are relatively similar, mRNA vaccines in clinical development for cancer vaccination show marked differences in mRNA modification, lipid carrier, and administration route. In this review, we describe findings on how these factors can impact the potency of mRNA vaccines in cancer therapy and provide insights into the complex interplay between them. We discuss how lipid carrier composition can affect passive targeting to immune cells to improve the efficacy and safety of mRNA vaccines. Finally, we summarize strategies that are established or still being explored to improve the efficacy of mRNA cancer vaccines and include next-generation vaccines that are on the horizon in clinical development.
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Affiliation(s)
- Sofie Meulewaeter
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent 9000, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent 9000, Belgium
| | - Yao Zhang
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Abishek Wadhwa
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Kevin Fox
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Ine Lentacker
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent 9000, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent 9000, Belgium
| | - Kenneth W Harder
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Pieter R Cullis
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Stefaan C De Smedt
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent 9000, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent 9000, Belgium
| | - Miffy H Y Cheng
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
| | - Rein Verbeke
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent 9000, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent 9000, Belgium.
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3
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Lichtensteiger C, Koblischke M, Berner F, Jochum AK, Sinnberg T, Balciunaite B, Purde MT, Walter V, Abdou MT, Hofmeister K, Kohler P, Vernazza P, Albrich WC, Kahlert CR, Zoufaly A, Traugott MT, Kern L, Pietsch U, Kleger GR, Filipovic M, Kneilling M, Cozzio A, Pop O, Bomze D, Bergthaler A, Hasan Ali O, Aberle J, Flatz L. Autoreactive T cells targeting type II pneumocyte antigens in COVID-19 convalescent patients. J Autoimmun 2023; 140:103118. [PMID: 37826919 DOI: 10.1016/j.jaut.2023.103118] [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: 03/09/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND The role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease. OBJECTIVE The aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease. METHODS We collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells. RESULTS We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells. CONCLUSIONS Our data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance.
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Affiliation(s)
| | | | - Fiamma Berner
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Ann-Kristin Jochum
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Insitute of Pathology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Tobias Sinnberg
- Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) Image-Guided and Functionally Instructed Tumor Therapies, Eberhard Karls University Hospital Tübingen, Tübingen, Germany
| | - Beatrice Balciunaite
- Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany
| | - Mette-Triin Purde
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Vincent Walter
- Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany
| | - Marie-Therese Abdou
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Kathrin Hofmeister
- Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany
| | - Philipp Kohler
- Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Pietro Vernazza
- Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Werner C Albrich
- Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Christian R Kahlert
- Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Alexander Zoufaly
- Department of Medicine IV, Clinic Favoriten, Vienna Healthcare Group, Vienna, Austria; Faculty of Medicine, Sigmund Freud University Vienna, Austria
| | - Marianna T Traugott
- Department of Medicine IV, Clinic Favoriten, Vienna Healthcare Group, Vienna, Austria
| | - Lukas Kern
- Department of Pneumology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Urs Pietsch
- Surgical Intensive Care Unit, Division of Anaesthesiology, Intensive Care, Rescue and Pain Medicine, Kantonsspital St. Gallen, Switzerland
| | - Gian-Reto Kleger
- Division of Intensive Care Medicine, Kantonsspital St. Gallen, Switzerland
| | - Miodrag Filipovic
- Surgical Intensive Care Unit, Division of Anaesthesiology, Intensive Care, Rescue and Pain Medicine, Kantonsspital St. Gallen, Switzerland
| | - Manfred Kneilling
- Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) Image-Guided and Functionally Instructed Tumor Therapies, Eberhard Karls University Hospital Tübingen, Tübingen, Germany; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University of Tübingen, Germany
| | - Antonio Cozzio
- Department of Dermatology, Venereology and Allergology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Oltin Pop
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - David Bomze
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Sackler Faculty of Medicine, Tel Aviv University; Tel Aviv, Israel
| | - Andreas Bergthaler
- Institute for Hygiene and Applied Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria; CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Vienna, Austria
| | - Omar Hasan Ali
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Judith Aberle
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany; Department of Dermatology, Venereology and Allergology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
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Russell MA, Richardson SJ, Morgan NG. The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes. Front Endocrinol (Lausanne) 2023; 14:1270325. [PMID: 37867531 PMCID: PMC10588626 DOI: 10.3389/fendo.2023.1270325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/06/2023] [Indexed: 10/24/2023] Open
Abstract
The hyperexpression of human leukocyte antigen class I (HLA-I) molecules on pancreatic beta-cells is widely accepted as a hallmark feature of type 1 diabetes pathogenesis. This response is important clinically since it may increase the visibility of beta-cells to autoreactive CD8+ T-cells, thereby accelerating disease progression. In this review, key factors which drive HLA-I hyperexpression will be explored, and their clinical significance examined. It is established that the presence of residual beta-cells is essential for HLA-I hyperexpression by islet cells at all stages of the disease. We suggest that the most likely drivers of this process are interferons released from beta-cells (type I or III interferon; possibly in response to viral infection) or those elaborated from influent, autoreactive immune cells (type II interferon). In both cases, Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways will be activated to induce the downstream expression of interferon stimulated genes. A variety of models have highlighted that HLA-I expression is enhanced in beta-cells in response to interferons, and that STAT1, STAT2 and interferon regulatory factor 9 (IRF9) play key roles in mediating these effects (depending on the species of interferon involved). Importantly, STAT1 expression is elevated in the beta-cells of donors with recent-onset type I diabetes, and this correlates with HLA-I hyperexpression on an islet-by-islet basis. These responses can be replicated in vitro, and we consider that chronically elevated STAT1 may have a role in maintaining HLA-I hyperexpression. However, other data have highlighted that STAT2-IRF9 may also be critical to this process. Thus, a better understanding of how these factors regulate HLA-I under chronically stimulated conditions needs to be gathered. Finally, JAK inhibitors can target interferon signaling pathways to diminish HLA-I expression in mouse models. It seems probable that these agents may also be effective in patients; diminishing HLA-I hyperexpression on islets, reducing the visibility of beta-cells to the immune system and ultimately slowing disease progression. The first clinical trials of selective JAK inhibitors are underway, and the outcomes should have important implications for type 1 diabetes clinical management.
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Affiliation(s)
- Mark A. Russell
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom
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Ko KH, Cha SB, Lee SH, Bae HS, Ham CS, Lee MG, Kim DH, Han SH. A novel defined TLR3 agonist as an effective vaccine adjuvant. Front Immunol 2023; 14:1075291. [PMID: 36761735 PMCID: PMC9902914 DOI: 10.3389/fimmu.2023.1075291] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/06/2023] [Indexed: 01/25/2023] Open
Abstract
Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without any signs of serious toxicity. NVT stimulated TLR3 and increased the expression of viral nucleic acid sensors TLR3, MDA-5, and RIG-1. When intramuscularly injected into C57BL/6 mice, ovalbumin (OVA) plus NVT highly increased the migration of dendritic cells (DCs), macrophages, and neutrophils into inguinal lymph node (iLN) compared with OVA alone. In addition, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-β production. Furthermore, NVT exhibited an appropriate adjuvanticity because it elevated OVA-specific IgG, in particular, higher levels of IgG2c (Th1-type) but lower IgG1 (Th2-type). Concomitantly, NVT increased the levels of Th1-type T cells such as IFN-γ+CD4+ and IFN-γ+CD8+ cells in response to OVA stimulation. Collectively, we suggest that NVT with appropriate safety and effectiveness is a novel and promising adjuvant for vaccines, especially those requiring T cell mediated immunity such as viral and cancer vaccines.
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Affiliation(s)
- Kwang Hyun Ko
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea.,Interdisciplinary Program in Genetic Engineering, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seung Bin Cha
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Seung-Hwan Lee
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Hyun Shik Bae
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Chul Soo Ham
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Min-Gyu Lee
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Dong-Ho Kim
- Research and Development Center, NA Vaccine Institute, Seoul, Republic of Korea
| | - Seung Hyun Han
- Interdisciplinary Program in Genetic Engineering, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.,Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
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Jarzebska NT, Tusup M, Frei J, Weiss T, Holzinger T, Mellett M, Diken M, Bredl S, Weller M, Speck RF, Kündig TM, Sahin U, Pascolo S. RNA with chemotherapeutic base analogues as a dual-functional anti-cancer drug. Oncoimmunology 2022; 11:2147665. [DOI: 10.1080/2162402x.2022.2147665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Natalia Teresa Jarzebska
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Science, University of Zürich, Zürich, Switzerland
| | - Marina Tusup
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Julia Frei
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Tobias Weiss
- Department of Neurology and Clinical Neuroscience Center, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland
| | - Tim Holzinger
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Mark Mellett
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | | | - Simon Bredl
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland
| | - Michael Weller
- Department of Neurology and Clinical Neuroscience Center, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland
| | - Roberto F. Speck
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland
| | - Thomas M. Kündig
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | | | - Steve Pascolo
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
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7
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Lee J, Ahn SY, Le CTT, Lee DH, Jung J, Ko EJ. Protective and vaccine dose-sparing efficacy of Poly I:C-functionalized calcium phosphate nanoparticle adjuvants in inactivated influenza vaccination. Int Immunopharmacol 2022; 112:109240. [PMID: 36115278 DOI: 10.1016/j.intimp.2022.109240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/30/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
Adjuvants are required to increase the immunogenicity and efficacy of vaccination and enable vaccine dose sparing. Polyinosinic-polycytidylic acid (Poly I:C), a toll-like receptor 3 agonist, is a promising adjuvant candidate that can induce cell-mediated immune responses; however, it remains unlicensed owing to its low stability and toxicity. Calcium phosphate (CaP), a biocompatible and biodegradable nanoparticle, is widely used in biomedicine for stable and targeted drug delivery. In this study, we developed Poly I:C-functionalized CaP (Poly-CaP) and evaluated its vaccine adjuvant efficacy in vitro and in vivo. A half dose of Poly-CaP nanoparticles showed similar efficacy to a full dose of soluble Poly I:C in stimulating bone marrow-derived dendritic cells and macrophages to secrete proinflammatory cytokines and express their activation markers. Immunization with a half dose of inactivated influenza vaccine in the presence of Poly I:C or Poly-CaP adjuvants induced sufficient antigen-specific humoral responses after boost immunization. Immunization with Poly I:C, CaP, or Poly-CaP-adjuvanted with a half dose of influenza vaccine showed comparable protective efficacy against lethal virus infection, with lower weight loss and virus titer than a full dose of influenza vaccine. The Poly-CaP adjuvant was effective in stimulating antigen-specific CD4+ T cell proliferation in the lungs. Collectively, our results showed that the Poly-CaP adjuvant enhanced antigen-specific cell-mediated immunity and humoral immune responses with vaccine dose-sparing effects, suggesting its potential as a novel vaccine adjuvant candidate.
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Affiliation(s)
- Jueun Lee
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - So Yeon Ahn
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Chau Thuy Tien Le
- Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Republic of Korea
| | - Dong-Ha Lee
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Jaehan Jung
- Department of Materials Science and Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
| | - Eun-Ju Ko
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea; Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Republic of Korea; Veterinary Medical Research Institute, Jeju National University, Jeju 63243, Republic of Korea.
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8
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Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Comput Struct Biotechnol J 2022; 20:4415-4436. [PMID: 36051878 PMCID: PMC9420432 DOI: 10.1016/j.csbj.2022.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 12/02/2022] Open
Abstract
Recognition of pathogen-derived nucleic acids by host cells is an effective host strategy to detect pathogenic invasion and trigger immune responses. In the context of pathogen-specific pharmacology, there is a growing interest in mapping the interactions between pathogen-derived nucleic acids and host proteins. Insight into the principles of the structural and immunological mechanisms underlying such interactions and their roles in host defense is necessary to guide therapeutic intervention. Here, we discuss the newest advances in studies of molecular interactions involving pathogen nucleic acids and host factors, including their drug design, molecular structure and specific patterns. We observed that two groups of nucleic acid recognizing molecules, Toll-like receptors (TLRs) and the cytoplasmic retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) form the backbone of host responses to pathogen nucleic acids, with additional support provided by absent in melanoma 2 (AIM2) and DNA-dependent activator of Interferons (IFNs)-regulatory factors (DAI) like cytosolic activity. We review the structural, immunological, and other biological aspects of these representative groups of molecules, especially in terms of their target specificity and affinity and challenges in leveraging host-pathogen protein-nucleic acid interactions (HP-PNI) in drug discovery.
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Affiliation(s)
- Anuja Jain
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Shikha Mittal
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173234, India
| | - Lokesh P. Tripathi
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
- Riken Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa, Japan
| | - Ruth Nussinov
- Computational Structural Biology Section, Basic Science Program, Frederick National, Laboratory for Cancer Research, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel
| | - Shandar Ahmad
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
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9
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Yue C, Gao S, Li S, Xing Z, Qian H, Hu Y, Wang W, Hua C. TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front Immunol 2022; 13:911919. [PMID: 35720417 PMCID: PMC9203892 DOI: 10.3389/fimmu.2022.911919] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/13/2022] [Indexed: 12/19/2022] Open
Abstract
Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.
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Affiliation(s)
- Chenran Yue
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou, China
| | - Shuting Li
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhouhang Xing
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hengrong Qian
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ying Hu
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wenqian Wang
- Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
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10
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Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors. Mol Ther 2022; 30:1163-1170. [PMID: 34563676 PMCID: PMC8899519 DOI: 10.1016/j.ymthe.2021.09.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/11/2021] [Accepted: 09/20/2021] [Indexed: 01/05/2023] Open
Abstract
The adenosine deaminase inhibitor 2'-deoxycoformycin (pentostatin, Nipent) has been used since 1982 to treat leukemia and lymphoma, but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from pentostatin-treated cells or mice has enhanced immunostimulating capacities. Accordingly, we demonstrated in mice that the anticancer activity of pentostatin required Toll-like receptor 3, the type I interferon receptor, and T cells. Upon systemic administration of pentostatin, type I interferon is produced locally in tumors, resulting in immune cell infiltration. We combined pentostatin with immune checkpoint inhibitors and observed synergistic anti-cancer activities. Our work identifies pentostatin as a new class of an anticancer immunostimulating drug that activates innate immunity within tumor tissues and synergizes with systemic T cell therapies.
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11
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Aghamiri SH, Komlakh K, Ghaffari M. The crosstalk among TLR2, TLR4 and pathogenic pathways; a treasure trove for treatment of diabetic neuropathy. Inflammopharmacology 2022; 30:51-60. [PMID: 35020096 DOI: 10.1007/s10787-021-00919-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 12/19/2021] [Indexed: 11/25/2022]
Abstract
Diabetes is correlated with organ failures as a consequence of microvascular diabetic complications, including neuropathy, nephropathy, and retinopathy. These difficulties come with serious clinical manifestations and high medical costs. Diabetic neuropathy (DN) is one of the most prevalent diabetes complications, affecting at least 50% of diabetic patients with long disease duration. DN has serious effects on patients' life since it interferes with their daily physical activities and causes psychological comorbidities. There are some potential risk factors for the development of neuropathic injuries. It has been shown that inflammatory mechanisms play a pivotal role in the progression of DN. Among inflammatory players, TLR2 and TLR4 have gained immense importance because of their ability in recognizing distinct molecular patterns of invading pathogens and also damage-associated molecular patterns (DAMPs) providing inflammatory context for the progression of a wide array of disorders. We, therefore, sought to explore the possible role of TLR2 and TLR4 in DN pathogenesis and if whether manipulating TLRs is likely to be successful in fighting off DN.
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Affiliation(s)
- Seyed Hossein Aghamiri
- Department of Neurology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khalil Komlakh
- Department of Neurosurgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehran Ghaffari
- Department of Neurology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Akache B, Stark FC, Agbayani G, Renner TM, McCluskie MJ. Adjuvants: Engineering Protective Immune Responses in Human and Veterinary Vaccines. Methods Mol Biol 2022; 2412:179-231. [PMID: 34918246 DOI: 10.1007/978-1-0716-1892-9_9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Adjuvants are key components of many vaccines, used to enhance the level and breadth of the immune response to a target antigen, thereby enhancing protection from the associated disease. In recent years, advances in our understanding of the innate and adaptive immune systems have allowed for the development of a number of novel adjuvants with differing mechanisms of action. Herein, we review adjuvants currently approved for human and veterinary use, describing their use and proposed mechanisms of action. In addition, we will discuss additional promising adjuvants currently undergoing preclinical and/or clinical testing.
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Affiliation(s)
- Bassel Akache
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada
| | - Felicity C Stark
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada
| | - Gerard Agbayani
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada
| | - Tyler M Renner
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada
| | - Michael J McCluskie
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada.
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13
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Tusup M, Läuchli S, Jarzebska NT, French LE, Chang YT, Vonow-Eisenring M, Su A, Kündig TM, Guenova E, Pascolo S. mRNA-Based Anti-TCR CDR3 Tumour Vaccine for T-Cell Lymphoma. Pharmaceutics 2021; 13:pharmaceutics13071040. [PMID: 34371731 PMCID: PMC8308944 DOI: 10.3390/pharmaceutics13071040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022] Open
Abstract
Efficient vaccination can be achieved by injections of in vitro transcribed mRNA (ivt mRNA) coding for antigens. This vaccine format is particularly versatile and allows the production of individualised vaccines conferring, T-cell immunity against specific cancer mutations. The CDR3 hypervariable regions of immune receptors (T-cell receptor, TCR or B-cell receptor, BCR) in the context of T- or B-cell leukaemia or lymphoma are targetable and specific sequences, similar to cancer mutations. We evaluated the functionality of an mRNA-based vaccine designed to trigger immunity against TCR CDR3 regions in an EL4 T-lymphoma cell line-derived murine in vivo model. Vaccination against the hypervariable TCR regions proved to be a feasible approach and allowed for protection against T-lymphoma, even though immune escape in terms of TCR downregulation paralleled the therapeutic effect. However, analysis of human cutaneous T-cell lymphoma samples indicated that, as is the case in B-lymphomas, the clonotypic receptor may be a driver mutation and is not downregulated upon treatment. Thus, vaccination against TCR CDR3 regions using customised ivt mRNA is a promising immunotherapy method to be explored for the treatment of patients with T-cell lymphomas.
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Affiliation(s)
- Marina Tusup
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
| | - Severin Läuchli
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
| | - Natalia Teresa Jarzebska
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Science, University of Zürich, 8006 Zürich, Switzerland
| | - Lars E. French
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany;
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33146, USA
| | - Yun-Tsan Chang
- Department of Dermatology, Lausanne University Hospital (CHUV), University of Lausanne, 1000 Lausanne, Switzerland;
| | - Maya Vonow-Eisenring
- Department of Immunology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland;
| | | | - Thomas M. Kündig
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
- Department of Dermatology, Lausanne University Hospital (CHUV), University of Lausanne, 1000 Lausanne, Switzerland;
- Correspondence: authors: (E.G.); (S.P.)
| | - Steve Pascolo
- Department of Dermatology, University Hospital of Zürich, Raemistrasse 100, 8091 Zürich, Switzerland; (M.T.); (S.L.); (N.T.J.); (T.M.K.)
- Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
- Correspondence: authors: (E.G.); (S.P.)
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14
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Friedrich SK, Schmitz R, Bergerhausen M, Lang J, Duhan V, Hardt C, Tenbusch M, Prinz M, Asano K, Bhat H, Hamdan TA, Lang PA, Lang KS. Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation. Pathogens 2021; 10:pathogens10050622. [PMID: 34069514 PMCID: PMC8160763 DOI: 10.3390/pathogens10050622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 11/23/2022] Open
Abstract
The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs; however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 (Usp18). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.
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Affiliation(s)
- Sarah-Kim Friedrich
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Rosa Schmitz
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Michael Bergerhausen
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Judith Lang
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Vikas Duhan
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Cornelia Hardt
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
| | - Matthias Tenbusch
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
- Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, 79106 Freiburg, Germany
- Centre for NeuroModulation (NeuroModBasics), University of Freiburg, 79106 Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79106 Freiburg, Germany
| | - Kenichi Asano
- Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan;
| | - Hilal Bhat
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
- Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Robert Koch-Strasse 21, 50931 Köln, Germany
| | - Thamer A. Hamdan
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
- Department of Medical Laboratories, Faculty of Health Sciences, American University of Madaba, Amman 11821, Jordan
- Correspondence: (T.A.H.); (K.S.L.)
| | - Philipp Alexander Lang
- Institute of Molecular Medicine II, University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany;
| | - Karl Sebastian Lang
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany; (S.-K.F.); (R.S.); (M.B.); (J.L.); (V.D.); (C.H.); (H.B.)
- Correspondence: (T.A.H.); (K.S.L.)
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15
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Oakes RS, Tostanoski LH, Kapnick SM, Froimchuk E, Black SK, Zeng X, Jewell CM. Exploiting Rational Assembly to Map Distinct Roles of Regulatory Cues during Autoimmune Therapy. ACS NANO 2021; 15:4305-4320. [PMID: 33645967 PMCID: PMC8116774 DOI: 10.1021/acsnano.0c07440] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.
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Affiliation(s)
- Robert S. Oakes
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
- United States Department of Veterans Affairs, VA Maryland Health Care System, 10 N Greene St, Baltimore, MD, 21201, USA
| | - Lisa H. Tostanoski
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Senta M. Kapnick
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Eugene Froimchuk
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Sheneil K. Black
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Xiangbin Zeng
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Christopher M. Jewell
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
- United States Department of Veterans Affairs, VA Maryland Health Care System, 10 N Greene St, Baltimore, MD, 21201, USA
- Robert E. Fischell Institute for Biomedical Devices, 5102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
- Department of Microbiology and Immunology, University of Maryland Medical School, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, MD, 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S Greene St, Baltimore, MD, 21201, USA
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16
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Type I interferons as key players in pancreatic β-cell dysfunction in type 1 diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:1-80. [PMID: 33832648 DOI: 10.1016/bs.ircmb.2021.02.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet inflammation (insulitis) and specific pancreatic β-cell destruction by an immune attack. Although the precise underlying mechanisms leading to the autoimmune assault remain poorly understood, it is well accepted that insulitis takes place in the context of a conflicting dialogue between pancreatic β-cells and the immune cells. Moreover, both host genetic background (i.e., candidate genes) and environmental factors (e.g., viral infections) contribute to this inadequate dialogue. Accumulating evidence indicates that type I interferons (IFNs), cytokines that are crucial for both innate and adaptive immune responses, act as key links between environmental and genetic risk factors in the development of T1D. This chapter summarizes some relevant pathways involved in β-cell dysfunction and death, and briefly reviews how enteroviral infections and genetic susceptibility can impact insulitis. Moreover, we present the current evidence showing that, in β-cells, type I IFN signaling pathway activation leads to several outcomes, such as long-lasting major histocompatibility complex (MHC) class I hyperexpression, endoplasmic reticulum (ER) stress, epigenetic changes, and induction of posttranscriptional as well as posttranslational modifications. MHC class I overexpression, when combined with ER stress and posttranscriptional/posttranslational modifications, might lead to sustained neoantigen presentation to immune system and β-cell apoptosis. This knowledge supports the concept that type I IFNs are implicated in the early stages of T1D pathogenesis. Finally, we highlight the promising therapeutic avenues for T1D treatment directed at type I IFN signaling pathway.
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17
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Abstract
PURPOSE OF REVIEW Skin injury is the most common clinical manifestation of SLE and is disfiguring, difficult to treat, and incompletely understood. We provide an overview of recently published articles covering the immunopathogenesis of skin injury in SLE. RECENT FINDINGS Skin of SLE has an inherent susceptibility to apoptosis, the cause of which may be multifactorial. Chronic IFN overexpression leads to barrier disruption, infiltration of inflammatory cells, cytokine production, and release of autoantigens and autoantibody production that result in skin injury. Ultraviolet light is the most important CLE trigger and amplifies this process leading to skin inflammation and potentially systemic disease flares. SUMMARY The pathogenesis of skin injury in CLE is complex but recent studies highlight the importance of mechanisms driving dysregulated epidermal cell death likely influenced by genetic risk factors, environmental triggers (UV light), and cytotoxic cells and cellular signaling.
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Affiliation(s)
- Grace A. Hile
- Department of Dermatology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - J. Michelle Kahlenberg
- Department of Dermatology, University of Michigan, Ann Arbor, 48109, MI, USA
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
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18
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Cui L, Wang X, Zhang D. TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer. Front Cell Dev Biol 2021; 8:611444. [PMID: 33469538 PMCID: PMC7813757 DOI: 10.3389/fcell.2020.611444] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world, and the incidence of gastric cancer in Asia appears to increase in recent years. Although there is a lot of improvement in treatment approaches, the prognosis of GC is poor. So it is urgent to search for a novel and more effective treatment to improve the survival rate of patients. Both innate immunity and adaptive immunity are important in cancer. In the innate immune system, pattern recognition receptors (PRRs) activate immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs). Many studies have reported that TLRs are involved in the occurrence, development, and treatment of GC. Therefore, TLRs are potential targets for immunotherapy to gastric cancer. However, gastric cancer is a heterogeneous disorder, and TLRs function in GC is complex. TLRs agonists can be potentially used not only as therapeutic agents to treat gastric cancer but also as adjuvants in conjunction with other immunotherapies. They might provide a promising new target for GC treatment. In the review, we sort out the mechanism of TLRs involved in tumor immunity and summarize the current progress in TLRs-based therapeutic approaches and other immunotherapies in the treatment of GC.
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Affiliation(s)
- Lin Cui
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuqing Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Texas A&M University, Houston, TX, United States
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19
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Fox LE, Locke MC, Lenschow DJ. Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease. Front Immunol 2020; 11:606874. [PMID: 33408718 PMCID: PMC7779635 DOI: 10.3389/fimmu.2020.606874] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022] Open
Abstract
Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.
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Affiliation(s)
- Lindsey E. Fox
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Marissa C. Locke
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Deborah J. Lenschow
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
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20
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Yang L, Han X, Zhang C, Sun C, Huang S, Xiao W, Gao Y, Liang Q, Luo F, Lu W, Fu J, Zhou Y. Hsa_circ_0060450 Negatively Regulates Type I Interferon-Induced Inflammation by Serving as miR-199a-5p Sponge in Type 1 Diabetes Mellitus. Front Immunol 2020; 11:576903. [PMID: 33133095 PMCID: PMC7550460 DOI: 10.3389/fimmu.2020.576903] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 08/31/2020] [Indexed: 12/15/2022] Open
Abstract
Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5′ and 3′ end back-splicing. The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs. Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce. In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM). We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450. Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.
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Affiliation(s)
- Lan Yang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Xiao Han
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Caiyan Zhang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Chengjun Sun
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Saihua Huang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Wenfeng Xiao
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Yajing Gao
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Qiuyan Liang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Feihong Luo
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Wei Lu
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jinrong Fu
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yufeng Zhou
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
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21
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Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy. Pharmaceutics 2020; 12:pharmaceutics12070663. [PMID: 32674488 PMCID: PMC7408110 DOI: 10.3390/pharmaceutics12070663] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/29/2020] [Accepted: 07/04/2020] [Indexed: 02/07/2023] Open
Abstract
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.
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22
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Lang PA, Crome SQ, Xu HC, Lang KS, Chapatte L, Deenick EK, Grusdat M, Pandyra AA, Pozdeev VI, Wang R, Holderried TAW, Cantor H, Diefenbach A, Elford AR, McIlwain DR, Recher M, Häussinger D, Mak TW, Ohashi PS. NK Cells Regulate CD8 + T Cell Mediated Autoimmunity. Front Cell Infect Microbiol 2020; 10:36. [PMID: 32117809 PMCID: PMC7031256 DOI: 10.3389/fcimb.2020.00036] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 01/20/2020] [Indexed: 01/17/2023] Open
Abstract
Elucidating key factors that regulate immune-mediated pathology in vivo is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8+ T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8+ T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV. High-dose LCMV infection induced an impaired CD8+ T cell response, which coincided with increased NK cell activity during early time points following infection. Notably, we observed increased NKp46 expression on NK cells during infection with higher doses, which resulted in an NK cell dependent suppression of T cells. Accordingly, depletion with antibodies specific for NK1.1 as well as NKp46 deficiency (Ncr1gfp/gfp mice) could restore CD8+ T cell immunity and permitted the induction of diabetes even following infection of RIP-GP mice with high-dose LCMV. Therefore, we identify conditions where innate lymphoid cells can play a regulatory role and interfere with CD8+ T cell mediated tissue specific pathology using an NKp46 dependent mechanism.
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Affiliation(s)
- Philipp A Lang
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.,Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.,Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sarah Q Crome
- Department of Immunology, University of Toronto, Toronto, ON, Canada.,Toronto General Hospital Research Institute and UHN Transplant, University Health Network, Toronto, ON, Canada
| | - Haifeng C Xu
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.,Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Karl S Lang
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.,Institute of Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Laurence Chapatte
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada
| | - Elissa K Deenick
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Melanie Grusdat
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Aleksandra A Pandyra
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Vitaly I Pozdeev
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Ruifeng Wang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tobias A W Holderried
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.,Department of Hematology, Oncology and Rheumatology, University Hospital Bonn, Bonn, Germany
| | - Harvey Cantor
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Immunology, Harvard Medical School, Boston, MA, United States
| | - Andreas Diefenbach
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
| | - Alisha R Elford
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada
| | - David R McIlwain
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Mike Recher
- Medical Outpatient Clinic and Immunodeficiency Lab, University Hospital Basel, Basel, Switzerland
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Tak W Mak
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Pamela S Ohashi
- Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada
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23
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Miller PDE, Snowden JA, De Latour RP, Iacobelli S, Eikema DJ, Knol C, Marsh JCW, Rice C, Koh M, Fagioli F, Chaganti S, Finke J, Duarte RF, Bader P, Farge D, Passweg JR, Madrigal JA, Dufour C. Autoimmune cytopenias (AIC) following allogeneic haematopoietic stem cell transplant for acquired aplastic anaemia: a joint study of the Autoimmune Diseases and Severe Aplastic Anaemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2020; 55:441-451. [PMID: 31554929 PMCID: PMC6995778 DOI: 10.1038/s41409-019-0680-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 07/06/2019] [Accepted: 07/20/2019] [Indexed: 12/03/2022]
Abstract
This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2-3.9 95% CI), 4.4% (2.6-6.2 95% CI), 4.6% (2.8-6.5 95% CI) and 5.1% (3.1-7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71-100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6-91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06-7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11-7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12-0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12-0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.
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Affiliation(s)
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Simona Iacobelli
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Cora Knol
- EBMT Data Office, Leiden, Netherlands
| | - Judith C W Marsh
- Department of Haematological Medicine, Kings College Hospital, London, UK
| | - Carmel Rice
- Department of Haematological Medicine, Kings College Hospital, London, UK
| | - Mickey Koh
- Department of Haematology, St George's Hospital NHS Foundation Trust, London, UK
| | - Franca Fagioli
- Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy
| | - Sridhar Chaganti
- Centre for Clinical Haematology, University Hospital Birmingham, Birmingham, UK
| | - Jürgen Finke
- Department of Hematology and Oncology, University Medical Center, Freiburg, Germany
| | - Rafael F Duarte
- Department of Hematology, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Peter Bader
- University Children's Hospital Frankfurt, Frankfurt, Germany
| | - Dominique Farge
- Department of Autoimmune Diseases and Vascular Pathology, Hopital Saint-Louis, Paris, France
| | - Jakob R Passweg
- Division of Hematology, University Hospital of Santander, Basel, Switzerland
| | | | - Carlo Dufour
- Hematology Unit, G. Gaslini Children's Hospital, Genova, Italy
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24
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Herold KC, Bucktrout SL, Wang X, Bode BW, Gitelman SE, Gottlieb PA, Hughes J, Joh T, McGill JB, Pettus JH, Potluri S, Schatz D, Shannon M, Udata C, Wong G, Levisetti M, Ganguly BJ, Garzone PD. Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes. JCI Insight 2019; 4:126054. [PMID: 31852846 DOI: 10.1172/jci.insight.126054] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION NCT02038764. FUNDING Pfizer Inc.
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Affiliation(s)
- Kevan C Herold
- Department of Immunobiology and.,Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Xiao Wang
- Rinat, Pfizer Inc., South San Francisco, California, USA
| | - Bruce W Bode
- Atlanta Diabetes Associates Research, Atlanta, Georgia, USA
| | - Stephen E Gitelman
- Department of Pediatrics and.,Diabetes Center, UCSF, San Francisco, California, USA
| | - Peter A Gottlieb
- Department of Pediatrics.,Department of Medicine, and.,Barbara Davis Diabetes Center, University of Colorado School of Medicine Anschutz Medical Campus, Anschutz, Colorado, USA
| | - Jing Hughes
- Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Internal Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA
| | - Tenshang Joh
- Worldwide R&D, Pfizer Inc., San Diego, California, USA
| | - Janet B McGill
- Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Internal Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA
| | - Jeremy H Pettus
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Shobha Potluri
- Rinat, Pfizer Inc., South San Francisco, California, USA
| | - Desmond Schatz
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Megan Shannon
- Worldwide R&D, Pfizer Inc., San Diego, California, USA
| | | | - Gilbert Wong
- Rinat, Pfizer Inc., South San Francisco, California, USA
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25
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Friedrich SK, Lang PA, Friebus-Kardash J, Duhan V, Bezgovsek J, Lang KS. Mechanisms of lymphatic system-specific viral replication and its potential role in autoimmune disease. Clin Exp Immunol 2019; 195:64-73. [PMID: 30444956 DOI: 10.1111/cei.13241] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2018] [Indexed: 12/15/2022] Open
Abstract
Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti-viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169+ macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin-specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169+ macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169+ macrophages. Tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cell signaling (NF-κB) have been found to promote the survival of infected CD169+ macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein-Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies.
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Affiliation(s)
- S-K Friedrich
- University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany
| | - P A Lang
- Heinrich-Heine-University, Insitute of Molecular Medicine II, Düsseldorf, Germany
| | - J Friebus-Kardash
- University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany
| | - V Duhan
- University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany
| | - J Bezgovsek
- University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany
| | - K S Lang
- University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany
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26
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Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance. Viruses 2019; 11:v11100885. [PMID: 31546586 PMCID: PMC6832701 DOI: 10.3390/v11100885] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 12/11/2022] Open
Abstract
Viral infections are a natural part of our existence. They can affect us in many ways that are the result of the interaction between the viral pathogen and our immune system. Most times, the resulting immune response is beneficial for the host. The pathogen is cleared, thus protecting our vital organs with no other consequences. Conversely, the reaction of our immune system against the pathogen can cause organ damage (immunopathology) or lead to autoimmune disease. To date, there are several mechanisms for virus-induced autoimmune disease, including molecular mimicry and bystander activation, in support of the “fertile field” hypothesis (terms defined in our review). In contrast, viral infections have been associated with protection from autoimmunity through mechanisms that include Treg invigoration and immune deviation, in support of the “hygiene hypothesis”, also defined here. Infection with lymphocytic choriomeningitis virus (LCMV) is one of the prototypes showing that the interaction of our immune system with viruses can either accelerate or prevent autoimmunity. Studies using mouse models of LCMV have helped conceive and establish several concepts that we now know and use to explain how viruses can lead to autoimmune activation or induce tolerance. Some of the most important mechanisms established during the course of LCMV infection are described in this short review.
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27
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Comberlato A, Paloja K, Bastings MMC. Nucleic acids presenting polymer nanomaterials as vaccine adjuvants. J Mater Chem B 2019; 7:6321-6346. [PMID: 31460563 DOI: 10.1039/c9tb01222b] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Most vaccines developed today include only the antigens that best stimulate the immune system rather than the entire virus or microbe, which makes vaccine production and use safer and easier, though they lack potency to induce acceptable immunity and long-term protection. The incorporation of additional immune stimulating components, named adjuvants, is required to generate a strong protective immune response. Nucleic acids (DNA and RNA) and their synthetic analogs are promising candidates as vaccine adjuvants activating Toll-like receptors (TLRs). Additionally, in the last few years several nanocarriers have emerged as platforms for targeted co-delivery of antigens and adjuvants. In this review, we focus on the recent developments in polymer nanomaterials presenting nucleic acids as vaccine adjuvants. We aim to compare the effectiveness of the various classes of polymers in immune modulating materials (nanoparticles, dendrimers, single-chain particles, nanogels, polymersomes and DNA-based architectures). In particular, we address the critical role of parameters such as size, shape, complexation and release of TLR ligands, cellular uptake, stability, toxicity and potential importance of spatial control in ligand presentation.
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Affiliation(s)
- Alice Comberlato
- IMX/IBI, EPFL, EPFL-STI-IMX-PBL MXC 340 Station 12, Lausanne, 1015, Switzerland.
| | - Kaltrina Paloja
- IMX/IBI, EPFL, EPFL-STI-IMX-PBL MXC 340 Station 12, Lausanne, 1015, Switzerland.
| | - Maartje M C Bastings
- IMX/IBI, EPFL, EPFL-STI-IMX-PBL MXC 340 Station 12, Lausanne, 1015, Switzerland.
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28
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Tran TH, Tran TTP, Truong DH, Nguyen HT, Pham TT, Yong CS, Kim JO. Toll-like receptor-targeted particles: A paradigm to manipulate the tumor microenvironment for cancer immunotherapy. Acta Biomater 2019; 94:82-96. [PMID: 31129358 DOI: 10.1016/j.actbio.2019.05.043] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/26/2019] [Accepted: 05/19/2019] [Indexed: 12/15/2022]
Abstract
The expression of Toll-like receptors (TLRs) on antigen presenting cells, especially dendritic cells, offers several sensitive mediators to trigger an adaptive immune response, which potentially can be exploited to detect and eliminate pathogenic objects. Consequently, numerous agonists that target TLRs are being used clinically either alone or in combination with other therapies to strengthen the immune system in the battle against cancer. This review summarizes the roles of TLRs in tumor biology, and focuses on relevant TLR-dependent antitumor pathways and the conjugation of TLR agonists as adjuvants to nano- and micro-particles for boosting responses leading to cancer suppression and eradication. STATEMENT OF SIGNIFICANCE: Toll-like receptors (TLRs), which express on antigen presenting cells, such as dendritic cells and macrophages, play an important role in sensing pathogenic agents and inducing adaptive immunity. As a result, several TLR agonists have been investigating as therapeutic agents individually or in combination with other treatment modalities for cancer treatment through boosting the immune system. This review aims to focus on the roles of TLRs in cancer and TLR-dependent antitumor pathways as well as the use of different nano- or micro-particles bearing TLR agonists for tumor inhibition and elimination.
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Affiliation(s)
- Tuan Hiep Tran
- Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Viet Nam; Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Viet Nam.
| | - Thi Thu Phuong Tran
- The Institute of Molecular Genetics of Montpellier, CNRS, Montpellier, France
| | - Duy Hieu Truong
- Institute of Research and Development, Duy Tan University, Da Nang, Viet Nam.
| | - Hanh Thuy Nguyen
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Tung Thanh Pham
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
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29
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Lamrayah M, Charriaud F, Hu S, Megy S, Terreux R, Verrier B. Molecular modelling of TLR agonist Pam 3CSK 4 entrapment in PLA nanoparticles as a tool to explain loading efficiency and functionality. Int J Pharm 2019; 568:118569. [PMID: 31352045 DOI: 10.1016/j.ijpharm.2019.118569] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 12/18/2022]
Abstract
Designing potent and safe-of-use therapies against cancers and infections remains challenging despite the emergence of novel molecule classes like checkpoint inhibitors or Toll-Like-Receptor ligands. The latest therapeutic perspectives under development for immune modulator administration exploits vectorization, and biodegradable delivery systems are one of the most promising vehicles. Nanoparticles based on Poly (D,L) Lactic Acid (PLA) as polymer for formulation are widely investigated due to its bioresorbable, biocompatible and low immunogen properties. We propose a PLA-based nanoparticle delivery system to vectorize Pam3CSK4, a lipopeptide TLR1/2 ligand and a potent activator of the proinflammatory transcription factor NF-κB that shows a self-assembling behavior from 30 µg/mL onwards. We demonstrate successful encapsulation of Pam3CSK4 in PLA nanoparticles by nanoprecipitation in a 40-180 µg/mL concentration range, with 99% of entrapment efficiency. By molecular modelling, we characterize drug/carrier interactions and conclude that Pam3CSK4 forms clusters onto the nanoparticle and is not encapsulated into the hydrophobic core. In silico predictions provide nanoprecipitation optimization and the mechanistic understanding of the particle dynamics. The loaded-Pam3CSK4 maintains bioactivity on TLR2, confirmed by in vitro experiments using reporter cell line HEK-Blue hTLR2. Our presented data and results are convincing evidence that Pam3CSK4-loaded in PLA nanoparticles represent a promising immune modulating system.
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Affiliation(s)
- Myriam Lamrayah
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
| | - Fanny Charriaud
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France
| | - Shangnong Hu
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France; Pôle Rhône-Alpes de Bioinformatique - Lyon Gerland, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France
| | - Simon Megy
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France; Pôle Rhône-Alpes de Bioinformatique - Lyon Gerland, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France
| | - Raphael Terreux
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France; Pôle Rhône-Alpes de Bioinformatique - Lyon Gerland, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France
| | - Bernard Verrier
- Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France
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30
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Govea-Alonso DO, Arevalo-Villalobos JI, Márquez-Escobar VA, Vimolmangkang S, Rosales-Mendoza S. An overview of tolerogenic immunotherapies based on plant-made antigens. Expert Opin Biol Ther 2019; 19:587-599. [PMID: 30892096 DOI: 10.1080/14712598.2019.1597048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Over the last two decades, genetically engineered plants became attractive and mature platforms for producing vaccines and other relevant biopharmaceuticals. Autoimmune and inflammatory disorders demand the availability of accessible treatments, and one alternative therapy is based on therapeutic vaccines able to downregulate immune responses that favor pathology progression. AREAS COVERED The current status of plant-made tolerogenic vaccines is presented with emphasis on the candidates under evaluation in test animals. Nowadays, this concept has been assessed in models of food and pollen allergies, autoimmune diabetes, asthma, arthritis, and prevention of blocking antibodies induction against a biopharmaceutical used in replacement therapies. EXPERT OPINION According to the current evidence generated at the preclinical level, plant-made tolerogenic therapies are a promise to treat several immune-related conditions, and the beginning of clinical trials is envisaged for the next decade. Advantages and limitations for this technology are discussed.
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Affiliation(s)
- Dania O Govea-Alonso
- a Laboratorio de Biofarmacéuticos Recombinantes, Facultad de Ciencias Químicas , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México.,b Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México
| | - Jaime I Arevalo-Villalobos
- a Laboratorio de Biofarmacéuticos Recombinantes, Facultad de Ciencias Químicas , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México.,b Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México
| | - Verónica A Márquez-Escobar
- a Laboratorio de Biofarmacéuticos Recombinantes, Facultad de Ciencias Químicas , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México.,b Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México
| | - Sornkanok Vimolmangkang
- c Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok , Thailand.,d Research Unit for Plant-Produced Pharmaceuticals , Chulalongkorn University , Bangkok , Thailand
| | - Sergio Rosales-Mendoza
- a Laboratorio de Biofarmacéuticos Recombinantes, Facultad de Ciencias Químicas , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México.,b Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina , Universidad Autónoma de San Luis Potosí , San Luis Potosí , México
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31
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Marro BS, Legrain S, Ware BC, Oldstone MB. Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model. JCI Insight 2019; 4:125067. [PMID: 30674713 DOI: 10.1172/jci.insight.125067] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/11/2018] [Indexed: 01/05/2023] Open
Abstract
Here, we report a pathogenic role for type I IFN (IFN-I) signaling in macrophages, and not β cells in the islets, for the development of type 1 diabetes (T1D). Following lymphocytic choriomeningitis (LCMV) infection in the Rip-LCMV-GP T1D model, macrophages accumulated near islets and in close contact to islet-infiltrating GP-specific (autoimmune) CD8+ T cells. Depletion of macrophages with clodronate liposomes or genetic ablation of Ifnar in macrophages aborted T1D, despite proliferation of GP-specific (autoimmune) CD8+ T cells. Histopathologically, disrupted IFNα/β receptor (IFNAR) signaling in macrophages resulted in restriction of CD8+ T cells entering into the islets with significant lymphoid accumulation around the islet. Collectively, these results provide evidence that macrophages via IFN-I signaling, while not entering the islets, are directly involved in interacting, directing, or restricting trafficking of autoreactive-specific T cells into the islets as an important component in causing T1D.
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32
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Walsh SR, Bastin D, Chen L, Nguyen A, Storbeck CJ, Lefebvre C, Stojdl D, Bramson JL, Bell JC, Wan Y. Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity. J Clin Invest 2018; 129:518-530. [PMID: 30422820 DOI: 10.1172/jci121004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 11/06/2018] [Indexed: 12/27/2022] Open
Abstract
Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.
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Affiliation(s)
- Scott R Walsh
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Donald Bastin
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Lan Chen
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Andrew Nguyen
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Christopher J Storbeck
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Charles Lefebvre
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - David Stojdl
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Jonathan L Bramson
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John C Bell
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Yonghong Wan
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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33
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Pearson JA, Agriantonis A, Wong FS, Wen L. Modulation of the immune system by the gut microbiota in the development of type 1 diabetes. Hum Vaccin Immunother 2018; 14:2580-2596. [PMID: 30156993 PMCID: PMC6314421 DOI: 10.1080/21645515.2018.1514354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/29/2018] [Accepted: 08/17/2018] [Indexed: 02/08/2023] Open
Abstract
T1D is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing β-cells in the pancreatic islets of Langerhans, resulting in hyperglycemia, with patients requiring lifelong insulin treatment. Many studies have shown that genetics alone are not sufficient for the increase in T1D incidence and thus other factors have been suggested to modify the disease risk. T1D incidence has sharply increased in the developed world, especially amongst youth. In Europe, T1D incidence is increasing at an annual rate of 3-4%. Increasing evidence shows that gut microbiota, as one of the environmental factors influencing diabetes development, play an important role in development of T1D. Here, we summarize the current knowledge about the relationship between the microbiota and T1D. We also discuss the possibility of T1D prevention by changing the composition of gut microbiota.
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Affiliation(s)
- James A. Pearson
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA
| | - Andrew Agriantonis
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA
| | - F. Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - Li Wen
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA
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34
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Lombardi A, Tsomos E, Hammerstad SS, Tomer Y. Interferon alpha: The key trigger of type 1 diabetes. J Autoimmun 2018; 94:7-15. [PMID: 30115527 DOI: 10.1016/j.jaut.2018.08.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 08/04/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes. In this review, we dissect the role of IFNα in T1D, focusing on the potential pathophysiological mechanisms involved. Evidence from human and mouse studies indicates that IFNα plays a key role in enhancing islet expression of HLA-I in patients with T1D, thereby increasing autoantigen presentation and beta cell activation of autoreactive cytotoxic CD8 T-lymphocytes. The binding of IFNα to its receptor induces the secretion of chemokines, attracting monocytes, T lymphocytes, and NK cells to the infected tissue triggering autoimmunity in susceptible individuals. Furthermore, IFNα impairs insulin production through the induction of endoplasmic reticulum stress as well as by impairing mitochondrial function. Due to its central role in the early phases of beta cell death, targeting IFNα and its pathways in genetically predisposed individuals may represent a potential novel therapeutic strategy in the very early stages of T1D.
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Affiliation(s)
- Angela Lombardi
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Effie Tsomos
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Sara S Hammerstad
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Aker, Oslo, Norway; Department of Pediatrics, Oslo University Hospital, Ulleval, Oslo, Norway
| | - Yaron Tomer
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
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35
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Conrad C, Di Domizio J, Mylonas A, Belkhodja C, Demaria O, Navarini AA, Lapointe AK, French LE, Vernez M, Gilliet M. TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat Commun 2018; 9:25. [PMID: 29295985 PMCID: PMC5750213 DOI: 10.1038/s41467-017-02466-4] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 12/01/2017] [Indexed: 02/08/2023] Open
Abstract
Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2–5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity. The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.
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Affiliation(s)
- Curdin Conrad
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland.
| | - Jeremy Di Domizio
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Alessio Mylonas
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Cyrine Belkhodja
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Olivier Demaria
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Alexander A Navarini
- Department of Dermatology, University Hospital of Zurich, Zurich, 8091, Switzerland
| | - Anne-Karine Lapointe
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Lars E French
- Department of Dermatology, University Hospital of Zurich, Zurich, 8091, Switzerland
| | - Maxime Vernez
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland
| | - Michel Gilliet
- Department of Dermatology, University Hospital CHUV, Lausanne, 1011, Switzerland.
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36
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Effective antitumor peptide vaccines can induce severe autoimmune pathology. Oncotarget 2017; 8:70317-70331. [PMID: 29050282 PMCID: PMC5642557 DOI: 10.18632/oncotarget.19688] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 06/26/2017] [Indexed: 12/21/2022] Open
Abstract
Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated ∼ 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice. Boosting with BiVax in combination with αCD40 antibody (TriVax) or BiVax in combination with IL-2/αIL-2 antibody complexes (IL2Cx) significantly increased the immune responses (∼30-50%). Interestingly, although both boosts were equally effective in generating vast T cell responses, BiVax/IL2Cx showed better control of tumor growth than TriVax. However, this effect was associated with high incidence of diabetes in an antigen and CD8 dependent fashion. T cell responses generated by BiVax/IL2Cx, but not those generated by TriVax were highly resistant to PD-1/PD-L1 inhibitory signals. Nevertheless, PD-1 blockade enhanced the ability of TriVax to control tumor growth but increased the incidence of diabetes. Finally, we show that severe autoimmunity by BiVax/IL2Cx was prevented while preserving outstanding antitumor responses by utilizing a tumor antigen not expressed in the pancreas. Our data provides a clear evidence that peptide based vaccines can expand vast endogenous T cell responses which effectively control tumor growth but with high potential of autoimmune pathology.
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37
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Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling. Proc Natl Acad Sci U S A 2017; 114:3708-3713. [PMID: 28325871 DOI: 10.1073/pnas.1700878114] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.
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38
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Morse ZJ, Horwitz MS. Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset. Front Endocrinol (Lausanne) 2017; 8:249. [PMID: 29018409 PMCID: PMC5623193 DOI: 10.3389/fendo.2017.00249] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 09/12/2017] [Indexed: 12/25/2022] Open
Abstract
Heritable susceptibility of the autoimmune disorder, type 1 diabetes (T1D), only partially equates for the incidence of the disease. Significant evidence attributes several environmental stressors, such as vitamin D deficiency, gut microbiome, dietary antigens, and most notably virus infections in triggering the onset of T1D in these genetically susceptible individuals. Extensive epidemiological and clinical studies have provided credibility to this causal relationship. Infection by the enterovirus, coxsackievirus B, has been closely associated with onset of T1D and is considered a significant etiological agent for disease induction. Recognition of viral antigens via innate pathogen-recognition receptors induce inflammatory events which contribute to autoreactivity of pancreatic self-antigens and ultimately the destruction of insulin-secreting beta cells. The activation of these specific innate pathways and expression of inflammatory molecules, including type I and III interferon, prime the immune system to elicit either a protective regulatory response or a diabetogenic effector response. Therefore, sensing of viral antigens by retinoic acid-inducible gene I-like receptors and toll-like receptors may be detrimental to inducing autoreactivity initiated by viral stress and resulting in T1D.
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Affiliation(s)
- Zachary J. Morse
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Marc S. Horwitz,
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39
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Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016; 8:1354-1369. [PMID: 27917262 PMCID: PMC5114472 DOI: 10.4254/wjh.v8.i32.1354] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/17/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
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Affiliation(s)
- Safak Kiziltas
- Safak Kiziltas, Department of Gastroenterology, Baskent University Istanbul Hospital, 34662 Istanbul, Turkey
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40
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Overall SA, Bourges D, van Driel IR, Gleeson PA. Increased endogenous antigen presentation in the periphery enhances susceptibility to inflammation-induced gastric autoimmunity in mice. Eur J Immunol 2016; 47:155-167. [PMID: 27759162 DOI: 10.1002/eji.201646572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/06/2016] [Accepted: 10/17/2016] [Indexed: 11/12/2022]
Abstract
How the immune system maintains peripheral tolerance under inflammatory conditions is poorly understood. Here we assessed the fate of gastritogenic T cells following inflammatory activation in vivo. Self-reactive T cells (A23 T cells) specific for the gastric H+ /K+ ATPase α subunit (HKα) were transferred into immunosufficient recipient mice and immunised at a site distant to the stomach with adjuvant containing the cognate HKα peptide antigen. Activation of A23 T cells by immunisation did not impact on either immune tolerance or protection from gastric autoimmunity in wild-type BALB/c mice. However, increased presentation of endogenously derived HKα epitopes by dendritic cells (DCs) in the gastric lymph node of IE-H+ /K+ β transgenic mice (IEβ) reduces A23 T-cell tolerance to gastric antigens after inflammatory activation, with subsequent development of gastritis. While HKα-specific A23 T cells from immunised wild-type mice were poorly responsive to in vitro antigen specific activation, A23 T cells from immunised IEβ transgenic mice were readily re-activated, indicating loss of T-cell anergy. These findings show that DCs of gastric lymph nodes can maintain tolerance of pathogenic T cells following inflammatory stimulation and that the density of endogenous antigen presented to self-reactive T cells is critical in the balance between tolerance and autoimmunity.
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Affiliation(s)
- Sarah A Overall
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia
| | - Dorothée Bourges
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia
| | - Ian R van Driel
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia
| | - Paul A Gleeson
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia
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41
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Yin C, Mohanta SK, Srikakulapu P, Weber C, Habenicht AJR. Artery Tertiary Lymphoid Organs: Powerhouses of Atherosclerosis Immunity. Front Immunol 2016; 7:387. [PMID: 27777573 PMCID: PMC5056324 DOI: 10.3389/fimmu.2016.00387] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/14/2016] [Indexed: 11/15/2022] Open
Abstract
Artery tertiary lymphoid organs (ATLOs) are atherosclerosis-associated lymphoid aggregates with varying degrees of complexity ranging from small T/B-cell clusters to well-structured lymph node-like though unencapsulated lymphoid tissues. ATLOs arise in the connective tissue that surrounds diseased arteries, i.e., the adventitia. ATLOs have been identified in aged atherosclerosis-prone hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice: they are organized into distinct immune cell compartments, including separate T-cell areas, activated B-cell follicles, and plasma cell niches. Analyses of ATLO immune cell subsets indicate antigen-specific T- and B-cell immune reactions within the atherosclerotic arterial wall adventitia. Moreover, ATLOs harbor innate immune cells, including a large component of inflammatory macrophages, B-1 cells, and an aberrant set of antigen-presenting cells. There is marked neoangiogenesis, irregular lymphangiogenesis, neoformation of high endothelial venules, and de novo synthesis of lymph node-like conduits. Molecular mechanisms of ATLO formation remain to be identified though media vascular smooth muscle cells may adopt features of lymphoid tissue organizer-like cells by expressing lymphorganogenic chemokines, i.e., CXCL13 and CCL21. Although these data are consistent with the view that ATLOs participate in primary T- and B-cell responses against elusive atherosclerosis-specific autoantigens, their specific protective or disease-promoting roles remain to be identified. In this review, we discuss what is currently known about ATLOs and their potential impact on atherosclerosis and make attempts to define challenges ahead.
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Affiliation(s)
- Changjun Yin
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Sarajo Kumar Mohanta
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
| | - Prasad Srikakulapu
- Cardiovascular Research Center (CVRC), University of Virginia, Charlottesville, VA, USA
| | - Christian Weber
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
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42
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Rashedi I, Gómez-Aristizábal A, Wang XH, Viswanathan S, Keating A. TLR3 or TLR4 Activation Enhances Mesenchymal Stromal Cell-Mediated Treg Induction via Notch Signaling. Stem Cells 2016; 35:265-275. [PMID: 27571579 DOI: 10.1002/stem.2485] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 07/11/2016] [Accepted: 08/04/2016] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are the subject of numerous clinical trials, largely due to their immunomodulatory and tissue regenerative properties. Toll-like receptors (TLRs), especially TLR3 and TLR4, are highly expressed on MSCs and their activation can significantly modulate the immunosuppressive and anti-inflammatory functions of MSCs. While MSCs can recruit and promote the generation of regulatory T cells (Tregs), the effect of TLR activation on MSC-mediated Treg induction is unknown. In this study, we investigated the effect of ligand-mediated activation of TLR3 and TLR4 on Treg induction by human MSCs. We found that generation of Tregs in human CD4(+) lymphocyte and MSC cocultures was enhanced by either TLR3 or TLR4 activation of MSCs and that the increase was abolished by TLR3 and TLR4 gene-silencing. Augmented Treg induction by TLR-activated MSCs was cell contact-dependent and associated with increased gene expression of the Notch ligand, Delta-like 1. Moreover, inhibition of Notch signaling abrogated the augmented Treg levels in the MSC cocultures. Our data show that TLR3 or TLR4 activation of MSCs increases Treg induction via the Notch pathway and suggest new means to enhance the potency of MSCs for treating disorders with an underlying immune dysfunction, including steroid resistant acute graft-versus-host disease. Stem Cells 2017;35:265-275.
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Affiliation(s)
- Iran Rashedi
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Cell Therapy Program, University Health Network, Toronto, Canada
| | - Alejandro Gómez-Aristizábal
- Cell Therapy Program, University Health Network, Toronto, Canada.,Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada
| | - Xing-Hua Wang
- Cell Therapy Program, University Health Network, Toronto, Canada.,Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada
| | - Sowmya Viswanathan
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Cell Therapy Program, University Health Network, Toronto, Canada.,Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada
| | - Armand Keating
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Cell Therapy Program, University Health Network, Toronto, Canada.,Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada.,Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
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43
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Vo MC, Lee HJ, Kim JS, Hoang MD, Choi NR, Rhee JH, Lakshmanan VK, Shin SJ, Lee JJ. Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity. Oncotarget 2016; 6:33781-90. [PMID: 26418952 PMCID: PMC4741802 DOI: 10.18632/oncotarget.5281] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 09/04/2015] [Indexed: 11/30/2022] Open
Abstract
Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response.
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Affiliation(s)
- Manh-Cuong Vo
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea
| | - Hyun-Ju Lee
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea.,Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea
| | - Jong-Seok Kim
- Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University, Seoul, Republic of Korea
| | - My-Dung Hoang
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea
| | - Nu-Ri Choi
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea
| | - Joon Haeng Rhee
- Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Vinoth-Kumar Lakshmanan
- Department of Biomedical Science, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sung-Jae Shin
- Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University, Seoul, Republic of Korea
| | - Je-Jung Lee
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea.,Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea
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44
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Sala M, Elaissari A, Fessi H. Advances in psoriasis physiopathology and treatments: Up to date of mechanistic insights and perspectives of novel therapies based on innovative skin drug delivery systems (ISDDS). J Control Release 2016; 239:182-202. [PMID: 27381248 DOI: 10.1016/j.jconrel.2016.07.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 11/26/2022]
Abstract
Psoriasis is a chronic inflammatory disease affecting mainly the skin but which can be complicated by psoriatic arthritis (PsA).This autoimmune skin disorder concerns 2-5% of the world population. To date, the physiopathology of psoriasis is not still completely elucidated but many researches are ongoing which have led for example to the discovery of the Th17/Th22 pathway. The conventional therapeutic approaches (local or systemic route) appeal to various classes of drugs with complex mechanisms of action and non-negligible side effects. Although there is no therapy capable to cure psoriasis, the current goal is to relieve symptoms as longer as possible with a good benefit/risk ratio. That is one of the principal limits of conventional antipsoriatic drugs. New formulations based on nanoencapsulation are a promising opportunity to answer to this limit by offering an optimization of the conventional antipsoriatic drug use (higher activity, lower side effects and frequency of application, etc.). Herein, we tried to put in perspective the mechanistic insights (histological and immunological views) proposed into scientific literature these last years in order to have a better comprehension of psoriasis physiopathology resulting in skin lesions and PsA. The therapeutic armamentarium and the different strategies in the management of psoriasis are discussed in greater details. To finish, the field of encapsulation in nanoparticles is broached in order to put forward recent advances in innovative skin drug delivery systems (ISDDSs) of antipsoriatic active agents for a better efficacy, safety and compliance.
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Affiliation(s)
- M Sala
- University Claude Bernard Lyon 1, Laboratoire d'Automatique et de Génie des Procédés, CNRS, UMR 5007, LAGEP-CPE-308G, 43 bd. du 11 Nov.1918, F-69622 Villeurbanne, France; Pharmacie centrale, Hospices Civils de Lyon, 57, Rue Francisque Darcieux, 69563 Saint Genis Laval, France
| | - A Elaissari
- University Claude Bernard Lyon 1, Laboratoire d'Automatique et de Génie des Procédés, CNRS, UMR 5007, LAGEP-CPE-308G, 43 bd. du 11 Nov.1918, F-69622 Villeurbanne, France
| | - H Fessi
- University Claude Bernard Lyon 1, Laboratoire d'Automatique et de Génie des Procédés, CNRS, UMR 5007, LAGEP-CPE-308G, 43 bd. du 11 Nov.1918, F-69622 Villeurbanne, France.
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45
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Tai N, Wong FS, Wen L. The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes. J Autoimmun 2016; 71:26-34. [PMID: 27021275 DOI: 10.1016/j.jaut.2016.03.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Accepted: 03/12/2016] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cell mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or Nod-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease.
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Affiliation(s)
- Ningwen Tai
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, USA
| | - F Susan Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, USA.
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46
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Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol 2015; 15:771-83. [PMID: 26567920 PMCID: PMC5079184 DOI: 10.1038/nri3919] [Citation(s) in RCA: 229] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this Opinion article, we discuss the function of tissues as a crucial checkpoint for the regulation of effector T cell responses, and the notion that interleukin-15 (IL-15) functions as a danger molecule that communicates to the immune system that the tissue is under attack and poises it to mediate tissue destruction. More specifically, we propose that expression of IL-15 in tissues promotes T helper 1 cell-mediated immunity and provides co-stimulatory signals to effector cytotoxic T cells to exert their effector functions and drive tissue destruction. Therefore, we think that IL-15 contributes to tissue protection by promoting the elimination of infected cells but that when its expression is chronically dysregulated, it can promote the development of complex T cell-mediated disorders associated with tissue destruction, such as coeliac disease and type 1 diabetes.
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Affiliation(s)
- Bana Jabri
- Departments of Medicine, Pathology and Pediatrics, University of Chicago, Knapp Center for Biomedical Discovery (KCBD), Chicago, Illinois 60637, USA
| | - Valérie Abadie
- Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada
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47
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Nakashima H, Nguyen T, Chiocca EA. Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy. Oncolytic Virother 2015; 4:183-91. [PMID: 27512681 PMCID: PMC4918398 DOI: 10.2147/ov.s66081] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.
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Affiliation(s)
- Hiroshi Nakashima
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
| | - Tran Nguyen
- Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
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48
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Gianchecchi E, Fierabracci A. Gene/environment interactions in the pathogenesis of autoimmunity: new insights on the role of Toll-like receptors. Autoimmun Rev 2015; 14:971-983. [PMID: 26184547 DOI: 10.1016/j.autrev.2015.07.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 07/08/2015] [Indexed: 12/17/2022]
Abstract
Autoimmune disorders are increasing worldwide. Although their pathogenesis has not been elucidated yet, a complex interaction of genetic and environmental factors is involved in their onset. Toll-like receptors (TLRs) represent a family of pattern recognition receptors involved in the recognition and in the defense of the host from invading microorganisms. They sense a wide range of pathogen associated molecular patterns (PAMPs) deriving from metabolic pathways selective of bacterial, viral, fungal and protozoan microorganisms. TLR activation plays a critical role in the activation of the downstream signaling pathway by interacting and recruiting several adaptor molecules. Although TLRs are involved in the protection of the host, several studies suggest that, in certain conditions, they play a critical role in the pathogenesis of autoimmune diseases. We review the most recent advances showing a correlation between some single nucleotide polymorphisms or copy number variations in TLR genes or in adaptor molecules involved in TLR signaling and the onset of several autoimmune conditions, such as Type I diabetes, autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. In light of the foregoing we finally propose that molecules involved in TLR pathway may represent the targets for novel therapeutic treatments in order to stop autoimmune processes.
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Affiliation(s)
- Elena Gianchecchi
- Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Vismederi Srl, Siena, Italy
| | - Alessandra Fierabracci
- Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
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Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest 2015; 125:4135-48. [PMID: 26457731 DOI: 10.1172/jci80477] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 09/03/2015] [Indexed: 12/12/2022] Open
Abstract
Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.
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50
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Pearson JA, Wong FS, Wen L. The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun 2015; 66:76-88. [PMID: 26403950 DOI: 10.1016/j.jaut.2015.08.019] [Citation(s) in RCA: 196] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 08/26/2015] [Indexed: 02/06/2023]
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non-Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mouse and the development of humanized NOD mice, providing novel insights into human T1D.
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Affiliation(s)
- James A Pearson
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA
| | - F Susan Wong
- Diabetes Research Group, Institute of Molecular & Experimental Medicine, School of Medicine, Cardiff University, Wales, UK
| | - Li Wen
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA.
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