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1
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Svensson M, Limeres MJ, Zeyn Y, Gambaro RC, Islan GA, Berti IR, Fraude-El Ghazi S, Pretsch L, Hilbert K, Schneider P, Kaps L, Bros M, Gehring S, Cacicedo ML. mRNA-LNP vaccine strategies: Effects of adjuvants on non-parenchymal liver cells and tolerance. Mol Ther Methods Clin Dev 2025; 33:101427. [PMID: 40027262 PMCID: PMC11872076 DOI: 10.1016/j.omtm.2025.101427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 01/31/2025] [Indexed: 03/05/2025]
Abstract
The liver, which plays pivotal roles in metabolism and immunity, often confers tolerance, suppressing immune responses to pathogens. Adjuvanted, lipid nanoparticle-encapsulated mRNA vaccines (mRNA-LNPs) offer a promising approach to overcome immune tolerance. In this study, the immunostimulatory activity of well-documented adjuvants, i.e., 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C), on non-parenchymal liver cells was determined. When co-applied with mRNA-loaded LNPs, these adjuvants enhanced immune responses at variable extents. Moreover, the efficiency of mRNA translation in the presence of cGAMP was comparable with the non-adjuvanted control. Repetitive co-application of adjuvants with mRNA-LNPs showed improvement in cellular responses when R848 or R848/cGAMP treatments were used. These findings emphasize the need to delineate the delicate balance between immunomodulatory properties and the efficiency of mRNA translation when selecting adjuvants for mRNA-LNP vaccines and offer insights on how to enhance immunity to infectious diseases and cancers that affect the liver.
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Affiliation(s)
- Malin Svensson
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - María José Limeres
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Yanira Zeyn
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Rocio C. Gambaro
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - German A. Islan
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Ignacio Rivero Berti
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Silvia Fraude-El Ghazi
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Leah Pretsch
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Katja Hilbert
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Paul Schneider
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Leonard Kaps
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
- Department of Medicine II Saarland University Medical Center Saarland University 66421 Homburg, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Stephan Gehring
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Maximiliano L. Cacicedo
- Children’s Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
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2
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Singer M, Elsayed AM, Husseiny MI. Regulatory T-cells: The Face-off of the Immune Balance. FRONT BIOSCI-LANDMRK 2024; 29:377. [PMID: 39614434 DOI: 10.31083/j.fbl2911377] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/29/2024] [Accepted: 08/13/2024] [Indexed: 12/01/2024]
Abstract
Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring a balanced immune response. Tregs primarily operate in an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. Tregs have been studied extensively, from their point of origin in the thymus origin to their fate in the periphery or organs. Signals received from antigen-presenting cells (APCs) stimulate Tregs to dampen inflammation. Almost all tumors are characterized by a pathological abundance of immune suppression in their microenvironment. Conversely, the lack thereof proves detrimental to immunological disorders. Achieving a balanced expression of Tregs in relation to other immune compartments is important in establishing an effective and adaptable immune tolerance towards cancer cells and autoantigens. In the context of cancer, it is essential to decrease the frequency of Tregs to overcome tumor suppression. A lower survival rate is associated with the presence of excessive exhausted effector immune cells and an increased frequency of regulatory cells. However, when it comes to treating graft rejection and autoimmune diseases, the focus lies on immune tolerance and the transfer of Tregs. Here, we explore the complex mechanisms that Tregs use in human disease to balance effector immune cells.
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Affiliation(s)
- Mahmoud Singer
- School of Medicine, University of California Irvine, Irvine, CA 92617, USA
| | - Ahmed M Elsayed
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Mohamed I Husseiny
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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3
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De Groot AS, Khan S, Mattei AE, Lelias S, Martin WD. Does human homology reduce the potential immunogenicity of non-antibody scaffolds? Front Immunol 2023; 14:1215939. [PMID: 38022550 PMCID: PMC10664710 DOI: 10.3389/fimmu.2023.1215939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on 'natural' protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of "non-antibody" scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T "helper" epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.
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Affiliation(s)
- Anne S. De Groot
- EpiVax, Providence, RI, United States
- University of Georgia, Center for Vaccines and Immunology, Athens, GA, United States
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4
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Chen Q, Benamar M, Chan TMF, Wang M, Chatila TA. CPHEN-014: Comprehensive phenotyping of mouse regulatory T cells relevant to viral infections. Cytometry A 2022; 101:1000-1005. [PMID: 35593538 DOI: 10.1002/cyto.a.24655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/06/2022] [Accepted: 05/05/2022] [Indexed: 01/27/2023]
Abstract
Regulatory T (Treg) cells are a specialized subpopulation of CD4+ T cells that enforce peripheral immune tolerance. Treg cells act to suppress exuberant immune responses, limit inflammation, and promote tissue repair, thereby maintaining homeostasis and tolerance to self-antigens and those of the commensal microbial flora. Treg cells are characterized by the expression of the master regulator Foxp3, which plays a major role in Treg cells development and function. Under inflammatory conditions, Foxp3+ Treg cells may acquire effector T cell programs that modify their phenotype and function, reflecting their plasticity. During microbial infections, Treg cells act to limit the immunopathology triggered by the host immune response to pathogens albeit at the potential risk of pathogen persistence. In this review, we will discuss the influence of Treg cells on the outcome of viral infection and will give an overview of the Treg phenotype at steady-state and in inflammatory conditions.
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Affiliation(s)
- Qian Chen
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Tsz Man Fion Chan
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Muyun Wang
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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5
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Hann A, Oo YH, Perera MTPR. Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease. Front Immunol 2021; 12:719954. [PMID: 34721383 PMCID: PMC8552037 DOI: 10.3389/fimmu.2021.719954] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/24/2021] [Indexed: 12/29/2022] Open
Abstract
The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological "braking" mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells' function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Ye H Oo
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Disease (ERN-Rare Liver Centre), University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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6
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Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis. J Fungi (Basel) 2021; 7:jof7080656. [PMID: 34436195 PMCID: PMC8398010 DOI: 10.3390/jof7080656] [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: 06/15/2021] [Revised: 07/30/2021] [Accepted: 08/07/2021] [Indexed: 11/17/2022] Open
Abstract
The existence of a hyperinflammatory state has been observed in patients with invasive fungal infections (IFI). It is being postulated whether morbidity from IFI may, in part, be a consequence of an unnecessarily prolonged or exaggerated proinflammatory immune response including interleukin 6 (IL-6) post-infection, in a host with dysregulated or compromised immunity. This, in turn, induces collateral host injury at the tissue and organ level, leading to adverse outcomes. Tocilizumab has become widely used as an immunomodulator in the treatment of inflammatory conditions. Here, we evaluated the use of tocilizumab to curb post-infective inflammatory flare in the setting of an in-vivo mouse model for invasive candidiasis. Following Candida infection, the tocilizumab-treated mice showed improved short-term survival compared with the saline-treated control mice. There was a reduced inflammatory response mounted by the host, coupled with reduced IL-6 but increased IL-10 levels. TNF-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ conventional dendritic cells (DCs) and peripheral T-regulatory cells, over CD11b+ conventional DCs and plasmacytoid DCs. We demonstrate here the sequelae from immunomodulatory manipulation and the basis whereby the use of monoclonal antibodies may be further explored in IFI.
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7
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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8
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Drescher HK, Bartsch LM, Weiskirchen S, Weiskirchen R. Intrahepatic T H17/T Reg Cells in Homeostasis and Disease-It's All About the Balance. Front Pharmacol 2020; 11:588436. [PMID: 33123017 PMCID: PMC7566778 DOI: 10.3389/fphar.2020.588436] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/15/2020] [Indexed: 12/14/2022] Open
Abstract
Both acute and chronic hepatic inflammation likely result from an imbalance in the TH1/TH2 cell response and can lead to liver fibrosis and end-stage liver disease. More recently, a novel CD4+ T helper cell subset was described, characterized by the production of IL-17 and IL-22. These TH17 cells 50were predominantly implicated in host defense against infections and in autoimmune diseases. Interestingly, studies over the last 10 years revealed that the development of TH17 cells favors pro-inflammatory responses in almost all tissues and there is a reciprocal relationship between TH17 and TReg cells. The balance between TH17and TReg cells is critical for immune reactions, especially in injured liver tissue and the return to immune homeostasis. The pathogenic contribution of TH17 and TReg cells in autoimmunity, acute infection, and chronic liver injury is diverse and varies among disease etiologies. Understanding the mechanisms underlying TH17 cell development, recruitment, and maintenance, along with the suppression of TReg cells, will inform the development of new therapeutic strategies in liver diseases. Active manipulation of the balance between pathogenic and regulatory processes in the liver may assist in the restoration of homeostasis, especially in hepatic inflammation.
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Affiliation(s)
- Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen, Aachen, Germany
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9
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Egarnes B, Gosselin J. Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection. Front Immunol 2018; 9:132. [PMID: 29445379 PMCID: PMC5797787 DOI: 10.3389/fimmu.2018.00132] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 01/26/2023] Open
Abstract
Influenza A virus (IAV) is recognized to cause severe pulmonary illnesses in humans, particularly in elderly and children. One of the features associated with IAV infection is an excessive lung inflammation due to an uncontrolled immune response. The nucleotide-binding oligomerization domain 2 (NOD2) receptor is known to recognize ssRNA viruses such as IAV, but its role in the inflammatory process during viral infections remains to be clarified. In a previous report, we have shown that activation of NOD2 with muramyl dipeptide (MDP) significantly reduces both viral loads and lung inflammation and also improves pulmonary function during IAV infection. These findings prompted us to further investigate whether NOD2 receptor may contribute to regulate inflammation during viral infection. In the present study, we show that administration of MDP to mice infected with IAV stimulates the migration of regulatory T (Treg) cells to the lungs. Such a presence of Treg cells was also accompanied with a reduction of neutrophils in the lungs during IAV infection, which correlated, with a significant decrease of Th17 cells. In our model, Treg cell recruitment is dependent of CXCL12 and CCL5 chemokines. Moreover, we show that the presence of Ly6Clow patrolling monocytes is required for Treg cells mobilization to the lung of mice treated with MDP. In fact, following monocyte depletion by administration of clodronate liposome, mobilization of Treg cells to the lungs of treated mice was found to occur when circulating Ly6Clow monocytes begin to reemerge. In addition, we also detected an increased production of TGF-β, a cytokine contributing to Treg activity when blood Ly6Clow monocytes are restored. Together, our results demonstrate that MDP treatment can promote an anti-inflammatory environment through the mobilization of Treg cells to the lung, a mechanism that requires the presence of Ly6Clow monocytes during IAV infection. Overall, our results suggest that activation of NOD2 receptor could be an appealing approach to control pulmonary inflammation in patients infected with IAV.
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Affiliation(s)
- Benoit Egarnes
- Laboratory of Innate Immunology, Centre de recherche du CHU de Québec-Université Laval, Université Laval, Quebec City, QC, Canada
| | - Jean Gosselin
- Laboratory of Innate Immunology, Centre de recherche du CHU de Québec-Université Laval, Université Laval, Quebec City, QC, Canada.,Department of Molecular Medicine, Université Laval, Quebec City, QC, Canada
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10
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Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans.
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Affiliation(s)
- Jijing Shi
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | - Yuanyuan Li
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | | | - Xuexiu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 460000, China
| | - Fu-Sheng Wang
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
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11
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Fast LD, Mishra S, Promrat K, Losikoff PT, Gregory SH. Viral epitope-specific T cell responses induced in chronic, hepatitis C virus-infected patients. Dig Liver Dis 2017; 49:709-713. [PMID: 28256402 DOI: 10.1016/j.dld.2017.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Approximate 180 million people worldwide are infected with hepatitis C virus (HCV). Historically, vaccination has been the most effective strategy for controlling infections of such major health concern. Therapeutic vaccine strategies for HCV, however, have demonstrated negligible success. AIM Demonstrate the ability of highly-conserved viral epitopes to overcome the immune dysfunction often associated with chronic HCV infections. METHODS T cells from five chronic, HCV-infected patients were immunophenotyped by flow cytometry. The ex vivo T cell responses to highly-conserved viral epitopes were assessed by ELISpot assay and cytokine bead array analysis. RESULTS Both HLA-DRB-1- and HLA-A2-restricted viral epitopes induced specific, TH1-type cytokine production by T cells derived from the patients. Induction occurred despite expression of cell-surface inhibitory molecules and the presence of regulatory T cells. CONCLUSION These findings support the potential ability of a broad, multi-epitope-based therapeutic vaccine to elicit virus-specific immune responses in chronic hepatitis C virus-infected patients.
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Affiliation(s)
- Loren D Fast
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Sasmita Mishra
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Kittichai Promrat
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Stephen H Gregory
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States.
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12
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Sehrawat S, Rouse BT. Interplay of Regulatory T Cell and Th17 Cells during Infectious Diseases in Humans and Animals. Front Immunol 2017; 8:341. [PMID: 28421070 PMCID: PMC5377923 DOI: 10.3389/fimmu.2017.00341] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 03/09/2017] [Indexed: 12/14/2022] Open
Abstract
It is now clear that the outcome of an inflammatory process caused by infections depends on the balance of responses by several components of the immune system. Of particular relevance is the interplay between regulatory T cells (Tregs) and CD4+ T cells that produce IL-17 (Th17 cells) during immunoinflammatory events. In addition to discussing studies done in mice to highlight some unresolved issues in the biology of these cells, we emphasize the need to include outbred animals and humans in analyses. Achieving a balance between Treg and Th17 cells responses represents a powerful approach to control events during immunity and immunopathology.
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Affiliation(s)
- Sharvan Sehrawat
- Indian Institute of Science Education and Research Mohali, Mohali, Punjab, India
| | - Barry T Rouse
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA
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13
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Hartling HJ, Ballegaard VC, Nielsen NS, Gaardbo JC, Nielsen SD. Immune regulation in chronic hepatitis C virus infection. Scand J Gastroenterol 2016; 51:1387-97. [PMID: 27436030 DOI: 10.3109/00365521.2016.1170875] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The immunological result of infection with Hepatitis C virus (HCV) depends on the delicate balance between a vigorous immune response that may clear the infection, but with a risk of unspecific inflammation and, or a less inflammatory response that leads to chronic infection. In general, exhaustion and impairment of cytotoxic function of HCV-specific T cells and NK cells are found in patients with chronic HCV infection. In contrast, an increase in immune regulatory functions is found primarily in form of increased IL-10 production possibly due to increased level and function of anti-inflammatory Tregs. Thus, the major immune players during chronic HCV infection are characterized by a decrease of cytotoxic function and increase of inhibitory functions. This may be an approach to diminish intrahepatic and systemic inflammation. Finally, there has been increasing awareness of regulatory functions of epigenetic changes in chronic HCV infection. A vast amount of studies have revealed the complexity of immune regulation in chronic HCV infection, but the interplay between immune regulation in virus and host remains incompletely understood. This review provides an overview of regulatory functions of HCV-specific T cells, NK cells, Tregs, IL-10, and TGF-β, as well as epigenetic changes in the setting of chronic HCV infection.
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Affiliation(s)
- Hans Jakob Hartling
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Vibe Cecilie Ballegaard
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Nick Schou Nielsen
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Julie Christine Gaardbo
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Susanne Dam Nielsen
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
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Diagnostic performance of T lymphocyte subpopulations in assessment of liver fibrosis stages in hepatitis C virus patients: simple noninvasive score. Eur J Gastroenterol Hepatol 2016; 28:931-9. [PMID: 27159125 DOI: 10.1097/meg.0000000000000656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND/AIMS Evaluation of liver fibrosis in patients infected with hepatitis C virus is highly useful for the diagnosis of the disease as well as therapeutic decision. Our aim was to develop and validate a simple noninvasive score for liver fibrosis staging in chronic hepatitis C (CHC) patients and compare its performance against three published simple noninvasive indexes. MATERIALS AND METHODS CHC patients were divided into two groups: an estimated group (n=70) and a validated group (n=52). Liver fibrosis was tested in biopsies using the Metavair score system. CD4 and CD8 count/percentage were assayed by fluorescence-activated cell sorting analysis. RESULTS The multivariate discriminant analysis selects a function on the basis of absolute values of five biochemical markers: immune fibrosis index (IFI); score=3.07+3.06×CD4/CD8+0.02×α-fetoprotein (U/l)-0.07×alanine aminotransferase ratio-0.005×platelet count (10/l)-1.4×albumin (g/dl). The IFI score produced areas under curve of 0.949, 0.947, and 0.806 for differentiation of all patient categories [significant fibrosis (F2-F4), advanced fibrosis (F3-F4), and cirrhosis (F4)]. CONCLUSION The IFI score, a novel noninvasive test, can be used easily for the prediction of liver fibrosis stage in CHC patients. Our score was more efficient than aspartate aminotransferase to platelet ratio index, fibrosis index, and fibroQ and more suitable for use in Egyptian hepatitis C virus patients.
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15
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HCV-Induced Oxidative Stress: Battlefield-Winning Strategy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7425628. [PMID: 27293514 PMCID: PMC4880679 DOI: 10.1155/2016/7425628] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 04/21/2016] [Accepted: 04/26/2016] [Indexed: 02/08/2023]
Abstract
About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). The persistence of the infection is controlled by several mechanisms including the induction of oxidative stress. HCV relies on this strategy to redirect lipid metabolism machinery and escape immune response. The 3β-hydroxysterol Δ24-reductase (DHCR24) is one of the newly discovered host markers of oxidative stress. This protein, as HCV-induced oxidative stress responsive protein, may play a critical role in the pathogenesis of HCV chronic infection and associated liver diseases, when aberrantly expressed. The sustained expression of DHCR24 in response to HCV-induced oxidative stress results in suppression of nuclear p53 activity by blocking its acetylation and increasing its interaction with MDM2 in the cytoplasm leading to its degradation, which may induce hepatocarcinogenesis.
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Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE, Shata MTM. Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 2016; 65:703-712. [PMID: 27166142 DOI: 10.1099/jmm.0.000272] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.
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Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud I Nassar
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
| | - Mohamed Tarek M Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
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17
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Castellaneta A, Massaro A, Rendina M, D'Errico F, Carparelli S, Rizzi SF, Thomson AW, Di Leo A. Immunomodulating effects of the anti-viral agent Silibinin in liver transplant patients with HCV recurrence. Transplant Res 2016; 5:1. [PMID: 26798454 PMCID: PMC4721199 DOI: 10.1186/s13737-016-0030-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 01/05/2016] [Indexed: 01/27/2023] Open
Abstract
Background Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Methods Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student’s t test and Pearson correlation test. Results After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. Conclusions This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.
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Affiliation(s)
- Antonino Castellaneta
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Antonio Massaro
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Maria Rendina
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Francesca D'Errico
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Sonia Carparelli
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Salvatore Fabio Rizzi
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA
| | - Angus W Thomson
- Department of Emergency and Organ Transplantation, Unit of Gastroenterology, University Hospital, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Alfredo Di Leo
- Department of Emergency and Organ Transplantation, Unit of Gastroenterology, University Hospital, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
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18
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Puck A, Aigner R, Modak M, Cejka P, Blaas D, Stöckl J. Expression and regulation of Schlafen (SLFN) family members in primary human monocytes, monocyte-derived dendritic cells and T cells. RESULTS IN IMMUNOLOGY 2015; 5:23-32. [PMID: 26623250 PMCID: PMC4625362 DOI: 10.1016/j.rinim.2015.10.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 08/26/2015] [Accepted: 10/14/2015] [Indexed: 12/03/2022]
Abstract
Schlafen (SLFN/Slfn) family members have been investigated for their involvement in fundamental cellular processes including growth regulation, differentiation and control of viral replication. However, most research has been focused on the characterization of Slfns within the murine system or in human cell lines. Since little is known about SLFNs in primary human immune cells, we set out to analyze the expression and regulation of the six human SLFN genes in monocytes, monocyte-derived dendritic cells (moDCs) and T cells. Comparison of SLFN gene expression across these three cell types showed high mRNA expression of SLFN11 in monocytes and moDCs and high SLFN5 expression in T cells, indicating functional importance within these cell types. Differentiation of monocytes to moDCs leads to the gradual upregulation of SLFN12L and SLFN13 while SLFN12 levels were decreased by differentiation stimuli. Stimulation of moDCs via human rhinovirus, lipopolysaccharide, or IFN-α lead to strong upregulation of SLFN gene expression, while peptidoglycan poorly stimulated regulation of both SLFNs and the classical interferon-stimulated gene MxA. T cell activation was found to downregulate the expression of SLFN5, SLFN12 and SLFN12L, which was reversible upon addition of exogenous IFN-α. In conclusion, we demonstrate, that SLFN gene upregulation is mainly dependent on autocrine type I interferon signaling in primary human immune cells. Rapid decrease of SLFN expression levels following T cell receptor stimulation indicates a role of SLFNs in the regulation of human T cell quiescence.
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Affiliation(s)
- Alexander Puck
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Regina Aigner
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Madhura Modak
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Petra Cejka
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Dieter Blaas
- Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, Medical University of Vienna, Vienna, Austria
| | - Johannes Stöckl
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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De Groot AS, Moise L, Liu R, Gutierrez AH, Tassone R, Bailey-Kellogg C, Martin W. Immune camouflage: relevance to vaccines and human immunology. Hum Vaccin Immunother 2015; 10:3570-5. [PMID: 25483703 PMCID: PMC4514035 DOI: 10.4161/hv.36134] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
High strain sequence variability, interference with innate immune mechanisms, and epitope deletion are all examples of strategies that pathogens have evolved to subvert host defenses. To this list we would add another strategy: immune camouflage. Pathogens whose epitope sequences are cross-conserved with multiple human proteins at the TCR-facing residues may be exploiting “ignorance and tolerance," which are mechanisms by which mature T cells avoid immune responses to self-antigens. By adopting amino acid configurations that may be recognized by autologous regulatory T cells, pathogens may be actively suppressing protective immunity. Using the new JanusMatrix TCR-homology-mapping tool, we have identified several such ‘camouflaged’ tolerizing epitopes that are present in the viral genomes of pathogens such as emerging H7N9 influenza. Thus in addition to the overall low number of T helper epitopes that is present in H7 hemaglutinin (as described previously, see http://dx.doi.org/10.4161/hv.24939), the presence of such tolerizing epitopes in H7N9 could explain why, in recent vaccine trials, whole H7N9-HA was poorly immunogenic and associated with low seroconversion rates (see http://dx.doi.org/10.4161/hv.28135). In this commentary, we provide an overview of the immunoinformatics process leading to the discovery of tolerizing epitopes in pathogen genomic sequences, provide a brief summary of laboratory data that validates the discovery, and point the way forward. Removal of viral, bacterial and parasite tolerizing epitopes may permit researchers to develop more effective vaccines and immunotherapeutics in the future.
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Key Words
- Biologic
- Deimmunization
- EpiMatrix
- HA, hemagglutinin
- HCV, Hepatitis C virus
- HIV, human immunodeficiency virus
- HLA, human leukocyte antigen
- IAVs, influenza A viruses
- JanusMatrix
- TCR, T cell receptor
- Td response, T cell-driven response
- Tolerance
- Treg
- Treg, regulatory T cell
- Tregitope
- Tregitope, Treg epitope
- Vaccine
- nTreg, natural regulatory T cells
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20
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Monocyte-derived dendritic cells in children with chronic hepatitis C: correlation with interferon and ribavirin therapy. Eur J Gastroenterol Hepatol 2015; 27:1170-4. [PMID: 26148246 DOI: 10.1097/meg.0000000000000422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a major health problem worldwide. Defective dendritic cell (DC) activation of T cells may underlie poor T-cell responsiveness in HCV infection. OBJECTIVE To evaluate the DCs' functions in chronically infected HCV patients and its correlation with the response to therapy. PATIENTS AND METHODS This prospective study included 30 chronic hepatitis C (CHC) patients and 30 healthy age-matched and sex-matched controls. The first group received combined pegylated interferon-α-2b (Peg-IFN-α2b)/ribavirin therapy for 48 weeks. A quantitative HCV-RNA PCR was performed for all patients before treatment and at 12, 24, 48, and 24 weeks after treatment. To clarify the functions of DCs, we induced maturation of peripheral DCs from blood samples of CHC patients and healthy controls using Resiquimod (R848). The functions of DCs were assessed by measurement of the levels of IFN-γ and interleukin-10 (IL-10). RESULTS Sixteen (53.3%) of the patients were treatment responders and the other 14 (46.4%) were nonresponders. The current study showed a statistically significant difference between CHC patients and the control group in IFN-γ production, which was higher in the control group (1.53±0.38 IU/ml) than in the CHC patients (1.19±0.21 IU/ml); in contrast, IL-10 was higher in CHC (249.4±27.6 pg/ml) than the control group (217.0±29.9 pg/ml). However, there was no significant difference between treatment responders and nonresponders in both IFN-γ and IL-10 levels. CONCLUSION HCV infection is associated with impaired production of IFN-γ, which may be an indication of a defect in DC function.
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21
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Abdel-Latif MS. Plasma Levels of Matrix Metalloproteinase (MMP)-2, MMP-9 and Tumor Necrosis Factor-α in Chronic Hepatitis C Virus Patients. Open Microbiol J 2015; 9:136-40. [PMID: 26464613 PMCID: PMC4598372 DOI: 10.2174/1874285801509010136] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 02/27/2015] [Accepted: 03/02/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND In chronic HCV infection, pathological accumulation of the extracellular matrix is the main feature of liver fibrosis; that indicates the imbalanced rate of increased matrix synthesis to decreased breakdown of connective tissue proteins. Matrix metalloproteinases (MMPs) play a crucial role in remodeling of extracellular matrix. It is known that expression of MMPs is regulated by Tumor necrosis factor (TNF)-α. Also, levels of TNF-α in liver and serum are increased in chronic HCV patient. Accordingly, this study aimed to correlate the plasma levels of MMP-2, MMP-9 and TNF-α in chronic HCV patients with the pathogenesis of the liver. METHODS The current study was conducted on 15 fibrotic liver cases with detectable HCV RNA, 10 HCV cirrhotic liver cases, and 15 control subjects of matched age and sex. Plasma MMP-2, MMP-9 and TNF-α were measured by ELISA. RESULTS Data revealed that the MMP2, MMP9 and TNF-α levels showed a significant elevation in chronic HCV patients compared to control group (p= 0.001). But, no significant correlation was observed in levels of MMP-2, MMP-9, and TNF-α between fibrotic and cirrhotic cases. CONCLUSIONS MMP-2, MMP-9 and TNF-α showed high reproducibility to differentiate chronic HCV patients from control group. On the contrary, MMP-2, MMP-9 and TNF-α were not able to differentiate fibrotic from cirrhotic liver cases. Thus, MMP-2, MMP-9 and TNF-α could not be correlated with the progression of liver disease. Rather they could be used as prognostic markers of liver fibrosis.
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Affiliation(s)
- Mohamed S Abdel-Latif
- Department of Medical Laboratory Technology, Faculty of Allied Medical Science, Pharos University in Alexandria, Egypt
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22
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Zhang W, Nilles TL, Johnson JR, Margolick JB. Regulatory T Cells, Frailty, and Immune Activation in Men Who Have Sex With Men in the Multicenter AIDS Cohort Study. J Gerontol A Biol Sci Med Sci 2015; 70:1533-41. [PMID: 26297938 DOI: 10.1093/gerona/glv132] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 07/14/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Both HIV infection and frailty have been associated with chronic immune activation. One possible explanation for this chronic immune activation could be low levels of CD4(+) T regulatory cells (Tregs), which suppress immune responses. METHODS HIV-uninfected (HIV-) and HIV-infected (HIV+) men in the Multicenter AIDS Cohort Study (MACS) were classified as frail (or nonfrail) if they expressed (or did not express) the Fried frailty phenotype at two consecutive study visits. Percentages and absolute numbers of total Tregs, and percentages of different subsets of Tregs and of activated T cells were measured by flow cytometry. The function of Tregs was measured by suppression of T-cell proliferation. RESULTS Percentages of Tregs were higher, rather than lower, in frail men than in nonfrail men, and this difference was significant for HIV- men. Percentages of subsets of Tregs did not differ significantly by frailty status. Among HIV+ men, the suppressive function of Tregs was similar between frail and nonfrail men. Percentages of Tregs and activated T cells were negatively correlated in nonfrail men (HIV- and HIV+) and in frail HIV- men, but this correlation was strongly positive in frail HIV+ men. CONCLUSION These data suggest that: (a) Tregs were not deficient in frail men; and (b) the immunological pathophysiology of frailty may differ by HIV status.
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Affiliation(s)
- Weiying Zhang
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Tricia L Nilles
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jacquett R Johnson
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Joseph B Margolick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
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Schulz S, Landi A, Garg R, Wilson JA, van Drunen Littel-van den Hurk S. Indolamine 2,3-dioxygenase expression by monocytes and dendritic cell populations in hepatitis C patients. Clin Exp Immunol 2015; 180:484-98. [PMID: 25605587 DOI: 10.1111/cei.12586] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 12/31/2014] [Accepted: 01/09/2015] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) play an important role in the induction of the primary immune response to infection. DCs may express the tryptophan-catabolizing enzyme indolamine2,3-dioxygenase (IDO), which is an inducer of immune tolerance. Because there is evidence that chronic hepatitis C virus (HCV) infection leads to functional impairment of certain DC populations, we analysed IDO expression in DCs and monocytes from chronically infected and recovered HCV patients. The IDO1 and -2 expression was increased significantly in the monocytes of chronic HCV patients but, interestingly, not in those from recovered patients. The myeloid DCs from chronically infected HCV patients also showed enhanced IDO1 expression, while no change in either IDO1 or -2 was found for plasmacytoid DCs. Up-regulation of IDO1 gene expression was confirmed by the presence of enhanced kynurenine/tryptophan ratios in the plasma from chronic HCV patients. Increased IDO1 and -2 expression was also observed in monocytes from healthy donors infected with an adapted mutant of the HCV JFH-1 strain ex vivo, confirming a direct effect of HCV infection. These changes in IDO expression could be prevented by treatment with the IDO inhibitor 1-methyl tryptophan (1-mT). Furthermore, maturation of monocyte-derived DCs from chronically infected HCV patients, as well as well as monocyte-derived DCs infected ex vivo with HCV, was impaired, but this was reversed by 1-mT treatment. This suggests that IDO inhibitors may be used to treat chronic HCV patients in vivo, in conjunction with current therapies, or to activate DCs from patients ex vivo, such that they can be administered back as a DC-based therapeutic vaccine.
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Affiliation(s)
- S Schulz
- VIDO-InterVac, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - A Landi
- Li Ka Shing Institute of Virology, Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - R Garg
- VIDO-InterVac, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - J A Wilson
- Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - S van Drunen Littel-van den Hurk
- VIDO-InterVac, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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24
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Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis. J Immunol Res 2015; 2015:479703. [PMID: 26106627 PMCID: PMC4464004 DOI: 10.1155/2015/479703] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 05/21/2015] [Indexed: 12/26/2022] Open
Abstract
In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. .
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25
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Boer MC, Joosten SA, Ottenhoff THM. Regulatory T-Cells at the Interface between Human Host and Pathogens in Infectious Diseases and Vaccination. Front Immunol 2015; 6:217. [PMID: 26029205 PMCID: PMC4426762 DOI: 10.3389/fimmu.2015.00217] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 04/20/2015] [Indexed: 12/20/2022] Open
Abstract
Regulatory T-cells (Tregs) act at the interface of host and pathogen interactions in human infectious diseases. Tregs are induced by a wide range of pathogens, but distinct effects of Tregs have been demonstrated for different pathogens and in different stages of infection. Moreover, Tregs that are induced by a specific pathogen may non-specifically suppress immunity against other microbes and parasites. Thus, Treg effects need to be assessed not only in homologous but also in heterologous infections and vaccinations. Though Tregs protect the human host against excessive inflammation, they probably also increase the risk of pathogen persistence and chronic disease, and the possibility of disease reactivation later in life. Mycobacterium leprae and Mycobacterium tuberculosis, causing leprosy and tuberculosis, respectively, are among the most ancient microbes known to mankind, and are master manipulators of the immune system toward tolerance and pathogen persistence. The majority of mycobacterial infections occur in settings co-endemic for viral, parasitic, and (other) bacterial coinfections. In this paper, we discuss recent insights in the activation and activity of Tregs in human infectious diseases, with emphasis on early, late, and non-specific effects in disease, coinfections, and vaccination. We highlight mycobacterial infections as important models of modulation of host responses and vaccine-induced immunity by Tregs.
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Affiliation(s)
- Mardi C Boer
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
| | - Simone A Joosten
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
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26
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Losikoff PT, Mishra S, Terry F, Gutierrez A, Ardito MT, Fast L, Nevola M, Martin WD, Bailey-Kellogg C, De Groot AS, Gregory SH. HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients. J Hepatol 2015; 62:48-55. [PMID: 25157982 DOI: 10.1016/j.jhep.2014.08.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 07/14/2014] [Accepted: 08/17/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Spontaneous resolution of hepatitis C virus (HCV) infection depends upon a broad T cell response to multiple viral epitopes. However, most patients fail to clear infections spontaneously and develop chronic disease. The elevated number and function of CD3(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg)) in HCV-infected patients suggest a role of Treg cells in impaired viral clearance. The factors contributing to increased Treg cell activity in chronic hepatitis C cases remain to be delineated. METHODS Immunoinformatics tools were used to predict promiscuous, highly-conserved HLA-DRB1-restricted immunogenic consensus sequences (ICS), each composed of multiple T cell epitopes. These sequences were synthesized and added to cultures of peripheral blood mononuclear cells (PBMCs), derived from patients who resolved HCV infection spontaneously, patients with persistent infection, and non-infected individuals. The cells were collected and following 5days incubation, quantified and characterized by flow cytometry. RESULTS One immunogenic consensus sequence (ICS), HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not in patients who spontaneously cleared HCV or in non-infected individuals. An analogous human peptide (p7_794), on the other hand, induced a significant increase in Treg cells among PBMCs derived from both HCV-infected and non-infected individuals. JanusMatrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome. CONCLUSIONS A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3(+)CD4(+)CD25(+)FoxP3(+) natural Treg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C.
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Affiliation(s)
- Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Sasmita Mishra
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | | | - Andres Gutierrez
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | | | - Loren Fast
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Martha Nevola
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | | | | | - Anne S De Groot
- EpiVax, Inc., Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Stephen H Gregory
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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Moise L, Terry F, Gutierrez AH, Tassone R, Losikoff P, Gregory SH, Bailey-Kellogg C, Martin WD, De Groot AS. Smarter vaccine design will circumvent regulatory T cell-mediated evasion in chronic HIV and HCV infection. Front Microbiol 2014; 5:502. [PMID: 25339942 PMCID: PMC4186478 DOI: 10.3389/fmicb.2014.00502] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/08/2014] [Indexed: 01/17/2023] Open
Abstract
Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4(+) and CD8(+) T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4(+) T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.
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Affiliation(s)
- Leonard Moise
- EpiVax, Inc., Providence, RI, USA
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | | | - Andres H. Gutierrez
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Ryan Tassone
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Phyllis Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, RI, USA
| | | | | | | | - Anne S. De Groot
- EpiVax, Inc., Providence, RI, USA
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
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Valva P, Gismondi MI, Casciato PC, Galoppo M, Lezama C, Galdame O, Gadano A, Galoppo MC, Mullen E, De Matteo EN, Preciado MV. Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection. Clin Microbiol Infect 2014; 20:O998-1009. [PMID: 24942073 DOI: 10.1111/1469-0691.12728] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/23/2014] [Accepted: 06/15/2014] [Indexed: 12/17/2022]
Abstract
Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.
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Affiliation(s)
- P Valva
- Laboratory of Molecular Biology, Pathology Division, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
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Mastroianni CM, Lichtner M, Mascia C, Zuccalà P, Vullo V. Molecular mechanisms of liver fibrosis in HIV/HCV coinfection. Int J Mol Sci 2014; 15:9184-208. [PMID: 24865485 PMCID: PMC4100089 DOI: 10.3390/ijms15069184] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 05/15/2014] [Accepted: 05/15/2014] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.
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Affiliation(s)
- Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Claudia Mascia
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Paola Zuccalà
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
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31
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Terrazzini N, Kern F. Cell-mediated immunity to human CMV infection: a brief overview. F1000PRIME REPORTS 2014; 6:28. [PMID: 24860650 PMCID: PMC4018181 DOI: 10.12703/p6-28] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The cellular immune response to human cytomegalovirus (HCMV) has different components originating from both the adaptive and innate immune systems. There is a significant global interest in understanding how the immune system keeps HCMV under control, in particular with a view to situations where HCMV infection causes severe damage. Such settings include HIV infection, transplantation, and maybe most importantly perinatal medicine, HCMV being a major cause of sometimes catastrophic birth defects. The development of an active HCMV vaccine has proven very difficult but some recent successes raise hope that this might be available in the future. However, adoptive transfer of HCMV-specific T cells has been successfully used to prevent CMV disease after bone marrow transplantation for many years. In fact, the CD8 T cell response has been thought to be the most important effector response, with numerous reports focusing on specific T cell subsets recognizing select peptides in select human leukocyte antigen (HLA) contexts. However, it is becoming increasingly clear now that other cells, first and foremost CD4 T cells, but also gamma/delta (γ/δ) T cells and natural killer cells, are critically involved in the cellular immune response to HCMV. This commentary aims to provide a brief overview of the field.
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Affiliation(s)
- Nadia Terrazzini
- Pathogen Host Interaction Group (PHI), Immunology, Division of Medicine, Brighton and Sussex Medical SchoolBiology Road, Brighton, BN1 9PSUK
| | - Florian Kern
- Pathogen Host Interaction Group (PHI), Immunology, Division of Medicine, Brighton and Sussex Medical SchoolBiology Road, Brighton, BN1 9PSUK
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Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 2014; 146:1193-207. [PMID: 24412289 DOI: 10.1053/j.gastro.2013.12.036] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/22/2013] [Accepted: 12/27/2013] [Indexed: 02/08/2023]
Abstract
The liver has unique immune regulatory functions that promote the induction of tolerance rather than responses to antigens encountered locally. These functions are mediated by local expression of coinhibitory receptors and immunosuppressive mediators that help prevent overwhelming tissue damage. Over the years, we have gained more insight into the local regulatory cues that determine the functional complexity of immune responses regulated locally in the liver. Both the unique hepatic microenvironment and the particular liver sinusoidal cell populations, in addition to hepatocytes, actively modulate immune responses locally in the liver and thereby determine the outcome of hepatic immune responses. This is of high biological and clinical relevance in hepatitis B virus and hepatitis C virus infections, which can cause acute and persistent infections associated with chronic inflammation in humans that eventually progress to cirrhosis and hepatocellular carcinoma. Here, we review current knowledge about the balance between immunity and tolerance in the liver and how this may affect our understanding of the determinants of hepatitis B virus and hepatitis C virus clearance, persistence, and virus-induced liver disease.
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Affiliation(s)
- Percy A Knolle
- Institute of Molecular Immunology, Technische Universität München and Institutes of Molecular Medicine and Experimental Immunology, Universität Bonn, Bonn.
| | - Robert Thimme
- Department of Medicine, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany
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Veiga-Parga T, Sehrawat S, Rouse BT. Role of regulatory T cells during virus infection. Immunol Rev 2014; 255:182-96. [PMID: 23947355 DOI: 10.1111/imr.12085] [Citation(s) in RCA: 177] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The host response to viruses includes multiple cell types that have regulatory function. Most information focuses on CD4(+) regulatory T cells that express the transcription factor Foxp3(+) (Tregs), which are the topic of this review. We explain how viruses through specific and non-specific means can trigger the response of thymus-derived natural Tregs as well as induce Tregs. The latter derive under appropriate stimulation conditions either from uncommitted precursors or from differentiated cells that convert to become Tregs. We describe instances where Tregs appear to limit the efficacy of antiviral protective immunity and other, perhaps more common, immune-mediated inflammatory conditions, where the Tregs function to limit the extent of tissue damage that occurs during a virus infection. We discuss the controversial roles that Tregs may play in the pathogenesis of human immunodeficiency and hepatitis C virus infections. The issue of plasticity is discussed, as this may result in Tregs losing their protective function when present in inflammatory environments. Finally, we mention approaches used to manipulate Treg numbers and function and assess their current value and likely future success to manage the outcome of virus infection, especially those that are responsible for chronic tissue damage.
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Affiliation(s)
- Tamara Veiga-Parga
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
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34
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Schadler KL, Crosby EJ, Zhou AY, Bhang DH, Braunstein L, Baek KH, Crawford D, Crawford A, Angelosanto J, Wherry EJ, Ryeom S. Immunosurveillance by antiangiogenesis: tumor growth arrest by T cell-derived thrombospondin-1. Cancer Res 2014; 74:2171-81. [PMID: 24590059 DOI: 10.1158/0008-5472.can-13-0094] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Recent advances in cancer immunotherapy suggest that manipulation of the immune system to enhance the antitumor response may be a highly effective treatment modality. One understudied aspect of immunosurveillance is antiangiogenic surveillance, the regulation of tumor angiogenesis by the immune system, independent of tumor cell lysis. CD4(+) T cells can negatively regulate angiogenesis by secreting antiangiogenic factors such as thrombospondin-1 (TSP-1). In tumor-bearing mice, we show that a Th1-directed viral infection that triggers upregulation of TSP-1 in CD4(+) and CD8(+) T cells can inhibit tumor angiogenesis and suppress tumor growth. Using bone marrow chimeras and adoptive T-cell transfers, we demonstrated that TSP-1 expression in the T-cell compartment was necessary and sufficient to inhibit tumor growth by suppressing tumor angiogenesis after the viral infection. Our results establish that tumorigenesis can be stanched by antiangiogenic surveillance triggered by an acute viral infection, suggesting novel immunologic approaches to achieve antiangiogenic therapy.
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Affiliation(s)
- Keri L Schadler
- Authors' Affiliations: Department of Cancer Biology, Abramson Family Cancer Research Institute; Department of Microbiology, Institute for Immunology, Perelman School of Medicine; Department of Pathobiology, Veterinary School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Children's Hospital, Boston, Massachusetts; and Department of Molecular and Cellular Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Aguilar-Noriega D, Alvarez-Lajonchere L, Brown E, Santana FL, Dubuisson J, Wychowski C, Guerra I, Martínez-Donato G, Pérez A, Amador-Cañizares Y, Dueñas-Carrera S. A chimeric protein encompassing hepatitis C virus epitopes is able to elicit both humoral and cell-mediated immune responses in mice. Biotechnol Appl Biochem 2014; 61:627-36. [PMID: 24575938 DOI: 10.1002/bab.1223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 02/19/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem. Vaccines against this pathogen are not available and advances in this field are limited because of the high genetic variability of the virus, inaccessibility of animal models, and incomplete definition of immunological correlates of protection. In the present work, a chimeric protein, Eq1, encompassing HCV amino acid regions from structural antigens, was generated. Eq1 was expressed in GC-366 bacterial cells. After cell disruption, Eq1 was purified from the insoluble fraction by sequential steps of differential solubilization and metal chelating affinity chromatography. Eq1 was specifically recognized by anti-HCV positive human sera. Moreover, immunization of BALB/c mice with different doses of Eq1 formulated either in Alum or Freund's incomplete adjuvant elicited both humoral- and cellular-specific immune responses. Doses of 20 µg of Eq1 induced the strongest cell-mediated immune responses and only the formulation of this dose in Alum elicited a neutralizing antibody response against heterologous cell culture HCV. All these data together indicate that Eq1 is immunogenic in mice and might be an interesting component of vaccine candidates against HCV infection.
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36
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Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19:859-68. [PMID: 23836236 DOI: 10.1038/nm.3251] [Citation(s) in RCA: 374] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 05/30/2013] [Indexed: 02/08/2023]
Abstract
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation.
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Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
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37
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Moise L, Gutierrez AH, Bailey-Kellogg C, Terry F, Leng Q, Abdel Hady KM, VerBerkmoes NC, Sztein MB, Losikoff PT, Martin WD, Rothman AL, De Groot AS. The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix. Hum Vaccin Immunother 2013; 9:1577-86. [PMID: 23584251 PMCID: PMC3974887 DOI: 10.4161/hv.24615] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to examine T cell epitope relatedness between pathogens to which humans are exposed (Dengue serotypes, or HCV and Influenza, for example). In Hand-Foot-Mouth disease (HFMD) for example, extensive enterovirus and human microbiome cross-reactivity (and limited cross-reactivity with the human genome) seemingly predicts immunodominance. In contrast, more extensive cross-reactivity with proteins contained in the human genome as compared to the human microbiome was observed for selected Treg epitopes. While it may be impossible to predict all immune response influences, the availability of sequence data from the human genome, the human microbiome, and an array of human pathogens and vaccines has made computationally–driven exploration of the effects of T cell epitope cross-reactivity now possible. This is the first description of JanusMatrix, an algorithm that assesses TCR cross-reactivity that may contribute to a means of predicting the phenotype of T cells responding to selected T cell epitopes. Whether used for explorations of T cell phenotype or for evaluating cross-conservation between related viral strains at the TCR face of viral epitopes, further JanusMatrix studies may contribute to developing safer, more effective vaccines.
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Affiliation(s)
- Leonard Moise
- Institute for Immunology and Informatics; University of Rhode Island; Providence, RI, USA; EpiVax Inc.; Providence, RI USA
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Brownell J, Polyak SJ. Molecular pathways: hepatitis C virus, CXCL10, and the inflammatory road to liver cancer. Clin Cancer Res 2013; 19:1347-52. [PMID: 23322900 DOI: 10.1158/1078-0432.ccr-12-0928] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
An estimated 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is characterized histologically by a persistent immune and inflammatory response that fails to clear HCV from hepatocytes. This response is recruited to the liver, in part, by the chemokine CXCL10, the serum and intrahepatic levels of which have been inversely linked to the outcome of interferon-based therapies for hepatitis C. Bystander tissue damage from this ineffective response is thought to lead to increased hepatocyte turnover and the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, CXCL10 is traditionally viewed as an orchestrator of the angiostatic and antitumor immune response. In this review, we will explore this duality and the pathways by which CXCL10 is produced by hepatocytes during HCV infection, its effects on resident and infiltrating immune cells, and how deregulation of these cell populations within the liver may lead to chronic liver inflammation. We will also discuss potential host-directed therapies to slow or reverse HCV-induced inflammation that leads to fibrosis, cirrhosis, and HCCs.
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Affiliation(s)
- Jessica Brownell
- Pathobiology Program, Department of Global Health, University of Washington, Seattle, Washington 98104, USA
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