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Henriques-Pons A, Vacani-Martins N, dos Santos CDLP, Meuser-Batista M. The liver's dilemma: sensing real danger in a sea of PAMPs: the (arterial) sinusoidal segment theory. Front Immunol 2025; 15:1503063. [PMID: 39931578 PMCID: PMC11808282 DOI: 10.3389/fimmu.2024.1503063] [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: 09/28/2024] [Accepted: 12/30/2024] [Indexed: 02/13/2025] Open
Abstract
The liver is susceptible to viruses and bacterial infections, tumors, and sterile tissue damage, but immunological danger recognition in the liver is highly unconventional. When analyzing innate and adaptive immunity in the organ, the valid concepts that guide danger recognition and immune response in the periphery should be put aside. In the liver, the vascular anatomy is a game changer, as about 80% of the blood that percolates the organ arrives from the hepatic portal vein, draining blood rich in molecules from the intestinal flora. This 24/7 exposure to high amounts of pathogen-associated molecular pattern (PAMPs) molecules results in hepatic immunological tolerance. In the liver, dendritic, Kupffer (KC), liver sinusoidal endothelial cells (LSECs), and even hepatocytes express PD-L1, a T lymphocyte downregulatory molecule. Most cells express Fas-L, IL-10, TGF-β, low levels of co-stimulatory molecules, lack of or have low levels of MHC-I and/or MHC-II expression. Moreover, other negative regulators such as CTLA-4, IDO-1, and prostaglandin E2 (PGE2) are regularly expressed. Then, how can real danger be discerned and recognized in this sea of PAMPs? This is an open question. Here, we hypothesize that conventional immunological danger recognition can occur in the liver but in specific and minor arterial sinusoidal segments,. Then, in the portal triad, where the hepatic artery ramificates into the stroma and carries arterial blood with no gut-derived PAMPs, there is no evolutive or environmental pressure for immunosuppressive pathways, and conventional immunological danger recognition could occur. Therefore, in arterial sinusoidal segments with no sea of PAMPs, the liver could recognize real danger and support innate and adaptive immunity.
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Affiliation(s)
- Andrea Henriques-Pons
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Natália Vacani-Martins
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Marcelo Meuser-Batista
- Laboratório de Educação Profissional em Técnicas Laboratoriais em Saúde, Escola Politecnica de Saúde Joaquim Venâncio, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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2
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Sankar K, Pearson AN, Worlikar T, Perricone MD, Holcomb EA, Mendiratta-Lala M, Xu Z, Bhowmick N, Green MD. Impact of immune tolerance mechanisms on the efficacy of immunotherapy in primary and secondary liver cancers. Transl Gastroenterol Hepatol 2023; 8:29. [PMID: 37601739 PMCID: PMC10432235 DOI: 10.21037/tgh-23-11] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 08/22/2023] Open
Abstract
The liver is a functionally unique organ with an immunosuppressive microenvironment. The liver is the sixth most common site of primary cancer in humans and is a frequent site of metastasis from other solid tumors. The development of effective therapies for primary and metastatic liver cancer has been challenging due to the complex metabolic and immune microenvironment of the liver. The liver tumor microenvironment (TME) in primary and secondary (metastatic) liver cancers is heterogenous and consists of unique immune and stromal cell populations. Crosstalk between these cell populations and tumor cells creates an immunosuppressive microenvironment within the liver which potentiates cancer progression. Immune checkpoint inhibitors (ICIs) are now clinically approved for the management of primary and secondary liver cancer and can partially overcome liver immune tolerance, but their efficacy is limited. In this review, we describe the liver microenvironment and the use of immunotherapy in primary and secondary liver cancer. We discuss emerging combination strategies utilizing locoregional and systemic therapy approaches which may enhance efficacy of immunotherapy in primary and secondary liver cancer. A deeper understanding of the immunosuppressive microenvironment of the liver will inform novel therapies and therapeutic combinations in order to improve outcomes of patients with primary and secondary liver cancer.
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Affiliation(s)
- Kamya Sankar
- Division of Medical Oncology, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ashley N. Pearson
- Graduate Program in Immunology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Tejaswi Worlikar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Matthew D. Perricone
- Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Erin A. Holcomb
- Graduate Program in Immunology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | | | - Zhen Xu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Neil Bhowmick
- Division of Medical Oncology, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michael D. Green
- Graduate Program in Immunology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
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3
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Dywicki J, Buitrago-Molina LE, Noyan F, Schlue J, Iordanidis K, Manns MP, Wedemeyer H, Jaeckel E, Hardtke-Wolenski M. Splenectomy induces biochemical remission and regeneration in experimental murine autoimmune hepatitis. Eur J Med Res 2022; 27:284. [PMID: 36496477 PMCID: PMC9737750 DOI: 10.1186/s40001-022-00933-3] [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: 10/04/2022] [Accepted: 12/04/2022] [Indexed: 12/13/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease. It is known that AIH originates not from the spleen but from the liver itself. Nonetheless, most details of the etiology and pathophysiology are unknown. We induced experimental murine AIH (emAIH) in NOD/Ltj mice by single administration of a replication-deficient adenovirus and performed splenectomy during late-stage disease. Biochemical disease remission occurred, which was characterized by improvement in transaminase levels. The causes of this remission included a shift in the transcriptomic signature of serum proteins toward regeneration. At the cellular level, there was a marked decrease in activated CD8+ T cells and an increase in intrahepatic regulatory T cells (Tregs). Here, intrahepatic Treg numbers correlated with biochemical remission. Notably, an imbalance in the T-cell/B-cell ratio was observed, with a disproportionate increase in total B cells. In summary, intrahepatic increases in Tregs, biochemical remission, and regeneration could be induced by splenectomy in the late stage of emAIH.
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Affiliation(s)
- Janine Dywicki
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Laura Elisa Buitrago-Molina
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jerome Schlue
- grid.10423.340000 0000 9529 9877Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Konstantinos Iordanidis
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P. Manns
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany ,grid.17063.330000 0001 2157 2938Department of Liver Transplantation, Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
| | - Matthias Hardtke-Wolenski
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany ,grid.5718.b0000 0001 2187 5445Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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4
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Pallett LJ, Maini MK. Liver-resident memory T cells: life in lockdown. Semin Immunopathol 2022; 44:813-825. [PMID: 35482059 PMCID: PMC9708784 DOI: 10.1007/s00281-022-00932-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
A subset of memory T cells has been identified in the liver with a tissue-resident profile and the capacity for long-term 'lockdown'. Here we review how they are retained in, and adapted to, the hepatic microenvironment, including its unique anatomical features and metabolic challenges. We describe potential interactions with other local cell types and the need for a better understanding of this complex bidirectional crosstalk. Pathogen or tumour antigen-specific tissue-resident memory T cells (TRM) can provide rapid frontline immune surveillance; we review the evidence for this in hepatotropic infections of major worldwide importance like hepatitis B and malaria and in liver cancers like hepatocellular carcinoma. Conversely, TRM can be triggered by pro-inflammatory and metabolic signals to mediate bystander tissue damage, with an emerging role in a number of liver pathologies. We discuss the need for liver sampling to gain a window into these compartmentalised T cells, allowing more accurate disease monitoring and future locally targeted immunotherapies.
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Affiliation(s)
- Laura J Pallett
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
| | - Mala K Maini
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
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Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
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Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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Fasano R, Malerba E, Prete M, Solimando AG, Buonavoglia A, Silvestris N, Leone P, Racanelli V. Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis. Front Immunol 2022; 12:814155. [PMID: 35116039 PMCID: PMC8804214 DOI: 10.3389/fimmu.2021.814155] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/31/2021] [Indexed: 12/21/2022] Open
Abstract
The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.
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Affiliation(s)
- Rossella Fasano
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Eleonora Malerba
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Marcella Prete
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Alessio Buonavoglia
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Nicola Silvestris
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- *Correspondence: Vito Racanelli,
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7
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Satilmis B, Sahin TT, Cicek E, Akbulut S, Yilmaz S. Hepatocellular Carcinoma Tumor Microenvironment and Its Implications in Terms of Anti-tumor Immunity: Future Perspectives for New Therapeutics. J Gastrointest Cancer 2021; 52:1198-1205. [PMID: 34625923 DOI: 10.1007/s12029-021-00725-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Hepatocellular cancer is an insidious tumor that is often diagnosed in a later stage of life. The tumor microenvironment is the key to tumorigenesis and progression. Many cellular and non-cellular components orchestrate the intricate process of hepatocarcinogenesis. The most important feature of hepatocellular cancer is the immune evasion process. The present review aims to summarize the key components of the tumor microenvironment in the immune evasion process. METHODS Google Scholar and PubMed databases have been searched for the mesh terms "Hepatocellular carcinoma" or "Liver Cancer" and "microenvironment." The articles were reviewed and the components of the tumor microenvironment were summarized. RESULTS The tumor microenvironment is composed of tumor cells and non-tumoral stromal and immune cells. HCC tumor microenvironment supports aggressive tumor behavior, provides immune evasion, and is an obstacle for current immunotherapeutic strategies. The components of the tumor microenvironment are intratumoral macrophages (tumor-associated macrophages (TAM)), bone marrow-derived suppressor cells, tumor-associated neutrophils (TAN), fibroblasts in the tumor microenvironment, and the activated hepatic stellate cells. CONCLUSION There are intricate mechanisms that drive hepatocarcinogenesis. The tumor microenvironment is at the center of all the complex and diverse mechanisms. Effective and multistep immunotherapies should be developed to target different components of the tumor microenvironment.
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Affiliation(s)
- Basri Satilmis
- Liver Transplant Institute and Faculty of Medicine Department of Surgery, Inonu University, Battalgazi, 44000, Malatya, Turkey
| | - Tevfik Tolga Sahin
- Liver Transplant Institute and Faculty of Medicine Department of Surgery, Inonu University, Battalgazi, 44000, Malatya, Turkey.
| | - Egemen Cicek
- Liver Transplant Institute and Faculty of Medicine Department of Surgery, Inonu University, Battalgazi, 44000, Malatya, Turkey
| | - Sami Akbulut
- Liver Transplant Institute and Faculty of Medicine Department of Surgery, Inonu University, Battalgazi, 44000, Malatya, Turkey
| | - Sezai Yilmaz
- Liver Transplant Institute and Faculty of Medicine Department of Surgery, Inonu University, Battalgazi, 44000, Malatya, Turkey
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8
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Knolle PA, Huang LR, Kosinska A, Wohlleber D, Protzer U. Improving Therapeutic Vaccination against Hepatitis B-Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection. Vaccines (Basel) 2021; 9:1333. [PMID: 34835264 PMCID: PMC8623083 DOI: 10.3390/vaccines9111333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 12/02/2022] Open
Abstract
Chronic hepatitis B affects more than 250 million individuals worldwide, putting them at risk of developing liver cirrhosis and liver cancer. While antiviral immune responses are key to eliminating hepatitis B virus (HBV) infections, insufficient antiviral immunity characterized by failure to eliminate HBV-infected hepatocytes is associated with chronic hepatitis B. Prophylactic vaccination against hepatitis B successfully established protective immunity against infection with the hepatitis B virus and has been instrumental in controlling hepatitis B. However, prophylactic vaccination schemes have not been successful in mounting protective immunity to eliminate HBV infections in patients with chronic hepatitis B. Here, we discuss the current knowledge on the development and efficacy of therapeutic vaccination strategies against chronic hepatitis B with particular emphasis on the pathogenetic understanding of dysfunctional anti-viral immunity. We explore the development of additional immune stimulation measures within tissues, in particular activation of immunogenic myeloid cell populations, and their use for combination with therapeutic vaccination strategies to improve the efficacy of therapeutic vaccination against chronic hepatitis B.
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Affiliation(s)
- Percy A. Knolle
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
- German Center for infection Research (DZIF), Munich Site, 81675 Munich, Germany;
| | - Li-Rung Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli City 350, Taiwan;
| | - Anna Kosinska
- Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
| | - Dirk Wohlleber
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
| | - Ulrike Protzer
- German Center for infection Research (DZIF), Munich Site, 81675 Munich, Germany;
- Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
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9
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Wang X, MacParland SA, Perciani CT. Immunological Determinants of Liver Transplant Outcomes Uncovered by the Rat Model. Transplantation 2021; 105:1944-1956. [PMID: 33417410 PMCID: PMC8376267 DOI: 10.1097/tp.0000000000003598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/12/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023]
Abstract
For many individuals with end-stage liver disease, the only treatment option is liver transplantation. However, liver transplant rejection is observed in 24%-80% of transplant patients and lifelong drug regimens that follow the transplant procedure lead to serious side effects. Furthermore, the pool of donor livers available for transplantation is far less than the demand. Well-characterized and physiologically relevant models of liver transplantation are crucial to a deeper understanding of the cellular processes governing the outcomes of liver transplantation and serve as a platform for testing new therapeutic strategies to enhance graft acceptance. Such a model has been found in the rat transplant model, which has an advantageous size for surgical procedures, similar postoperative immunological progression, and high genome match to the human liver. From rat liver transplant studies published in the last 5 years, it is clear that the rat model serves as a strong platform to elucidate transplant immunological mechanisms. Using the model, we have begun to uncover potential players and possible therapeutic targets to restore liver tolerance and preserve host immunocompetence. Here, we present an overview of recent literature for rat liver transplant models, with an aim to highlight the value of the models and to provide future perspectives on how these models could be further characterized to enhance the overall value of rat models to the field of liver transplantation.
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Affiliation(s)
- Xinle Wang
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Sonya A MacParland
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Ajmera Family Transplant Centre, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Catia T Perciani
- Ajmera Family Transplant Centre, Toronto General Hospital Research Institute, Toronto, ON, Canada
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10
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Vacani-Martins N, Meuser-Batista M, dos Santos CDLP, Hasslocher-Moreno AM, Henriques-Pons A. The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View. Pathogens 2021; 10:pathogens10091074. [PMID: 34578107 PMCID: PMC8465576 DOI: 10.3390/pathogens10091074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.
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Affiliation(s)
- Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | - Marcelo Meuser-Batista
- Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil;
| | - Carina de Lima Pereira dos Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | | | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
- Correspondence:
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11
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Nakano R, Tran LM, Geller DA, Macedo C, Metes DM, Thomson AW. Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection. Front Immunol 2021; 12:705465. [PMID: 34262574 PMCID: PMC8273384 DOI: 10.3389/fimmu.2021.705465] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/11/2021] [Indexed: 12/24/2022] Open
Abstract
Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via "cross-dressing", regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.
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Affiliation(s)
- Ryosuke Nakano
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lillian M. Tran
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - David A. Geller
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Camila Macedo
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Diana M. Metes
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Angus W. Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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12
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Bozward AG, Warricker F, Oo YH, Khakoo SI. Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade. Front Immunol 2021; 12:643310. [PMID: 33995362 PMCID: PMC8120158 DOI: 10.3389/fimmu.2021.643310] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Despite major advances in immunotherapy, hepatocellular carcinoma (HCC) remains a challenging target. Natural Killer (NK) cells are crucial components of the anti-HCC immune response, which can be manipulated for immunotherapeutic benefit as primary targets, modulators of the tumour microenvironment and in synchronising with tumour antigen specific effector CD8 cells for tumour clearance. Regulatory T cells shape the anti-tumour response from effector T cells via multiple suppressive mechanisms. Future research is needed to address the development of novel NK cell-targeted immunotherapy and on restraining Treg frequency and function in HCC. We have now entered a new era of anti-cancer treatment using checkpoint inhibitor (CPI)-based strategies. Combining GMP-NK cell immunotherapy to enhance the frequency of NK cells with CPI targeting both NK and CD8 T cells to release co-inhibitory receptors and enhance the cells anti-tumour immunity of HCC would be an attractive therapeutic option in the treatment of HCC. These therapeutic approaches should now be complemented by the application of genomic, proteomic and metabolomic approaches to understanding the microenvironment of HCC which, together with deep immune profiling of peripheral blood and HCC tissue before and during treatment, will provide the much-needed personalised medicine approach required to improve clinical outcomes for patients with HCC.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastroenterology Research and National Institute for Health Research Biomedical Research Centre (NIHR BRC) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, United Kingdom
| | - Frazer Warricker
- The School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Biomedical Research Centre, The School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
| | - Ye H. Oo
- Centre for Liver and Gastroenterology Research and National Institute for Health Research Biomedical Research Centre (NIHR BRC) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Salim I. Khakoo
- The School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Biomedical Research Centre, The School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
- Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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13
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Wooddell CI, Gehring AJ, Yuen MF, Given BD. RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies. Viruses 2021; 13:v13040581. [PMID: 33808298 PMCID: PMC8065501 DOI: 10.3390/v13040581] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection.
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Affiliation(s)
- Christine I. Wooddell
- Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA;
- Correspondence: ; Tel.: +1-608-316-3930
| | - Adam J. Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada;
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China;
| | - Bruce D. Given
- Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA;
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14
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Damo M, Wilson DS, Watkins EA, Hubbell JA. Soluble N-Acetylgalactosamine-Modified Antigens Enhance Hepatocyte-Dependent Antigen Cross-Presentation and Result in Antigen-Specific CD8 + T Cell Tolerance Development. Front Immunol 2021; 12:555095. [PMID: 33746941 PMCID: PMC7965950 DOI: 10.3389/fimmu.2021.555095] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 02/10/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8+ T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for in vivo targeted tolerogenic treatments.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 2/immunology
- ATP Binding Cassette Transporter, Subfamily B, Member 2/metabolism
- Acetylgalactosamine/immunology
- Adoptive Transfer/methods
- Animals
- Antigen Presentation/immunology
- Antigens/immunology
- CD8-Positive T-Lymphocytes/immunology
- Cells, Cultured
- Cross-Priming/immunology
- Hepatocytes/cytology
- Hepatocytes/immunology
- Immune Tolerance/immunology
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Ovalbumin/immunology
- Skin Transplantation/methods
- Solubility
- Vesicular Transport Proteins/immunology
- Vesicular Transport Proteins/metabolism
- Mice
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Affiliation(s)
- Martina Damo
- Institute for Molecular Engineering, University of Chicago, Chicago, IL, United States
- Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - D. Scott Wilson
- Institute for Molecular Engineering, University of Chicago, Chicago, IL, United States
- Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Elyse A. Watkins
- Institute for Molecular Engineering, University of Chicago, Chicago, IL, United States
| | - Jeffrey A. Hubbell
- Institute for Molecular Engineering, University of Chicago, Chicago, IL, United States
- Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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15
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Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021; 1:48-55. [PMID: 22720211 PMCID: PMC3376967 DOI: 10.4161/onci.1.1.18344] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
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16
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Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021. [PMID: 22720211 DOI: 10.4161/onc-i.1.1.18344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
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17
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Splenectomy Prior to Experimental Induction of Autoimmune Hepatitis Promotes More Severe Hepatic Inflammation, Production of IL-17 and Apoptosis. Biomedicines 2021; 9:biomedicines9010058. [PMID: 33435354 PMCID: PMC7827897 DOI: 10.3390/biomedicines9010058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 01/25/2023] Open
Abstract
Autoimmune hepatitis (AIH) is detected at a late stage in the course of the disease. Therefore, induction and etiology are largely unclear. It is controversial if the induction of autoimmunity occurs in the liver or in the spleen. In our experimental murine AIH model, the induction of autoimmunity did not occur in the spleen. Instead, a protective role of the spleen could be more likely. Therefore, we splenectomized mice followed by induction of experimental murine AIH. Splenectomized mice presented more severe portal inflammation. Furthermore, these mice had more IL-17, IL-23 receptor (IL-23R) and caspase 3 (casp3) and a decreased amount of erythropoietin in serum, while intrahepatic T cell compartments were unaffected. These results indicate that the spleen is not necessary for induction of AIH, and splenectomy disrupts the ability to immune regulate the intensity of hepatic inflammation, production of IL-17 and apoptosis.
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18
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Federico P, Petrillo A, Giordano P, Bosso D, Fabbrocini A, Ottaviano M, Rosanova M, Silvestri A, Tufo A, Cozzolino A, Daniele B. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives. Cancers (Basel) 2020; 12:E3025. [PMID: 33080958 PMCID: PMC7603151 DOI: 10.3390/cancers12103025] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an "ill-defined" small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.
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Affiliation(s)
- Piera Federico
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania “L. Vanvitelli”, 80131 Napoli, Italy
| | - Pasqualina Giordano
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Davide Bosso
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Antonietta Fabbrocini
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Margaret Ottaviano
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy
| | - Mario Rosanova
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Antonia Silvestri
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
| | - Andrea Tufo
- Surgical Unit, Ospedale del Mare, 80147 Napoli, Italy;
| | | | - Bruno Daniele
- Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy; (A.P.); (P.G.); (D.B.); (A.F.); (M.O.); (M.R.); (A.S.); (B.D.)
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19
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McCaughan GW, Bowen DG, Bertolino PJ. Induction Phase of Spontaneous Liver Transplant Tolerance. Front Immunol 2020; 11:1908. [PMID: 33013840 PMCID: PMC7516030 DOI: 10.3389/fimmu.2020.01908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/16/2020] [Indexed: 12/30/2022] Open
Abstract
The liver has long been known to possess tolerogenic properties. Early experiments in liver transplantation demonstrated that in animal models, hepatic allografts could be accepted across MHC-mismatch without the use of immunosuppression, and that transplantation of livers from the same donor was capable of inducing tolerance to other solid organs that would normally otherwise be rejected. Although this phenomenon is less pronounced in human liver transplantation, lower levels of immunosuppression are nevertheless required for graft acceptance than for other solid organs, and in a minority of individuals immunosuppression can be discontinued in the longer term. The mechanisms underlying this unique hepatic property have not yet been fully delineated, however it is clear that immunological events in the early period post-liver transplant are key to generation of hepatic allograft tolerance. Both the hepatic parenchyma and the large number of donor passenger leukocytes contained within the liver allograft have been demonstrated to contribute to the generation of donor-specific tolerance in the early post-transplant phase. In particular, the unique nature of hepatic-leukocyte interactions appears to play a crucial role in the ability of the liver to silence the recipient alloimmune response. In this review, we will summarize the evidence regarding the potential mechanisms that mediate the critical early phase in the generation of hepatic allograft tolerance.
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Affiliation(s)
- Geoffrey W McCaughan
- Liver Injury and Cancer Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick J Bertolino
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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20
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Ronca V, Wootton G, Milani C, Cain O. The Immunological Basis of Liver Allograft Rejection. Front Immunol 2020; 11:2155. [PMID: 32983177 PMCID: PMC7492390 DOI: 10.3389/fimmu.2020.02155] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.,National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Grace Wootton
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Owen Cain
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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21
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Priming of Antiviral CD8 T Cells without Effector Function by a Persistently Replicating Hepatitis C-Like Virus. J Virol 2020; 94:JVI.00035-20. [PMID: 32102885 DOI: 10.1128/jvi.00035-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 02/06/2020] [Indexed: 12/14/2022] Open
Abstract
Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.
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22
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Meuser-Batista M, Vacani-Martins N, Cascabulho CM, Beghini DG, Henriques-Pons A. In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte. J Leukoc Biol 2020; 107:695-706. [PMID: 32202341 PMCID: PMC7383480 DOI: 10.1002/jlb.3a0220-399rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 02/04/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
In secondary lymphoid organs, pathogen‐derived and endogenous danger molecules are recognized by pattern recognition receptors, leading to adaptive proinflammatory immune responses. This conceptual rule does not apply directly to the liver, as hepatic immune cells tolerate gut‐derived bacterial molecules from the flora. Therefore, the recognition of danger and proinflammatory stimuli differs between the periphery and the liver. However, the tolerant nature of the liver must be overcome in the case of infections or cancer, for example. The central paradigm is the basis for danger recognition and the balance between inflammation and tolerance in the liver. Here, we observed functional integration, with activated peripheral T lymphocytes playing a role in the induction of a proinflammatory environment in the liver in the presence of Trypanosoma cruzi antigens. When only parasite extract was orally administered, it led to the up‐regulation of hepatic tolerance markers, but oral treatment plus adoptively transferred activated splenic T lymphocytes led to a proinflammatory response. Moreover, treated/recipient mice showed increased levels of TNF, IFN‐γ, IL‐6, and CCL2 in the liver and increased numbers of effector and/or effector memory T lymphocytes and F4/80+ cells. There was a reduction in FoxP3+ Treg cells, NKT cells, and γδ T lymphocytes with increased liver damage in the presence of activated peripheral T cells. Our results show that the induction of a proinflammatory liver response against T. cruzi danger molecules is at least partially dependent on cooperation with activated peripheral T cells.
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Affiliation(s)
- Marcelo Meuser-Batista
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos from Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.,Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira. Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos from Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Cynthia Machado Cascabulho
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos from Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Daniela Gois Beghini
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos from Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos from Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
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Hoogeveen RC, Boonstra A. Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection. Front Immunol 2020; 11:401. [PMID: 32194573 PMCID: PMC7064714 DOI: 10.3389/fimmu.2020.00401] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
Treatment of chronic hepatitis B virus (HBV) infection is highly effective in suppressing viral replication, but complete cure is rarely achieved. In recent years, substantial progress has been made in the development of immunotherapy to treat cancer. Applying these therapies to improve the management of chronic HBV infection is now being attempted, and has become an area of active research. Immunotherapy with vaccines and checkpoint inhibitors can boost T cell functions in vitro, and therefore may be used to reinvigorate the impaired HBV-specific T cell response. However, whether these approaches will suffice and restore antiviral T cell immunity to induce long-term HBV control remains an open question. Recent efforts have begun to describe the phenotype and function of HBV-specific T cells on the single epitope level. An improved understanding of differing T cell specificities and their contribution to HBV control will be instrumental for advancement of the field. In this review, we outline correlates of successful versus inadequate T cell responses to HBV, and discuss the rationale behind therapeutic vaccines and checkpoint inhibitors for the treatment of chronic HBV infection.
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Affiliation(s)
- Ruben C Hoogeveen
- Division of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - André Boonstra
- Division of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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24
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Abstract
The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the “education” of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.
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Affiliation(s)
- Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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25
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Yee C, Main NM, Terry A, Stevanovski I, Maczurek A, Morgan AJ, Calabro S, Potter AJ, Iemma TL, Bowen DG, Ahlenstiel G, Warner FJ, McCaughan GW, McLennan SV, Shackel NA. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury. PLoS One 2019; 14:e0215557. [PMID: 31291257 PMCID: PMC6619953 DOI: 10.1371/journal.pone.0215557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/24/2019] [Indexed: 01/26/2023] Open
Abstract
Background Chronic inflammation is the driver of liver injury and results in progressive fibrosis and eventual cirrhosis with consequences including both liver failure and liver cancer. We have previously described increased expression of the highly multifunctional glycoprotein CD147 in liver injury. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury. Methods Non-diseased, progressive injury, and cirrhotic liver from humans and mice were examined using a mAb targeting CD147. Inflammatory cell subsets were assessed by multiparameter flow cytometry. Results In liver injury, we observe abundant, intrahepatic leukocyte clusters defined as ≥5 adjacent CD45+ cells which we have termed “leukocyte aggregates”. We have shown that these leukocyte aggregates have a significant effect in determining the extent of liver injury. If CD147 is blocked in vivo, these leukocyte aggregates diminish in size and number, together with a marked significant reduction in liver injury including fibrosis. This is accompanied by no change in overall intrahepatic leukocyte numbers. Further, blocking of aggregation formation occurs prior to an appreciable increase in inflammatory markers or fibrosis. Additionally, there were no observed, “off-target” or unpredicted effects in targeting CD147. Conclusion CD147 mediates leukocyte aggregation which is associated with the development of liver injury. This is not a secondary effect, but a cause of injury as aggregate formation proceeds other markers of injury. Leukocyte aggregation has been previously described in inflammation dating back over many decades. Here we demonstrate that leukocyte aggregates determine the extent of liver injury.
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Affiliation(s)
- Christine Yee
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Nathan M. Main
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Alexandra Terry
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Igor Stevanovski
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Annette Maczurek
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - Alison J. Morgan
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - Sarah Calabro
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - Alison J. Potter
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - Tina L. Iemma
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - David G. Bowen
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
- A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Golo Ahlenstiel
- Western Sydney School of Medicine, Blacktown Hospital, Blacktown, NSW, Australia
| | - Fiona J. Warner
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
| | - Geoffrey W. McCaughan
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
- A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Susan V. McLennan
- Department of Endocrinology, Department of Medicine and Bosch Institute, Royal Prince Alfred Hospital, The University of Sydney, NSW, Australia
| | - Nicholas A. Shackel
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
- A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
- Liverpool Hospital, Liverpool, NSW, Australia
- * E-mail:
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26
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Abrol N, Jadlowiec CC, Taner T. Revisiting the liver's role in transplant alloimmunity. World J Gastroenterol 2019; 25:3123-3135. [PMID: 31333306 PMCID: PMC6626728 DOI: 10.3748/wjg.v25.i25.3123] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.
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Affiliation(s)
- Nitin Abrol
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
| | | | - Timucin Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
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27
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Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol 2019; 25:2977-2989. [PMID: 31293335 PMCID: PMC6603808 DOI: 10.3748/wjg.v25.i24.2977] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/24/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.
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Affiliation(s)
- Michael P Johnston
- Department of Hepatology, Southampton General Hospital, University Hospital Southampton, Southampton SO16 6YD, United Kingdom
| | - Salim I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, United Kingdom
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28
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Bartolo L, Li Chung Tong S, Chappert P, Urbain D, Collaud F, Colella P, Richard I, Ronzitti G, Demengeot J, Gross DA, Mingozzi F, Davoust J. Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity. JCI Insight 2019; 4:127008. [PMID: 31167976 DOI: 10.1172/jci.insight.127008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 04/11/2019] [Indexed: 12/20/2022] Open
Abstract
Immune responses to therapeutic transgenes are a potential hurdle to treat monogenic muscle disorders. These responses result from the neutralizing activity of transgene-specific B cells and cytotoxic T cells recruited upon gene transfer. We explored here how dual muscle-liver expression of a foreign transgene allows muscle transgene engraftment after adenoassociated viral vector delivery. We found in particular that induction of transgene-specific tolerance is imposed by concurrent muscle and liver targeting, resulting in the absence of CD8+ T cell responses to the transgene. This tolerance can be temporally decoupled, because transgene engraftment can be achieved in muscle weeks after liver transduction. Importantly, transgene-specific CD8+ T cell tolerance can be established despite preexisting immunity to the transgene. Whenever preexisting, transgene-specific CD4+ and CD8+ memory T cell responses are present, dual muscle-liver transduction turns polyclonal, transgene-specific CD8+ T cells into typically exhausted T cells with high programmed cell death 1 (PD-1) expression and lack of IFN-γ production. Our results demonstrate that successful transduction of muscle tissue can be achieved through liver-mediated control of humoral and cytotoxic T cell responses, even in the presence of preexisting immunity to the muscle-associated transgene.
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Affiliation(s)
- Laurent Bartolo
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
| | - Stéphanie Li Chung Tong
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
| | - Pascal Chappert
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
| | - Dominique Urbain
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
| | - Fanny Collaud
- Integrare Research Unit UMR S951, Genethon, INSERM, Université Evry, Université Paris Saclay, École Pratique des Hautes Études, Evry, France
| | - Pasqualina Colella
- Integrare Research Unit UMR S951, Genethon, INSERM, Université Evry, Université Paris Saclay, École Pratique des Hautes Études, Evry, France
| | - Isabelle Richard
- Integrare Research Unit UMR S951, Genethon, INSERM, Université Evry, Université Paris Saclay, École Pratique des Hautes Études, Evry, France
| | - Giuseppe Ronzitti
- Integrare Research Unit UMR S951, Genethon, INSERM, Université Evry, Université Paris Saclay, École Pratique des Hautes Études, Evry, France
| | | | - David A Gross
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
| | - Federico Mingozzi
- Integrare Research Unit UMR S951, Genethon, INSERM, Université Evry, Université Paris Saclay, École Pratique des Hautes Études, Evry, France
| | - Jean Davoust
- Institut Necker Enfants-Malades, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM, U1151, Paris, France; CNRS UMR 8253, Paris, France
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29
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Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of Hepatitis B Virus-Specific CD8 + T Cell Responses. J Virol 2018; 92:JVI.00920-18. [PMID: 30089700 DOI: 10.1128/jvi.00920-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 07/31/2018] [Indexed: 01/05/2023] Open
Abstract
CD8+ T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8+ T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8+ T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8+ T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8+ T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8+ T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8+ T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8+ T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8+ T cells are primarily dependent on hepatocellular antigen presentation.IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8+ T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8+ T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8+ T cells. However, this notion has not been tested for HBV-specific CD8+ T cells. In this study, we show that HBV-specific CD8+ T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8+ T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8+ T cell responses.
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30
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Tagliamonte M, Petrizzo A, Mauriello A, Tornesello ML, Buonaguro FM, Buonaguro L. Potentiating cancer vaccine efficacy in liver cancer. Oncoimmunology 2018; 7:e1488564. [PMID: 30288355 PMCID: PMC6169594 DOI: 10.1080/2162402x.2018.1488564] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/08/2018] [Accepted: 06/10/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy with a poor prognosis and an overall 5-year survival rate of approximately 5-6%. This is due because standard of care treatment options are limited and none of them shows a sufficient efficacy. HCC is an "inflammation-induced cancer" and preliminary preclinical and clinical data suggest that immunotherapeutic approaches may be a good alternative candidate for the treatment of HCC patients improving the dismal prognosis associated with this cancer. However, recent findings strongly suggest that an optimal immunotherapy in HCC requires the combination of an immune activator with immune modulators, aiming at compensating the strong liver immune suppressive microenvironment. One of the most promising strategy could be represented by the combination of a cancer vaccine with immunomodulatory drugs, such as chemotherapy and checkpoint inhibitors. Very limited examples of such combinatorial strategies have been evaluated in HCC to date, because HCC easily develops resistance to standard chemotherapy, which is also poorly tolerated by patients with liver cirrhosis. The present review describes the most update knowledge in this field.
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Affiliation(s)
| | | | | | - Maria Lina Tornesello
- Lab of Molecular Biology & Viral Oncology, Dept Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” - IRCCS, Naples, Italy
| | - Franco M Buonaguro
- Lab of Molecular Biology & Viral Oncology, Dept Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale” - IRCCS, Naples, Italy
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31
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Fetal Hepatic Response to Bovine Viral Diarrhea Virus Infection in Utero. Pathogens 2018; 7:pathogens7020054. [PMID: 29882795 PMCID: PMC6027343 DOI: 10.3390/pathogens7020054] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/30/2018] [Accepted: 05/30/2018] [Indexed: 12/23/2022] Open
Abstract
Non-cytopathic bovine viral diarrhea virus (ncp BVDV) can cause persistent infection (PI) in animals infected in utero during early gestation. PI animals shed the virus for life and are the major source of the virus in herds. The mechanism responsible for BVDV immune tolerance in the PI fetus is unknown. We assessed the impact of BVDV infection on the fetal liver. Dams were inoculated with ncp BVDV at gestational day 75. Fetal liver samples were collected at necropsy, 7 and 14 days post-maternal-BVDV inoculation. BVDV antigen was not detected in the liver at gestational day 82 (7 days post-maternal inoculation). However, at 14 days post-maternal inoculation, BVDV was detected by immunohistochemistry in fetal Kupffer cells. Flow cytometry analysis showed a higher percentage of hepatic immune cells expressed MHC I and MHC II in BVDV-infected fetal liver (as compared to uninfected controls). Immunofluorescence was used to identify Kupffer cells, which were positive for BVDV antigen, near populations of CD3+ lymphocytes. The identification of BVDV in the fetal liver Kupffer cells at 14 days post inoculation is interesting in the context of establishment of tolerance in persistent infection. These data indicate the presence of a hepatic immune response to fetal infection.
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32
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CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc Natl Acad Sci U S A 2017; 114:10449-10454. [PMID: 28893990 DOI: 10.1073/pnas.1701428114] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal triglyceride transfer protein (MTP), a protein involved in the transfer of lipids onto CD1d, regulates liver iNKT cell homeostasis in a manner dependent on hepatocyte CD1d. Mice with hepatocyte-specific loss of MTP exhibit defects in the function of CD1d and show increased hepatic iNKT cell numbers as a consequence of altered iNKT cell apoptosis. Similar findings were made in mice with hepatocyte-specific loss of CD1d, confirming a critical role of CD1d in this process. Moreover, increased hepatic iNKT cell abundance in the absence of MTP is associated with susceptibility to severe iNKT cell-mediated hepatitis, thus demonstrating the importance of CD1d-dependent control of liver iNKT cells in maintaining immunological homeostasis in the liver. Together, these data demonstrate an unanticipated role of parenchymal cells, as shown here for hepatocytes, in tissue-specific regulation of CD1d-restricted immunity and further suggest that alterations in lipid metabolism may affect iNKT cell homeostasis through effects on CD1d-associated lipid antigens.
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33
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Loo K, Tsai KK, Mahuron K, Liu J, Pauli ML, Sandoval PM, Nosrati A, Lee J, Chen L, Hwang J, Levine LS, Krummel MF, Algazi AP, Pampaloni M, Alvarado MD, Rosenblum MD, Daud AI. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight 2017; 2:93433. [PMID: 28724802 DOI: 10.1172/jci.insight.93433] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Programmed death 1 (PD-1) inhibition activates partially exhausted cytotoxic T lymphocytes (peCTLs) and induces tumor regression. We previously showed that the peCTL fraction predicts response to anti-PD-1 monotherapy. Here, we sought to correlate peCTL and regulatory T lymphocyte (Treg) levels with response to combination immunotherapy, and with demographic/disease characteristics, in metastatic melanoma patients. METHODS Pretreatment melanoma samples underwent multiparameter flow cytometric analysis. Patients were treated with anti-PD-1 monotherapy or combination therapy, and responses determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria. peCTL and Treg levels across demographic/disease variables were compared. Low versus high peCTL (≤20% vs. >20%) were defined from a previous study. RESULTS One hundred and two melanoma patients were identified. The peCTL fraction was higher in responders than nonresponders. Low peCTL correlated with female sex and liver metastasis, but not with lactate dehydrogenase (LDH), tumor stage, or age. While overall response rates (ORRs) to anti-PD-1 monotherapy and combination therapy were similar in high-peCTL patients, low-peCTL patients given combination therapy demonstrated higher ORRs than those who received monotherapy. Treg levels were not associated with these factors nor with response. CONCLUSION In melanoma, pretreatment peCTL fraction is reduced in women and in patients with liver metastasis. In low-peCTL patients, anti-PD-1 combination therapy is associated with significantly higher ORR than anti-PD-1 monotherapy. Fewer tumor-infiltrating peCTLs may be required to achieve response to combination immunotherapy. TRIAL REGISTRATION UCSF IRB Protocol 138510FUNDING. NIH DP2-AR068130, K08-AR062064, AR066821, and Burroughs Wellcome CAMS-1010934 (M.D.R.). Amoroso and Cook Fund, and the Parker Institute for Cancer Immunotherapy (A.I.D.).
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Affiliation(s)
| | | | - Kelly Mahuron
- Department of Surgery, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA
| | | | | | | | | | | | | | - Jimmy Hwang
- Department of Epidemiology & Biostatistics, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA
| | | | | | | | | | - Michael D Alvarado
- Department of Surgery, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA
| | | | - Adil I Daud
- Department of Medicine and.,Department of Dermatology
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34
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Karpova Y, Ustichenko V, Alabedal’karim N, Stepanova A, Lyupina Y, Boguslavski K, Bozhok G, Sharova N. Change in the Content of Immunoproteasomes and Macrophages in Rat Liver At the Induction of Donor-Specific Tolerance. Acta Naturae 2017; 9:71-80. [PMID: 29104778 PMCID: PMC5662276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Indexed: 11/29/2022] Open
Abstract
Induction of donor specific tolerance (DST) by the introduction of donor cells into a recipient's portal vein is one of the approaches used to solve the problem of transplant engraftment. However, the mechanism of DST development remains unclear to this moment. In the present work, we first studied the change in the content of immunoproteasomes and macrophages of the liver at early stages of the development of allospecific portal tolerance in rats by Western blotting and flow cytofluorimetry. On the basis of the data obtained, we can conclude that the induction of DST is an active process characterized by two phases during which the level of the proteasome immune subunits LMP2 and LMP7 in liver mononuclear cells, including Kupffer cells, and the number of Kupffer cells change. The first phase lasts up to 5 days after the beginning of DST induction; the second phase - from 5 to 14 days. In both phases, the level of the subunits LMP2 and LMP7 in the total pool of mononuclear cells and Kupffer cells increases, with maximum values on days 1 and 7. In addition, the total number of Kupffer cells increases in both phases with a shift in several days. The most noticeable changes take place in the second phase. The third day is characterized by a lower content of mononuclear cells expressing immunoproteasomes compared to the control value in native animals. Presumably, at this time point a "window of opportunity" appears for subsequent filling of an empty niche with cells of different subpopulations and, depending on this fact, the development of tolerance or rejection. The results obtained raise the new tasks of finding ways to influence the cellular composition in the liver and the expression of immunoproteasomes on the third day after the beginning of DST induction to block the development of rejection.
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Affiliation(s)
- Ya.D. Karpova
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Str. 26, Moscow, 119334, Russia
| | - V.D. Ustichenko
- Institute of Problems in Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Pereyaslavskaya Str. 23, Kharkov, 61016, Ukraine
| | - N.M. Alabedal’karim
- Institute of Problems in Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Pereyaslavskaya Str. 23, Kharkov, 61016, Ukraine
| | - A.A. Stepanova
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Str. 26, Moscow, 119334, Russia
| | - Yu.V. Lyupina
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Str. 26, Moscow, 119334, Russia
| | - K.I. Boguslavski
- Institute of Problems in Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Pereyaslavskaya Str. 23, Kharkov, 61016, Ukraine
| | - G.A. Bozhok
- Institute of Problems in Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Pereyaslavskaya Str. 23, Kharkov, 61016, Ukraine
| | - N.P. Sharova
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Str. 26, Moscow, 119334, Russia
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Abstract
BACKGROUND The liver immune environment is tightly regulated to balance immune activation with immune tolerance. Understanding the dominant immune pathways initiated in the liver is important because the liver is a site for cell transplantation, such as for islet and hepatocyte transplantation. The purpose of this study is to examine the consequences of alloimmune stimulation when allogeneic cells are transplanted to the liver in comparison to a different immune locale, such as the kidney. METHODS We investigated cellular and humoral immune responses when allogeneic hepatocytes are transplanted directly to the recipient liver by intraportal injection. A heterotopic kidney engraftment site was used for comparison to immune activation in the liver microenvironment. RESULTS Transplantation of allogeneic hepatocytes delivered directly to the liver, via recipient portal circulation, stimulated long-term, high magnitude CD8 T cell-mediated allocytotoxicity. CD8 T cells initiated significant in vivo allocytotoxicity as well as rapid rejection of hepatocytes transplanted to the liver even in the absence of secondary lymph nodes or CD4 T cells. In contrast, in the absence of recipient peripheral lymphoid tissue and CD4 T cells, CD8-mediated in vivo allocytotoxicity was abrogated, and rejection was delayed when hepatocellular allografts were transplanted to the kidney subcapsular site. CONCLUSIONS These results highlight the CD8-dominant proinflammatory immune responses unique to the liver microenvironment. Allogeneic cells transplanted directly to the liver do not enjoy immune privilege but rather require immunosuppression to prevent rejection by a robust and persistent CD8-dependent allocytotoxicity primed in the liver.
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The Balance between CD8 + T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose. Mol Ther 2017; 25:880-891. [PMID: 28284982 DOI: 10.1016/j.ymthe.2017.02.014] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 02/14/2017] [Accepted: 02/15/2017] [Indexed: 12/20/2022] Open
Abstract
The liver continuously receives antigens from circulation and the gastrointestinal tract. A complex immune regulatory system has evolved in order to both limit inflammation and promote tolerance in the liver. Although in situ immune tolerance mechanisms enable successful gene therapy and liver transplantation, at the same time they facilitate chronic infections by pathogens such as hepatitis viruses. It is, however, poorly understood why hepatocytes infected with hepatitis viruses or transduced with adeno-associated virus (AAV)-based vectors may be rejected by CD8+ T cells several months later. We found that hepatic transfer of limited doses of an AAV-ovalbumin vector rapidly induced antigen-specific CD8+ T cells that only became functionally competent after >2 months. At this time, CD8+ T cells had downregulated negative checkpoint markers, e.g., the programmed death 1 [PD-1] receptor, and upregulated expression of relevant cytokines. At further reduced vector dose, only intrahepatic rather than systemic CD8+ T cell responses occurred, showing identical delay in antigen clearance. In contrast, PD-1-deficient mice rapidly cleared ovalbumin. Interestingly, higher vector dose directed sustained transgene expression without CD8+ T cell responses. Regulatory T cells, IL-10 expression, and Fas-L contributed to high-dose tolerance. Thus, viral vector doses profoundly impact CD8+ T cell responses.
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37
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Raufi A, Tirona MT. Prospect of the use of checkpoint inhibitors in hepatocellular cancer treatments. Cancer Manag Res 2017; 9:19-27. [PMID: 28223846 PMCID: PMC5308591 DOI: 10.2147/cmar.s111673] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular cancer (HCC) is a very fatal disease due to limited therapeutic options as well as due to its association with underlying chronic liver disease in the majority of cases. The immune evasion in HCC signifies a major barrier to the delivery of effective immunotherapy. Sorafenib is the only Food and Drug Administration-approved drug available with an overall response rate of 2%–3% and overall survival of 2.8 months. Chemotherapy has not been used routinely because of the relative refractoriness of advanced HCC. The introduction of immune checkpoint inhibitors (cytotoxic T-lymphocyte antigen 4, programmed death 1, and programmed death-ligand 1) has opened a new horizon for cancer immunotherapy. Future direction in immunotherapy for HCC is to rationally combine it with other treatment modalities, including surgery, radiofrequency ablation, and cytotoxic agents, to maximize its therapeutic efficacy.
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Affiliation(s)
- Ali Raufi
- Division of Hematology/Oncology, Department of Medicine, Joan C. Edwards School of Medicine at Marshall University, Edward Comprehensive Care Center, Huntington, WV, USA
| | - Maria Tria Tirona
- Division of Hematology/Oncology, Department of Medicine, Joan C. Edwards School of Medicine at Marshall University, Edward Comprehensive Care Center, Huntington, WV, USA
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38
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Tripathi D, Venkatasubramanian S, Cheekatla SS, Paidipally P, Welch E, Tvinnereim AR, Vankayalapati R. A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice. Nat Commun 2016; 7:13896. [PMID: 27982034 PMCID: PMC5171644 DOI: 10.1038/ncomms13896] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/08/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1+ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1+ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1+ cells in islet allograft-transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3-NK1.1+ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1+ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma.
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Affiliation(s)
- Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Sambasivan Venkatasubramanian
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Satyanarayana S. Cheekatla
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Elwyn Welch
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Amy R. Tvinnereim
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
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39
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Wohlleber D, Knolle PA. The role of liver sinusoidal cells in local hepatic immune surveillance. Clin Transl Immunology 2016; 5:e117. [PMID: 28090319 PMCID: PMC5192065 DOI: 10.1038/cti.2016.74] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/03/2016] [Accepted: 11/03/2016] [Indexed: 02/06/2023] Open
Abstract
Although the liver's function as unique immune organ regulating immunity has received a lot of attention over the last years, the mechanisms determining hepatic immune surveillance against infected hepatocytes remain less well defined. Liver sinusoidal cells, in particular, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), serve as physical platform for recruitment and anchoring of blood-borne immune cells in the liver. Liver sinusoidal cells also function as portal of entry for infectious microorganisms targeting the liver such as hepatotropic viruses, bacteria or parasites. At the same time, liver sinusoidal cells actively contribute to achieve immune surveillance against bacterial and viral infections. KCs function as adhesion hubs for CD8 T cells from the circulation, which initiates the interaction of virus-specific CD8 T cells with infected hepatocytes. Through their phagocytic function, KCs contribute to removal of bacteria from the circulation and engage in cross talk with sinusoidal lymphocyte populations to achieve elimination of phagocytosed bacteria. LSECs contribute to local immune surveillance through cross-presentation of viral antigens that causes antigen-specific retention of CD8 T cells from the circulation. Such cross-presentation of viral antigens activates CD8 T cells to release TNF that in turn triggers selective killing of virus-infected hepatocytes. Beyond major histocompatibility complex (MHC)-restricted T-cell immunity, CD1- and MR1-restricted innate-like lymphocytes are found in liver sinusoids whose roles in local immune surveillance against infection need to be defined. Thus, liver sinusoidal cell populations bear key functions for hepatic recruitment and for local activation of immune cells, which are both required for efficient immune surveillance against infection in the liver.
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Affiliation(s)
- Dirk Wohlleber
- Institute of Molecular Immunology and Experimental Oncology, Technische Universität München , München, Germany
| | - Percy A Knolle
- Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, München, Germany; Institute of Experimental Immunology, Universität Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany
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40
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Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
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41
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Lukacs-Kornek V. The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development. Front Immunol 2016; 7:548. [PMID: 27965673 PMCID: PMC5127193 DOI: 10.3389/fimmu.2016.00548] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 11/16/2016] [Indexed: 01/20/2023] Open
Abstract
Lymphatics and lymphatic endothelial cells (LECs) possess multiple immunological functions besides affecting immune cell migration, such as inhibiting T cell proliferation and antigen presentation by dendritic cells. Moreover, they control the trans-endothelial transport of multiple molecules and antigens. Emerging evidence suggest their active involvements in immunregulation, tumor, and metastases formation. In the liver, increased lymphangiogenesis, specifically at the portal area has been associated with multiple liver diseases in particular primary biliary cirrhosis, idiopathic portal hypertension, and liver malignancies. Nevertheless, the exact role and contribution of LECs to liver diseases are poorly understood. The review summarizes the current understanding of LECs in liver diseases.
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42
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The CD8 T-cell response during tolerance induction in liver transplantation. Clin Transl Immunology 2016; 5:e102. [PMID: 27867515 PMCID: PMC5099425 DOI: 10.1038/cti.2016.53] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/20/2016] [Accepted: 07/22/2016] [Indexed: 12/12/2022] Open
Abstract
Both experimental and clinical studies have shown that the liver possesses unique tolerogenic properties. Liver allografts can be spontaneously accepted across complete major histocompatibility mismatch in some animal models. In addition, some liver transplant patients can be successfully withdrawn from immunosuppressive medications, developing ‘operational tolerance'. Multiple mechanisms have been shown to be involved in inducing and maintaining alloimmune tolerance associated with liver transplantation. Here, we focus on CD8 T-cell tolerance in this setting. We first discuss how alloreactive cytotoxic T-cell responses are generated against allografts, before reviewing how the liver parenchyma, donor passenger leucocytes and the host immune system function together to attenuate alloreactive CD8 T-cell responses to promote the long-term survival of liver transplants.
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43
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Protective immunity to liver-stage malaria. Clin Transl Immunology 2016; 5:e105. [PMID: 27867517 PMCID: PMC5099428 DOI: 10.1038/cti.2016.60] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 09/14/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022] Open
Abstract
Despite decades of research and recent clinical trials, an efficacious long-lasting preventative vaccine for malaria remains elusive. This parasite infects mammals via mosquito bites, progressing through several stages including the relatively short asymptomatic liver stage followed by the more persistent cyclic blood stage, the latter of which is responsible for all disease symptoms. As the liver acts as a bottleneck to blood-stage infection, it represents a potential site for parasite and disease control. In this review, we discuss immunity to liver-stage malaria. It is hoped that the knowledge gained from animal models of malaria immunity will translate into a more powerful and effective vaccine to reduce this global health problem.
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44
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Sousa-Pinto B, Correia C, Gomes L, Gil-Mata S, Araújo L, Correia O, Delgado L. HLA and Delayed Drug-Induced Hypersensitivity. Int Arch Allergy Immunol 2016; 170:163-179. [PMID: 27576480 DOI: 10.1159/000448217] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Indexed: 01/05/2025] Open
Abstract
Delayed drug allergy reactions (DDAR) are potentially fatal. Certain human leukocyte antigen (HLA) alleles have been associated with delayed allergy reactions following the administration of particular drugs. Examples are HLA-B*57:01 (abacavir), HLA-B*15:02/HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). Based on the identification of these associations, it may now be possible to prevent certain allergy reactions that were, until recently, considered unpredictable. In this review, we will focus on the pharmacogenetics of the best-studied associations between specific HLA alleles and delayed allergy reactions and describe the pathogenesis models proposed so far. Finally, we will evaluate the genetic screening strategies available and discuss the clinical relevance of a better understanding of the immunogenetics and mechanisms involved in DDAR.
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Affiliation(s)
- Bernardo Sousa-Pinto
- Laboratory of Immunology, Basic and Clinical Immunology Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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45
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Moreno-Cubero E, Larrubia JR. Specific CD8 + T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis. World J Gastroenterol 2016; 22:6469-6483. [PMID: 27605882 PMCID: PMC4968127 DOI: 10.3748/wjg.v22.i28.6469] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/21/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.
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46
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Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13:267-76. [PMID: 27063467 PMCID: PMC4856809 DOI: 10.1038/cmi.2016.3] [Citation(s) in RCA: 743] [Impact Index Per Article: 82.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 01/08/2016] [Accepted: 01/09/2016] [Indexed: 12/12/2022] Open
Abstract
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear 'dangerous' stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.
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Affiliation(s)
- Mark W Robinson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
| | - Cathal Harmon
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
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47
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Abstract
PURPOSE OF REVIEW When it comes to tolerance induction, kidney allografts behave differently from heart allografts that behave differently from lung allografts. Here, we examine how and why different organ allografts respond differently to the same tolerance induction protocol. RECENT FINDINGS Allograft tolerance has been achieved in experimental and clinical kidney transplantation. Inducing tolerance in experimental recipients of heart and lung allografts has, however, proven to be more challenging. New protocols being developed in nonhuman primates based on mixed chimerism and cotransplantation of tolerogenic organs may provide mechanistic insights to help overcome these challenges. SUMMARY Tolerance induction protocols that are successful in patients transplanted with 'tolerance-prone' organs such as kidneys and livers will most likely not succeed in recipients of 'tolerance-resistant' organs such as hearts and lungs. Separate clinical trials using more robust tolerance protocols will be required to achieve tolerance in heart and lung recipients.
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48
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Effective intrahepatic CD8+ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes. Cell Mol Immunol 2015; 13:805-815. [PMID: 26412123 PMCID: PMC5101449 DOI: 10.1038/cmi.2015.80] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/13/2022] Open
Abstract
Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8+ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8+ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin (Ova) as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.
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49
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Eckert C, Klein N, Kornek M, Lukacs-Kornek V. The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation. Front Immunol 2015; 6:179. [PMID: 25941527 PMCID: PMC4403526 DOI: 10.3389/fimmu.2015.00179] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/30/2015] [Indexed: 12/23/2022] Open
Abstract
In recent years, it has been an explosion of information regarding the role of various myeloid cells in liver pathology. Macrophages and dendritic cell (DC) play crucial roles in multiple chronic liver diseases such as fibrosis and non-alcoholic fatty liver disease (NAFLD). The complexity of myeloid cell populations and the missing exclusive marker combination make the interpretation of the data often extremely difficult. The current review aims to summarize the multiple roles of macrophages and DCs in chronic liver diseases, especially pointing out how these cells influence liver immune and parenchymal cells thereby altering liver function and pathology. Moreover, the review outlines the currently known marker combinations for the identification of these cell populations for the study of their role in liver immunology.
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Affiliation(s)
- Christoph Eckert
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
| | - Niklas Klein
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
| | - Miroslaw Kornek
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
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50
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Bertolino P, Bowen DG. Malaria and the liver: immunological hide-and-seek or subversion of immunity from within? Front Microbiol 2015; 6:41. [PMID: 25741320 PMCID: PMC4332352 DOI: 10.3389/fmicb.2015.00041] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/12/2015] [Indexed: 12/28/2022] Open
Abstract
During the pre-erythrocytic asymptomatic phase of malarial infection, sporozoites develop transiently inside less than 100 hepatocytes that subsequently release thousands of merozoites. Killing of these hepatocytes by cytotoxic T cells (CTLs) confers protection to subsequent malarial infection, suggesting that this bottleneck phase in the parasite life cycle can be targeted by vaccination. During natural transmission, although some CTLs are generated in the skin draining lymph nodes, they are unable to eliminate the parasite, suggesting that the liver is important for the sporozoite to escape immune surveillance. The contribution of the organ to this process is unclear. Based on the known ability of several hepatic antigen-presenting cells (APCs) to induce primary activation of CD8 T cells and tolerance, malarial antigens presented by both infected hepatocytes and/or hepatic cross-presenting APCs should result in tolerance. However, our latest model predicts that due to the low frequency of infected hepatocytes, some T cells recognizing sporozoite epitopes with high affinity should differentiate into CTLs. In this review, we discuss two possible models to explain why CTLs generated in the liver and skin draining lymph nodes are unable to eliminate the parasite: (1) sporozoites harness the tolerogenic property of the liver; (2) CTLs are not tolerized but fail to detect infected cells due to sparse infection of hepatocytes and the very short liver stage. We propose that while malaria sporozoites might use the ability of the liver to tolerize both naive and effector cells, they have also developed strategies to decrease the probability of encounter between CTLs and infected liver cells. Thus, we predict that to achieve protection, vaccination strategies should aim to boost intrahepatic activation and/or increase the chance of encounter between sporozoite-specific CTLs and infected hepatocytes.
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Affiliation(s)
- Patrick Bertolino
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital Sydney, NSW, Australia
| | - David G Bowen
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital Sydney, NSW, Australia
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