1
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Du Y, Zhao M, Zeng X, Wang S, Wang Q, Chen L, Yang X, Feng X, Lu M, Dittmer U, Sutter K, Zheng X, Yang D, Xu C, Liu J. Regulatory T cells suppress TLR9-induced formation of intrahepatic myeloid-cell aggregates for T cell population expansion in liver. Med Microbiol Immunol 2025; 214:24. [PMID: 40366446 DOI: 10.1007/s00430-025-00834-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Abstract
Toll-like receptor (TLR) 9 ligand has been reported to induce the formation of intrahepatic myeloid-cell aggregates for T cell population expansion (iMATEs), which enhances responses of cytotoxic T lymphocytes (CTLs). However, little is known about how the formation of iMATEs is regulated. Previously, various studies have demonstrated that regulatory T cells (Tregs) can suppress CTL responses through soluble cytokines or co-inhibitory molecules. It's unclear whether and how Tregs regulate the formation of iMATEs. In this study, we investigated whether Tregs are involved in regulating TLR9-induced iMATEs formation and the mechanisms behind it by using different gene knockout mice and blocking antibodies. We observed that intravenous injection of TLR9 ligand CpG induced significant iMATEs formation, accompanied by a marked increase in the number of Tregs infiltrating the liver as well as upregulation of IL-10 in both peripheral blood and liver. Importantly, depletion of Tregs either by anti-CD4, anti-CD25 blocking antibodies or diphtheria toxin (DT) in DEREG transgenic mice resulted in enhanced CpG-induced iMATEs formation. Conversely, knocking out IL-10 led to increased intrahepatic Treg infiltration and decreased CpG ODN-induced iMATEs formation. Consistently, depleting Kupffer cells (KCs), one of the main source of IL-10, also resulted in reduced formation of iMATEs. In conclusion, our results suggest that IL-10 suppresses Treg infiltration in the liver and thus promote CpG ODN-induced iMATEs formation. These results fill the gap in our understanding of the intrahepatic regulation mechanism of iMATEs formation.
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Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengxiao Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shichuan Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
| | - Liwei Chen
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chunli Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China.
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China.
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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2
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Keeler AM, Zhan W, Ram S, Fitzgerald KA, Gao G. The curious case of AAV immunology. Mol Ther 2025; 33:1946-1965. [PMID: 40156190 DOI: 10.1016/j.ymthe.2025.03.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/17/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
Immune responses to adeno-associated virus (AAV) have long been perplexing, from its first discovery to the latest clinical trials of recombinant AAV (rAAV) therapy. Wild-type AAV (wtAAV) does not cause any known disease, making it an ideal vector for gene therapy, as viral vectors retain virus-like properties. Although AAV stimulates only a mild immune response compared with other viruses, it is still recognized by the innate immune system and induces adaptive immune responses. B cell responses against both wtAAV and rAAV are robust and can hinder gene therapy applications and prevent redosing. T cell responses can clear transduced cells or establish tolerance against gene therapy. Immune responses to AAV gene therapy are influenced by many factors. Most clinical immunotoxicities that develop in response to gene therapies have emerged as higher doses of AAV vectors have been utilized and were not properly modeled in preclinical animal studies. Thus, several strategies have been undertaken to reduce or mitigate immune responses to AAV. While we have learned a considerable amount about how the immune system responds to AAV gene therapy since the discovery of AAV virus, it still remains a curious case that requires more investigation to fully understand.
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Affiliation(s)
- Allison M Keeler
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; NeroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Wei Zhan
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Sanjay Ram
- Division of Infectious Diseases and Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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3
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Du W, Siwan E, Twigg SM, Min D. Alterations in Immune Cell Profiles in the Liver in Diabetes Mellitus: A Systematic Review. Int J Mol Sci 2025; 26:4027. [PMID: 40362271 PMCID: PMC12071842 DOI: 10.3390/ijms26094027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/17/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
The aim of this study was to systematically review literature on immune responses in liver tissue pathology in diabetes, focusing on immune cell populations and related cytokines. A systematic search of relevant English full-text articles up to June 2024 from online databases, covering animal and human studies, was conducted using the PRISMA workflow. Thirteen studies met criteria. Immune cells in the liver, including monocytes/macrophages, neutrophils, and iNKT and T cells, were implicated in liver inflammation and fibrosis in diabetes. Pro-inflammatory cytokines, including interferon-ɣ, tumor necrosis factor-α, interleukin (IL)-15, IL-18, and IL-1β were upregulated in the liver, potentially contributing to liver inflammation and fibrosis progression. In contrast, the anti-inflammatory cytokine IL-4 was downregulated, possibly attributing to chronic inflammation in diabetes. Pathological immune responses via the TLR4/MyD88/NF-κB pathway and the IL-17/IL-23 axis were also linked to liver fibrosis in diabetes. In conclusion, this review highlights the putative pivotal role of immune cells in diabetes-related liver fibrosis progression through their regulation of cytokines and signaling pathways. Further research on diabetes and dysmetabolic liver pathology is needed to clarify immune cell localization in the liver and their interactions with resident cells promoting fibrosis. Targeting immune mechanisms may provide therapeutic strategies for managing liver fibrosis in diabetes.
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Affiliation(s)
- Wanying Du
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (W.D.); (E.S.); (S.M.T.)
| | - Elisha Siwan
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (W.D.); (E.S.); (S.M.T.)
| | - Stephen M. Twigg
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (W.D.); (E.S.); (S.M.T.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - Danqing Min
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (W.D.); (E.S.); (S.M.T.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
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4
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He Y, Hu M, Miao X, Xu F, Deng J, Song Z, Li M, Ming Y, Leng S. Dynamic Status of Systemic Immune Inflammation Index Is Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: An Evidence From a Ten-Year Prospective Longitudinal Cohort Study. J Inflamm Res 2025; 18:4595-4606. [PMID: 40191090 PMCID: PMC11972002 DOI: 10.2147/jir.s509814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/13/2025] [Indexed: 04/09/2025] Open
Abstract
Objective Previous research studies have linked the systemic immune inflammation index (SII), derived from a complete blood count, to metabolic dysfunction-associated steatotic liver disease (MASLD). However, evidence on the relationship between longitudinal changes in SII and MASLD remains limited. This study aimed to explore distinct SII trajectories and their association with MASLD incidence. Methods A longitudinal study analyzed 25,600 individuals who underwent periodic health assessments at a Dalian City hospital between 2014 and 2023. MASLD was diagnosed via ultrasound. The SII was calculated using the formula SII = (platelet count × neutrophil count) / lymphocyte count. Group-based trajectory modeling was used to identify SII trajectories, and restricted cubic spline (RCS) analysis was employed to assesse the dose-response relationship. Stratified analyses and sensitivity analyses were also conducted. Results Three SII trajectories were identified: "low stable" (50.6%), "moderate stable" (35.1%), and "high stable" (8.9%). After adjustments, the hazard ratios (HR) for MASLD incidence were 1.118 (95% CI: 1.057-1.182, P<0.001) for the "moderate stable" group and 1.284 (95% CI: 1.172-1.408, P<0.001) for the "high stable" group. These associations persisted after adjusting for lifestyle factors. A significant non-linear relationship between SII and MASLD risk was found in both the overall population and among different genders. Subgroup and sensitivity analyses consistently confirmed these findings. Conclusion Elevated SII levels are significantly associated with an increased risk of MASLD, particularly among individuals under 45 and women. Regular SII monitoring may improve risk stratification and facilitate targeted prevention strategies for those at higher risk of MASLD.
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Affiliation(s)
- Yangxuan He
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Department of Gastroenterology,the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Manling Hu
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Department of Gastroenterology,the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Xinlei Miao
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Fei Xu
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- School of Public Health. Dalian Medical University, Dalian, People’s Republic of China
| | - Jiayi Deng
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Department of Gastroenterology,the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Ziping Song
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Department of Gastroenterology,the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Meng Li
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- School of Public Health. Dalian Medical University, Dalian, People’s Republic of China
| | - Yunxiang Ming
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Department of Gastroenterology,the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Song Leng
- Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- School of Public Health. Dalian Medical University, Dalian, People’s Republic of China
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5
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Ramirez CFA, Akkari L. Myeloid cell path to malignancy: insights into liver cancer. Trends Cancer 2025:S2405-8033(25)00054-8. [PMID: 40140328 DOI: 10.1016/j.trecan.2025.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/12/2025] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2+, and SPP1+ macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.
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Affiliation(s)
- Christel F A Ramirez
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Leila Akkari
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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6
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Ferriero R, Bruno G, Padula A, Pisano S, Boffa I, Gargaro M, Imperatore T, Battipaglia M, Vivenzio S, Perna C, Nusco E, Ferrante L, Westhaus A, Knight M, Manni G, Campione S, Di Napoli E, Polishchuk E, Polishchuk R, Paciello O, Brunetti-Pierri N, Lisowski L, Fallarino F, Piccolo P. Impact of liver fibrosis on AAV-mediated gene transfer to mouse hepatocytes. Nat Commun 2025; 16:2118. [PMID: 40064861 PMCID: PMC11893804 DOI: 10.1038/s41467-025-57382-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Liver fibrosis, characterized by scar tissue accumulation due to liver injury, poses significant barriers to liver-targeted gene therapy. Current clinical trials exclude patients with fibrosis, as intact liver architecture is considered essential for efficient and safe adeno-associated viral vector (AAV)-mediated gene delivery. Here, we show that liver fibrosis reduces the efficiency of hepatocyte transduction by AAV8 vectors across three mouse models with diverse fibrotic patterns. This inefficiency stems primarily from decreased vector uptake by the liver rather than loss of vector genomes due to hepatocyte turnover. Additionally, fibrosis alters blood vector clearance and redistributes AAV particles to extra-hepatic organs, such as spleen, lung, and kidney. At the cellular level, fibrosis decreases AAV genome content in hepatocytes while increasing it in non-parenchymal liver cells and splenic immune cells. Importantly, the capsid variant AAV-KP1 retains transduction efficiency in fibrotic livers, highlighting its potential for expanding gene therapy applications to fibrotic diseases.
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Affiliation(s)
- Rosa Ferriero
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Gemma Bruno
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Agnese Padula
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Simone Pisano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- European School of Molecular Medicine (SEMM), Milan, Italy
| | - Iolanda Boffa
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Marco Gargaro
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Teresa Imperatore
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Genomics and Experimental Medicine Program, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Naples, Italy
| | - Maria Battipaglia
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- European School of Molecular Medicine (SEMM), Milan, Italy
| | - Silvia Vivenzio
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Claudia Perna
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Edoardo Nusco
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Luigi Ferrante
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Adrian Westhaus
- Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia
- Integrare Research Unit UMR S951, INSERM, Genethon, Evry, France
| | - Maddison Knight
- Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia
| | - Giorgia Manni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Evaristo Di Napoli
- Department of Veterinary Medicine and Animal Production, "Federico II" University of Naples, Naples, Italy
| | - Elena Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Roman Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Orlando Paciello
- Department of Veterinary Medicine and Animal Production, "Federico II" University of Naples, Naples, Italy
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Genomics and Experimental Medicine Program, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Naples, Italy
- Department of Translational Medicine, "Federico II" University of Naples, Naples, Italy
| | - Leszek Lisowski
- Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia
- Australian Genome Therapeutics Centre, Children's Medical Research Institute and Sydney Children's Hospitals Network, Westmead, NSW, Australia
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, Poland
| | | | - Pasquale Piccolo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
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7
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McMurphy TB, Park A, Heizer PJ, Bottenfield C, Kurasawa JH, Ikeda Y, Doran MR. AAV-mediated co-expression of an immunogenic transgene plus PD-L1 enables sustained expression through immunological evasion. Sci Rep 2024; 14:28853. [PMID: 39572604 PMCID: PMC11582688 DOI: 10.1038/s41598-024-75698-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 10/08/2024] [Indexed: 11/24/2024] Open
Abstract
Adeno-associated virus (AAV) vectors can mediate long-term expression of immunogenic transgenes in vivo through transduction of tolerogenic cells in the liver. Tissue-targeted AAV vectors allow transduction of non-hepatic cells, but this necessitates development of strategies to minimize transgene immunogenicity. Here, we first validated that AAV capsids with tissue-specific tropism and transgene promoters enabled expression of the immunogenic protein, firefly luciferase, in liver, muscle, or adipose tissue. Cellular immunity was detectable in animals where luciferase was expressed in muscle or adipose, but not liver tissue. With the objective of enhancing tolerance of transduced non-hepatic cells, AAV vectors were engineered to co-express luciferase plus the immune checkpoint protein, PD-L1. In animals where transduced cells expressed luciferase but not PD-L1, there was incremental depletion of transduced cells over time. By contrast, the bioluminescent signal increased incrementally over the study, and was significantly greater, in the muscle and adipose tissue of animals where PD-L1 was co-expressed with luciferase. Our data demonstrate that PD-L1 co-expression facilitates persistent, tissue-targeted expression of immunogenic transgenes without transducing tolerogenic hepatic cells. Our strategy of PD-L1 co-expression may provide a versatile platform for sustained expression of immunogenic transgenes in gene and cell therapies.
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Affiliation(s)
- Travis B McMurphy
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | - Andrew Park
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | - Patrick J Heizer
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | - Crystal Bottenfield
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | - James H Kurasawa
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | - Yasuhiro Ikeda
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.
| | - Michael R Doran
- Biologics Engineering, Oncology R&D, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.
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8
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Cao D, Byrne BJ, de Jong YP, Terhorst C, Duan D, Herzog RW, Kumar SR. Innate Immune Sensing of Adeno-Associated Virus Vectors. Hum Gene Ther 2024; 35:451-463. [PMID: 38887999 PMCID: PMC11310564 DOI: 10.1089/hum.2024.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/04/2024] [Indexed: 06/20/2024] Open
Abstract
Adeno-associated virus (AAV) based viral vectors are widely used in human gene therapy and form the basis of approved treatments for several genetic diseases. Immune responses to vector and transgene products, however, substantially complicate these applications in clinical practice. The role of innate immune recognition of AAV vectors was initially unclear, given that inflammatory responses early after vector administration were typically mild in animal models. However, more recent research continues to identify innate immune pathways that are triggered by AAV vectors and that serve to provide activation signals for antigen-presenting cells and initiation of adaptive immune responses. Sensing of the AAV genome by the endosomal DNA receptor toll-like receptor 9 (TLR9) promotes early inflammatory response and interferon expression. Thus, activation of the TLR9>MyD88 pathway in plasmacytoid dendritic cells (pDCs) leads to the conditioning of antigen cross-presenting DCs through type I interferon (IFN-I) and ultimately CD8+ T cell activation. Alternatively, pDCs may also promote CD8+ T cell responses in a TLR9-independent manner by the production of IL-1 cytokines, thereby activating the IL-1R1>MyD88 signaling pathway. AAV can induce cytokine expression in monocyte-derived DCs, which in turn increases antibody formation. Binding of AAV capsid to complement components likely further elevates B cell activation. At high systemic vector doses in humans and in non-human primates, AAV vectors can trigger complement activation, with contributions by classical and alternative pathways, leading to severe toxicities. Finally, evidence for activation of TLR2 by the capsid and of additional innate receptors for nucleic acids has been presented. These observations show that AAV vectors can initiate several and likely redundant innate immune pathways resulting in an exaggerated adaptive immune response.
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Affiliation(s)
- Di Cao
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
| | - Barry J. Byrne
- Department of Pediatrics, University of Florida, Gainesville, Florida, USA
| | - Ype P. de Jong
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, New York, USA
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts, USA
| | - Dongsheng Duan
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Roland W. Herzog
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
| | - Sandeep R.P. Kumar
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
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9
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Muñoz-Melero M, Biswas M. Role of FoxP3 + Regulatory T Cells in Modulating Immune Responses to Adeno-Associated Virus Gene Therapy. Hum Gene Ther 2024; 35:439-450. [PMID: 38450566 PMCID: PMC11302314 DOI: 10.1089/hum.2023.227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/04/2024] [Indexed: 03/08/2024] Open
Abstract
Adeno-associated virus (AAV) gene therapy is making rapid strides owing to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to the viral vector or transgene, although there is no consensus on the best treatment regimen, dosage, or schedule. Regulatory T cells (Tregs) are crucial for maintaining tolerance against self or nonself antigens. Of importance, Tregs also play an important role in dampening immune responses to AAV gene therapy, including tolerance induction to the transgene product. Approaches to harness the tolerogenic effect of Tregs include the use of selective IS drugs that expand existing Tregs, and skew activated conventional T cells into antigen-specific peripherally induced Tregs. In addition, Tregs can be expanded ex vivo and delivered as cellular therapy. Furthermore, receptor engineering can be used to increase the potency and specificity of Tregs allowing for suppression at lower doses and reducing the risk of disrupting protective immunity. Because immune-mediated toxicities to AAV vectors are a concern in the clinic, strategies that can enhance or preserve Treg function should be considered to improve both the safety and efficacy of AAV gene therapy.
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Affiliation(s)
- Maite Muñoz-Melero
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
| | - Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
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10
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Meng X, Zhu G, Yang YG, Sun T. Targeted delivery strategies: The interactions and applications of nanoparticles in liver diseases. Biomed Pharmacother 2024; 175:116702. [PMID: 38729052 DOI: 10.1016/j.biopha.2024.116702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024] Open
Abstract
In recent years, nanoparticles have been broadly utilized in various drugs delivery formulations. Nanodelivery systems have shown promise in solving problems associated with the distribution of hydrophobic drugs and have promoted the accumulation of nanomedicines in the circulation or in organs. However, the injection dose of nanoparticles (NPs) is much greater than that needed by diseased tissues or organs. In other words, most of the NPs are localized off-target and do not reach the desired tissue or organs. With the rapid development of biodegradable and biosafety nanomaterials, the nanovectors represent assurance of safety. However, the off-target effects also induce concerns about the application of NPs, especially in the delivery of gene editing tools. Therefore, a complete understanding of the biological responses to NPs in the body will clearly guide the design of targeted delivery of NPs. The different properties of various nanodelivery systems may induce diverse interactions between carriers and organs. In this review, we describe the relationship between the liver, the most influenced organ of systemic administration of NPs, and targeted delivery nanoplatforms. Various transport vehicles have adopted multiple delivery strategies for the targeted delivery to the cells in the homeostasis liver and in diseased liver. Additionally, nanodelivery systems provide a novel strategy for treating incurable diseases. The appearance of a targeted delivery has profoundly improved the application of NPs to liver diseases.
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Affiliation(s)
- Xiandi Meng
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China
| | - Ge Zhu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China.
| | - Tianmeng Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China; State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin, China.
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11
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Mladenić K, Lenartić M, Marinović S, Polić B, Wensveen FM. The "Domino effect" in MASLD: The inflammatory cascade of steatohepatitis. Eur J Immunol 2024; 54:e2149641. [PMID: 38314819 DOI: 10.1002/eji.202149641] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic-associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue-resident immune cells including γδ T cells and CD4-CD8- double-negative T cells, followed by their secretion of pro-inflammatory mediators, most notably IL-17A. (2) Recruitment of pro-inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector-type cytokines such as TNF, TGF-β, and IL-1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD.
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Affiliation(s)
- Karlo Mladenić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Maja Lenartić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Sonja Marinović
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
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12
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Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, Sokal EM, Najimi M. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front Immunol 2024; 15:1371089. [PMID: 38571964 PMCID: PMC10987744 DOI: 10.3389/fimmu.2024.1371089] [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: 01/16/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.
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Affiliation(s)
- Ananya Ajith
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Makram Merimi
- Genetics and Immune Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Etienne Marc Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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13
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Gaddie CD, Senior KG, Chan C, Hoffman BE, Keeler GD. Upregulation of CD8 + regulatory T cells following liver-directed AAV gene therapy. Cell Immunol 2024; 397-398:104806. [PMID: 38244266 DOI: 10.1016/j.cellimm.2024.104806] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/21/2023] [Accepted: 01/10/2024] [Indexed: 01/22/2024]
Abstract
Liver-directed AAV gene therapy represents a unique treatment modality for a host of diseases. This is due, in part, to the induction of tolerance to transgene products. Despite the plethora of recognized regulatory cells in the body, there is currently a lack of literature supporting the induction of non-CD4+ regulatory cells following hepatic AAV gene transfer. In this work, we show that CD8+ regulatory T cells are up-regulated in PBMCs of mice following capsid only and therapeutic transgene AAV administration. Further, we demonstrate that hepatic AAV gene transfer results in a significant increase in CD8+ regulatory T cells following experimental autoimmune encephalomyelitis induction. Notably, this response occurred only in therapeutic vector treated animals, not capsid only controls. Understanding the role these cells play in treatment efficacy will result in the development of improved AAV vectors that take advantage of the full gamut of regulatory cells within the body.
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Affiliation(s)
- Cristina D Gaddie
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Kevin G Senior
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Christopher Chan
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Brad E Hoffman
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA; Department of Neuroscience, University of Florida, Gainesville, FL, USA
| | - Geoffrey D Keeler
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA.
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14
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Pan J, Ye F, Li H, Yu C, Mao J, Xiao Y, Chen H, Wu J, Li J, Fei L, Wu Y, Meng X, Guo G, Wang Y. Dissecting the immune discrepancies in mouse liver allograft tolerance and heart/kidney allograft rejection. Cell Prolif 2024; 57:e13555. [PMID: 37748771 PMCID: PMC10905343 DOI: 10.1111/cpr.13555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 08/23/2023] [Accepted: 09/15/2023] [Indexed: 09/27/2023] Open
Abstract
The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver).
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Affiliation(s)
- Jun Pan
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Fang Ye
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hui Li
- Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chengxuan Yu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiajia Mao
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yanyu Xiao
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Haide Chen
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Junqing Wu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiaqi Li
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lijiang Fei
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yijun Wu
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Xiaoming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of PharmacyAnhui Medical University, The Key Laboratory of Anti‐inflammatory of Immune Medicines, Ministry of EducationHefeiChina
| | - Guoji Guo
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative MedicineDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineHangzhouZhejiangChina
| | - Yingying Wang
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
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15
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Wang X, Zhou Y, Wu Z, Xie C, Xu W, Zhou Q, Yang D, Zhu D, Wang MW, Wang L. Single-cell transcriptomics reveals the role of antigen presentation in liver metastatic breast cancer. iScience 2024; 27:108896. [PMID: 38318373 PMCID: PMC10839686 DOI: 10.1016/j.isci.2024.108896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/28/2023] [Accepted: 01/09/2024] [Indexed: 02/07/2024] Open
Abstract
Liver metastasis (LM) is the primary cause of cancer-related mortality in late-stage breast cancer (BC) patients. Here we report an in-depth analysis of the transcriptional landscape of LM of 11 patients with secondary hepatic carcinoma at single-cell resolution. Our study reveals that terminally exhausted CD4+ and dysfunctional CD8+ T cells were enriched in LM along with low antigen presentation. We also found that macrophages were associated with the tumor infiltrating CD4+ T cells, while FCN3+ macrophages, type 1 conventional dendritic cells (cDC1) and LAMP3+ DC regulated T cell functions, probably via antigen processing and presentation. Major histocompatibility complex expression in FCN3+ macrophage, cDC1 and LAMP3+ DC was reduced in LM compared to those in normal tissues and primary BC. Malfunctioned antigen presentation in these cells is linked to a worse prognosis in invasive BC and hepatocellular carcinoma. Our results provide valuable insights into the role of tumor infiltrating T cells in LM.
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Affiliation(s)
- Xiaoshuang Wang
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yan Zhou
- The National Center for Drug Screening and the State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
| | - Zhongen Wu
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Cao Xie
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Weiqi Xu
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Qingtong Zhou
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Dehua Yang
- The National Center for Drug Screening and the State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
| | - Di Zhu
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Minhang Hospital and Shanghai Medical College, Fudan University, Shanghai 201100, China
| | - Ming-Wei Wang
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Research Center for Deepsea Bioresources, Sanya, Hainan 572025, China
| | - Lu Wang
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
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16
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Kumar SRP, Biswas M, Cao D, Arisa S, Muñoz-Melero M, Lam AK, Piñeros AR, Kapur R, Kaisho T, Kaufman RJ, Xiao W, Shayakhmetov DM, Terhorst C, de Jong YP, Herzog RW. TLR9-independent CD8 + T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling. Mol Ther 2024; 32:325-339. [PMID: 38053332 PMCID: PMC10861967 DOI: 10.1016/j.ymthe.2023.11.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/14/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023] Open
Abstract
Upon viral infection of the liver, CD8+ T cell responses may be triggered despite the immune suppressive properties that manifest in this organ. We sought to identify pathways that activate responses to a neoantigen expressed in hepatocytes, using adeno-associated viral (AAV) gene transfer. It was previously established that cooperation between plasmacytoid dendritic cells (pDCs), which sense AAV genomes by Toll-like receptor 9 (TLR9), and conventional DCs promotes cross-priming of capsid-specific CD8+ T cells. Surprisingly, we find local initiation of a CD8+ T cell response against antigen expressed in ∼20% of murine hepatocytes, independent of TLR9 or type I interferons and instead relying on IL-1 receptor 1-MyD88 signaling. Both IL-1α and IL-1β contribute to this response, which can be blunted by IL-1 blockade. Upon AAV administration, IL-1-producing pDCs infiltrate the liver and co-cluster with XCR1+ DCs, CD8+ T cells, and Kupffer cells. Analogous events were observed following coagulation factor VIII gene transfer in hemophilia A mice. Therefore, pDCs have alternative means of promoting anti-viral T cell responses and participate in intrahepatic immune cell networks similar to those that form in lymphoid organs. Combined TLR9 and IL-1 blockade may broadly prevent CD8+ T responses against AAV capsid and transgene product.
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Affiliation(s)
- Sandeep R P Kumar
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Moanaro Biswas
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Di Cao
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Sreevani Arisa
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Maite Muñoz-Melero
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Anh K Lam
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Annie R Piñeros
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Reuben Kapur
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Randal J Kaufman
- Center for Genetic Disorders and Aging Research, Samford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Weidong Xiao
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
| | - Dmitry M Shayakhmetov
- Lowance Center for Human Immunology, Emory Vaccine Center, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, USA
| | - Ype P de Jong
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Roland W Herzog
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA.
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17
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Wang Z, Liu N, Yang Y, Tu Z. The novel mechanism facilitating chronic hepatitis B infection: immunometabolism and epigenetic modification reprogramming. Front Immunol 2024; 15:1349867. [PMID: 38288308 PMCID: PMC10822934 DOI: 10.3389/fimmu.2024.1349867] [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: 12/05/2023] [Accepted: 01/02/2024] [Indexed: 01/31/2024] Open
Abstract
Hepatitis B Virus (HBV) infections pose a global public health challenge. Despite extensive research on this disease, the intricate mechanisms underlying persistent HBV infection require further in-depth elucidation. Recent studies have revealed the pivotal roles of immunometabolism and epigenetic reprogramming in chronic HBV infection. Immunometabolism have identified as the process, which link cell metabolic status with innate immunity functions in response to HBV infection, ultimately contributing to the immune system's inability to resolve Chronic Hepatitis B (CHB). Within hepatocytes, HBV replication leads to a stable viral covalently closed circular DNA (cccDNA) minichromosome located in the nucleus, and epigenetic modifications in cccDNA enable persistence of infection. Additionally, the accumulation or depletion of metabolites not only directly affects the function and homeostasis of immune cells but also serves as a substrate for regulating epigenetic modifications, subsequently influencing the expression of antiviral immune genes and facilitating the occurrence of sustained HBV infection. The interaction between immunometabolism and epigenetic modifications has led to a new research field, known as metabolic epigenomics, which may form a mutually reinforcing relationship with CHB. Herein, we review the recent studies on immunometabolism and epigenetic reprogramming in CHB infection and discuss the potential mechanisms of persistent HBV infection. A deeper understanding of these mechanisms will offer novel insights and targets for intervention strategies against chronic HBV infection, thereby providing new hope for the treatment of related diseases.
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Affiliation(s)
- Zhengmin Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Nan Liu
- Institute of Epigenetic Medicine, First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhengkun Tu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
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18
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Chen J, Chan TTH, Zhou J. Lipid metabolism in the immune niche of tumor-prone liver microenvironment. J Leukoc Biol 2024; 115:68-84. [PMID: 37474318 DOI: 10.1093/jleuko/qiad081] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/23/2023] [Accepted: 07/06/2023] [Indexed: 07/22/2023] Open
Abstract
The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.
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Affiliation(s)
- Jintian Chen
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Thomas T H Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
| | - Jingying Zhou
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
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19
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Valentino LA, Ozelo MC, Herzog RW, Key NS, Pishko AM, Ragni MV, Samelson-Jones BJ, Lillicrap D. A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment? J Thromb Haemost 2023; 21:3033-3044. [PMID: 37225021 DOI: 10.1016/j.jtha.2023.05.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/09/2023] [Accepted: 05/14/2023] [Indexed: 05/26/2023]
Abstract
The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.
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Affiliation(s)
- Leonard A Valentino
- National Hemophilia Foundation, New York, New York, USA; Rush University, Chicago, Illinois, USA.
| | | | - Roland W Herzog
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nigel S Key
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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20
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Li J, Karakas D, Xue F, Chen Y, Zhu G, Yucel YH, MacParland SA, Zhang H, Semple JW, Freedman J, Shi Q, Ni H. Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression. RESEARCH (WASHINGTON, D.C.) 2023; 6:0236. [PMID: 37808178 PMCID: PMC10551749 DOI: 10.34133/research.0236] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/02/2023] [Indexed: 10/10/2023]
Abstract
Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell-Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+ regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.
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Affiliation(s)
- June Li
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
| | - Danielle Karakas
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
| | - Feng Xue
- Departments of Pediatrics,
Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI, USA
| | - Yingyu Chen
- Departments of Pediatrics,
Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI, USA
| | - Guangheng Zhu
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
| | - Yeni H. Yucel
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Departments of Ophthalmology and Vision Sciences Medicine,
University of Toronto, Toronto, ON, Canada
- Faculty of Engineering and Architectural Science,
Ryerson University, Toronto, ON, Canada
| | - Sonya A. MacParland
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Multi-Organ Transplant Program,
Toronto General Hospital Research Institute, Toronto, ON, Canada
- Department of Immunology,
University of Toronto, Toronto, ON, Canada
| | - Haibo Zhang
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Critical Care Medicine, Department of Anesthesiology and Pain,
University of Toronto, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
| | - John W. Semple
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Pharmacology,
University of Toronto, Toronto, ON, Canada
- Division of Hematology and Transfusion Medicine,
Lund University, Lund, Sweden
- Clinical Immunology and Transfusion Medicine,
Office of Medical Services, Region Skåne, Lund, Sweden
| | - John Freedman
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Department of Medicine,
University of Toronto, Toronto, ON, Canada
| | - Qizhen Shi
- Departments of Pediatrics,
Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI, USA
- Children’s Research Institute, Children’s Wisconsin, Wauwatosa, WI, USA
- Midwest Athletes Against Childhood Cancer Fund Research Center, Milwaukee, WI, USA
| | - Heyu Ni
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
- Department of Medicine,
University of Toronto, Toronto, ON, Canada
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21
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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22
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Kaps L, Limeres MJ, Schneider P, Svensson M, Zeyn Y, Fraude S, Cacicedo ML, Galle PR, Gehring S, Bros M. Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications. Int J Mol Sci 2023; 24:11869. [PMID: 37511628 PMCID: PMC10380755 DOI: 10.3390/ijms241411869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/21/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.
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Affiliation(s)
- Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - María José Limeres
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Paul Schneider
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Malin Svensson
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Yanira Zeyn
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Silvia Fraude
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Maximiliano L Cacicedo
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Peter R Galle
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Stephan Gehring
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
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23
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Chung C, Kudchodkar SB, Chung CN, Park YK, Xu Z, Pardi N, Abdel-Mohsen M, Muthumani K. Expanding the Reach of Monoclonal Antibodies: A Review of Synthetic Nucleic Acid Delivery in Immunotherapy. Antibodies (Basel) 2023; 12:46. [PMID: 37489368 PMCID: PMC10366852 DOI: 10.3390/antib12030046] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 07/26/2023] Open
Abstract
Harnessing the immune system to combat disease has revolutionized medical treatment. Monoclonal antibodies (mAbs), in particular, have emerged as important immunotherapeutic agents with clinical relevance in treating a wide range of diseases, including allergies, autoimmune diseases, neurodegenerative disorders, cancer, and infectious diseases. These mAbs are developed from naturally occurring antibodies and target specific epitopes of single molecules, minimizing off-target effects. Antibodies can also be designed to target particular pathogens or modulate immune function by activating or suppressing certain pathways. Despite their benefit for patients, the production and administration of monoclonal antibody therapeutics are laborious, costly, and time-consuming. Administration often requires inpatient stays and repeated dosing to maintain therapeutic levels, limiting their use in underserved populations and developing countries. Researchers are developing alternate methods to deliver monoclonal antibodies, including synthetic nucleic acid-based delivery, to overcome these limitations. These methods allow for in vivo production of monoclonal antibodies, which would significantly reduce costs and simplify administration logistics. This review explores new methods for monoclonal antibody delivery, including synthetic nucleic acids, and their potential to increase the accessibility and utility of life-saving treatments for several diseases.
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Affiliation(s)
| | | | - Curtis N Chung
- GeneOne Life Science, Inc., Seoul 04500, Republic of Korea
| | - Young K Park
- GeneOne Life Science, Inc., Seoul 04500, Republic of Korea
| | - Ziyang Xu
- Massachusetts General Hospital, Harvard University, Boston, MA 02114, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Kar Muthumani
- GeneOne Life Science, Inc., Seoul 04500, Republic of Korea
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24
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Yang L, Meng Y, Shi Y, Fang H, Zhang L. Maternal hepatic immunology during pregnancy. Front Immunol 2023; 14:1220323. [PMID: 37457700 PMCID: PMC10348424 DOI: 10.3389/fimmu.2023.1220323] [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: 05/10/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
The liver plays pivotal roles in immunologic responses, and correct hepatic adaptations in maternal immunology are required during pregnancy. In this review, we focus on anatomical and immunological maternal hepatic adaptations during pregnancy, including our recent reports in this area. Moreover, we summarize maternal pregnancy-associated liver diseases, including hyperemesis gravidarum; intrahepatic cholestasis of pregnancy; preeclampsia, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute fatty liver of pregnancy. In addition, the latest information about the factors that regulate hepatic immunology during pregnancy are reviewed for the first time, including human chorionic gonadotropin, estrogen, progesterone, growth hormone, insulin like growth factor 1, oxytocin, adrenocorticotropic hormone, adrenal hormone, prolactin, melatonin and prostaglandins. In summary, the latest progress on maternal hepatic anatomy and immunological adaptations, maternal pregnancy-associated diseases and the factors that regulate hepatic immunology during pregnancy are discussed, which may be used to prevent embryo loss and abortion, as well as pregnancy-associated liver diseases.
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25
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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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26
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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27
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Shen W, Chen Y, Lei P, Sheldon M, Sun Y, Yao F, Ma L. Immunotherapeutic Approaches for Treating Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:5013. [PMID: 36291797 PMCID: PMC9599666 DOI: 10.3390/cancers14205013] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Liver cancer is a life-threatening disease, and its incidence is increasing globally. The most common form of liver cancer is hepatocellular carcinoma (HCC). Approximately half of patients with HCC, especially those at advanced disease stages, receive systemic therapies, including the tyrosine kinase inhibitors sorafenib and lenvatinib. Over the past few years, immune checkpoint inhibitors (ICIs) have changed the landscape of HCC treatment. In particular, the combination therapy with atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) significantly improved survival benefits compared with sorafenib as a single agent, a finding that has stimulated further preclinical and clinical development of immunotherapeutic approaches for treating HCC. In addition to ICIs, oncolytic immunotherapy and adoptive T cell therapy have also emerged as immunotherapeutic strategies. A major challenge is that the tumor microenvironment of HCC is usually immunosuppressive, leading to immune escape and immunotherapy resistance. Hence, combination therapies that could sensitize HCC to immunotherapy have become a growing area of investigation. In this review, we summarize recent advances in HCC immuno-oncology and review immunotherapeutic strategies that are under development for treating HCC.
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Affiliation(s)
- Wanying Shen
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
| | - Yujie Chen
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
| | - Pan Lei
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Marisela Sheldon
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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28
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Wang D, Fu B, Wei H. Advances in Immunotherapy for Hepatitis B. Pathogens 2022; 11:1116. [PMID: 36297173 PMCID: PMC9612046 DOI: 10.3390/pathogens11101116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus with the potential to cause chronic infection, and it is one of the common causes of liver disease worldwide. Chronic HBV infection leads to liver cirrhosis and, ultimately, hepatocellular carcinoma (HCC). The persistence of covalently closed circular DNA (cccDNA) and the impaired immune response in patients with chronic hepatitis B (CHB) has been studied over the past few decades. Despite advances in the etiology of HBV and the development of potent virus-suppressing regimens, a cure for HBV has not been found. Both the innate and adaptive branches of immunity contribute to viral eradication. However, immune exhaustion and evasion have been demonstrated during CHB infection, although our understanding of the mechanism is still evolving. Recently, the successful use of an antiviral drug for hepatitis C has greatly encouraged the search for a cure for hepatitis B, which likely requires an approach focused on improving the antiviral immune response. In this review, we discuss our current knowledge of the immunopathogenic mechanisms and immunobiology of HBV infection. In addition, we touch upon why the existing therapeutic approaches may not achieve the goal of a functional cure. We also propose how combinations of new drugs, and especially novel immunotherapies, contribute to HBV clearance.
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Affiliation(s)
- Dongyao Wang
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
- Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu 233030, China
| | - Binqing Fu
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
| | - Haiming Wei
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
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29
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Li X, Wei X, Lin J, Ou L. A versatile toolkit for overcoming AAV immunity. Front Immunol 2022; 13:991832. [PMID: 36119036 PMCID: PMC9479010 DOI: 10.3389/fimmu.2022.991832] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/17/2022] [Indexed: 12/12/2022] Open
Abstract
Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy and has been widely used in >200 clinical trials globally. There are already several approved gene therapy products, e.g., Luxturna and Zolgensma, highlighting the remarkable potential of AAV delivery. In the past, AAV has been seen as a relatively non-immunogenic vector associated with low risk of toxicity. However, an increasing number of recent studies indicate that immune responses against AAV and transgene products could be the bottleneck of AAV gene therapy. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment as there is high prevalence of antibodies among humans. Moreover, immune response could lead to loss of efficacy over time and severe toxicity, manifested as liver enzyme elevations, kidney injury, and thrombocytopenia, resulting in deaths of non-human primates and patients. Therefore, extensive efforts have been attempted to address these issues, including capsid engineering, plasmapheresis, IgG proteases, CpG depletion, empty capsid decoy, exosome encapsulation, capsid variant switch, induction of regulatory T cells, and immunosuppressants. This review will discuss these methods in detail and highlight important milestones along the way.
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Affiliation(s)
- Xuefeng Li
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital; State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Shenzhen Luohu People’s Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xiaoli Wei
- Guangzhou Dezheng Biotechnology Co., Ltd., Guangzhou, China
| | - Jinduan Lin
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital; State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Li Ou
- Genemagic Biosciences, Philadelphia, PA, United States
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
- *Correspondence: Li Ou,
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30
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The Roles of Skin Langerhans Cells in Immune Tolerance and Cancer Immunity. Vaccines (Basel) 2022; 10:vaccines10091380. [PMID: 36146458 PMCID: PMC9503294 DOI: 10.3390/vaccines10091380] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/14/2022] [Accepted: 08/19/2022] [Indexed: 12/19/2022] Open
Abstract
Langerhans cells (LC) are a unique population of tissue-resident macrophages with dendritic cell (DC) functionality that form a network of cells across the epidermis of the skin. Their location at the skin barrier suggests an important role for LC as immune sentinels at the skin surface. The classification of LC as DC over the past few decades has driven the scientific community to extensively study how LC function as DC-like cells that prime T cell immunity. However, LC are a unique type of tissue-resident macrophages, and recent evidence also supports an immunoregulatory role of LC at steady state and during specific inflammatory conditions, highlighting the impact of cutaneous environment in shaping LC functionality. In this mini review, we discuss the recent literature on the immune tolerance function of LC in homeostasis and disease conditions, including malignant transformation and progression; as well as LC functional plasticity for adaption to microenvironmental cues and the potential connection between LC population heterogeneity and functional diversity. Future investigation into the molecular mechanisms that LC use to integrate different microenvironment cues and adapt immunological responses for controlling LC functional plasticity is needed for future breakthroughs in tumor immunology, vaccine development, and treatments for inflammatory skin diseases.
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31
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Malko D, Elmzzahi T, Beyer M. Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology. Front Immunol 2022; 13:954798. [PMID: 35936011 PMCID: PMC9354719 DOI: 10.3389/fimmu.2022.954798] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/29/2022] [Indexed: 11/26/2022] Open
Abstract
Treg cells have been initially described as gatekeepers for the control of autoimmunity, as they can actively suppress the activity of other immune cells. However, their role goes beyond this as Treg cells further control immune responses during infections and tumor development. Furthermore, Treg cells can acquire additional properties for e.g., the control of tissue homeostasis. This is instructed by a specific differentiation program and the acquisition of effector properties unique to Treg cells in non-lymphoid tissues. These tissue Treg cells can further adapt to their tissue environment and acquire distinct functional properties through specific transcription factors activated by a combination of tissue derived factors, including tissue-specific antigens and cytokines. In this review, we will focus on recent findings extending our current understanding of the role and differentiation of these tissue Treg cells. As such we will highlight the importance of tissue Treg cells for tissue maintenance, regeneration, and repair in adipose tissue, muscle, CNS, liver, kidney, reproductive organs, and the lung.
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Affiliation(s)
- Darya Malko
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Tarek Elmzzahi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Marc Beyer
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- Platform foR SinglE Cell GenomIcS and Epigenomics (PRECISE), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and University of Bonn, Bonn, Germany
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32
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Chang H, Ni Y, Shen C, Li C, He K, Zhu X, Chen L, Chen L, Qiu J, Ji Y, Hou M, Ji M, Xu Z. Peritoneal GATA6 + macrophage drives hepatic immunopathogenesis and maintains the T reg cell niche in the liver. Immunol Suppl 2022; 167:77-93. [PMID: 35689656 DOI: 10.1111/imm.13519] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/25/2022] [Indexed: 11/28/2022]
Abstract
The source of macrophages that contribute to human liver disease remains poorly understood. The purpose of this study is to investigate the functional mechanism of peritoneal macrophages in the development of hepatic immunopathology. By performing the natural infection with the blood fluke Schistosoma japonicum (S. japonicum) and the chemically carbon tetrachloride (CCl4 )-induced liver injured mouse model, we identified the peritoneal cavity as an essential source of hepatic macrophages. Here, we show that a large number of F4/80+ macrophages was accumulated in the peritoneal cavity during liver injury. An unknown source population of macrophages, which highly expressed GATA6 that is specific to peritoneal macrophages, was found to exist in the injured livers. Peritoneal macrophage deletion by injection with clodronate-containing liposomes led to an attenuated hepatic pathology and the inflammatory microenvironment, while adoptive transfer of macrophages into the abdominal cavity, by contrast, results in restoring liver pathology. Importantly, there are set genes of monocyte chemoattractant protein (MCP)-1, -2, and -3 that are highly related to recruit GATA6+ macrophages during S. japonicum infection, while administration of bindarit, a selective inhibitor of MCPs synthesis, dramatically decreased the hepatic expression of GATA6+ macrophages and thus attenuated hepatic pathology. Furthermore, in vivo study showed that peritoneal macrophages promote hepatic immunopathology is dependent on the accumulation of regulatory T cells (Tregs) in the liver. Altogether, these data provide the first clear evidence that GATA6+ peritoneal macrophages play critical roles in both the formation of hepatic immunopathology and the accumulation of Tregs cells.
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Affiliation(s)
- Hao Chang
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yangyue Ni
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunxiang Shen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Li
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kaiyue He
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinyi Zhu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Chen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu Chen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingfan Qiu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yong Ji
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Min Hou
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Minjun Ji
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China.,NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhipeng Xu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China.,NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, China
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33
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Moayedfard Z, Sani F, Alizadeh A, Bagheri Lankarani K, Zarei M, Azarpira N. The role of the immune system in the pathogenesis of NAFLD and potential therapeutic impacts of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2022; 13:242. [PMID: 35672797 PMCID: PMC9175371 DOI: 10.1186/s13287-022-02929-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 05/23/2022] [Indexed: 12/15/2022] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by intra-hepatocyte triglyceride accumulation and concomitant involvement of the immune system with subsequent histological changes, tissue damage, and clinical findings. There are various molecular pathways involved in the progression of NAFLD including lipotoxicity, endoplasmic reticulum stress, and the immune response. Both innate and adaptive immune systems are involved in the NAFLD pathogenesis, and crosstalk between the immune cells and liver cells participates in its initiation and progression. Among the various treatments for this disease, new cell based therapies have been proposed. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC) (MSC-EVs) are new cell-free vehicles with low immunogenicity, which can suppress detrimental immune responses in inflamed tissues. This review aimed to express the immune system's molecular pathways associated with the initiation and progression of NAFLD. Then, the possible role of MSC-EVs in the treatment of this entity through immune response modulation was discussed. Finally, engineered EVs enhanced by specific therapeutic miRNA were suggested for alleviating the pathological cellular events in liver disease.
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Affiliation(s)
- Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farnaz Sani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mohammad Zarei
- Renal Division, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, P.O. Box: 7193711351, Shiraz, Iran.
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34
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Cao X, Lai SWT, Chen S, Wang S, Feng M. Targeting tumor-associated macrophages for cancer immunotherapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:61-108. [PMID: 35636930 DOI: 10.1016/bs.ircmb.2022.02.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.
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Affiliation(s)
- Xu Cao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
| | - Seigmund W T Lai
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Siqi Chen
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Sadira Wang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Mingye Feng
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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35
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Gottwick C, Carambia A, Herkel J. Harnessing the liver to induce antigen-specific immune tolerance. Semin Immunopathol 2022; 44:475-484. [PMID: 35513495 PMCID: PMC9256566 DOI: 10.1007/s00281-022-00942-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/20/2022] [Indexed: 12/17/2022]
Abstract
Autoimmune diseases develop when the adaptive immune system attacks the body’s own antigens leading to tissue damage. At least 80 different conditions are believed to have an autoimmune aetiology, including rheumatoid arthritis, type I diabetes, multiple sclerosis or systemic lupus erythematosus. Collectively, autoimmune diseases are a leading cause of severe health impairment along with substantial socioeconomic costs. Current treatments are mostly symptomatic and non-specific, and it is typically not possible to cure these diseases. Thus, the development of more causative treatments that suppress only the pathogenic immune responses, but spare general immunity is of great biomedical interest. The liver offers considerable potential for development of such antigen-specific immunotherapies, as it has a distinct physiological capacity to induce immune tolerance. Indeed, the liver has been shown to specifically suppress autoimmune responses to organ allografts co-transplanted with the liver or to autoantigens that were transferred to the liver. Liver tolerance is established by a unique microenvironment that facilitates interactions between liver-resident antigen-presenting cells and lymphocytes passing by in the low blood flow within the hepatic sinusoids. Here, we summarise current concepts and mechanisms of liver immune tolerance, and review present approaches to harness liver tolerance for antigen-specific immunotherapy.
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Affiliation(s)
- Cornelia Gottwick
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Antonella Carambia
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Johannes Herkel
- First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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36
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Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
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Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
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37
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Lu JQ, Wong KB, Shaw PC. A Sixty-Year Research and Development of Trichosanthin, a Ribosome-Inactivating Protein. Toxins (Basel) 2022; 14:178. [PMID: 35324675 PMCID: PMC8950148 DOI: 10.3390/toxins14030178] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Tian Hua Fen, a herbal powder extract that contains trichosanthin (TCS), was used as an abortifacient in traditional Chinese medicine. In 1972, TCS was purified to alleviate the side effects. Because of its clinical applications, TCS became one of the most active research areas in the 1960s to the 1980s in China. These include obtaining the sequence information in the 1980s and the crystal structure in 1995. The replication block of TCS on human immunodeficiency virus in lymphocytes and macrophages was found in 1989 and started a new chapter of its development. Clinical studies were subsequently conducted. TCS was also found to have the potential for gastric and colorectal cancer treatment. Studies on its mechanism showed TCS acts as an rRNA N-glycosylase (EC 3.2.2.22) by hydrolyzing and depurinating A-4324 in α-sarcin/ricin loop on 28S rRNA of rat ribosome. Its interaction with acidic ribosomal stalk proteins was revealed in 2007, and its trafficking in mammalian cells was elucidated in the 2000s. The adverse drug reactions, such as inducing immune responses, short plasma half-life, and non-specificity, somehow became the obstacles to its usage. Immunotoxins, sequence modification, or coupling with polyethylene glycerol and dextran were developed to improve the pharmacological properties. TCS has nicely shown the scientific basis of traditional Chinese medicine and how its research and development have expanded the knowledge and applications of ribosome-inactivating proteins.
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Affiliation(s)
- Jia-Qi Lu
- Centre for Protein Science and Crystallography, School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China; (J.-Q.L.); (K.-B.W.)
| | - Kam-Bo Wong
- Centre for Protein Science and Crystallography, School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China; (J.-Q.L.); (K.-B.W.)
| | - Pang-Chui Shaw
- Centre for Protein Science and Crystallography, School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China; (J.-Q.L.); (K.-B.W.)
- Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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38
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Hunt NJ, McCourt PAG, Kuncic Z, Le Couteur DG, Cogger VC. Opportunities and Challenges for Nanotherapeutics for the Aging Population. FRONTIERS IN NANOTECHNOLOGY 2022. [DOI: 10.3389/fnano.2022.832524] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Nanotherapeutics utilize the properties of nanomaterials to alter the pharmacology of the drugs and therapies being transported, leading to changes in their biological disposition (absorption, distribution, cellular uptake, metabolism and elimination) and ultimately, their pharmacological effect. This provides an opportunity to optimize the pharmacology of drugs, particularly for those that are dependent on hepatic action. Old age is associated with changes in many pharmacokinetic processes which tend to impair drug efficacy and increase risk of toxicity. While these age-related changes are drug-specific they could be directly addressed using nanotechnology and precision targeting. The benefits of nanotherapeutics needs to be balanced against toxicity, with future use in humans dependent upon the gathering of information about the clearance and long-term safety of nanomaterials.
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39
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Xu L, Liu W, Bai F, Xu Y, Liang X, Ma C, Gao L. Hepatic Macrophage as a Key Player in Fatty Liver Disease. Front Immunol 2021; 12:708978. [PMID: 34956171 PMCID: PMC8696173 DOI: 10.3389/fimmu.2021.708978] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
Fatty liver disease, characterized by excessive inflammation and lipid deposition, is becoming one of the most prevalent liver metabolic diseases worldwide owing to the increasing global incidence of obesity. However, the underlying mechanisms of fatty liver disease are poorly understood. Accumulating evidence suggests that hepatic macrophages, specifically Kupffer cells (KCs), act as key players in the progression of fatty liver disease. Thus, it is essential to examine the current evidence of the roles of hepatic macrophages (both KCs and monocyte-derived macrophages). In this review, we primarily address the heterogeneities and multiple patterns of hepatic macrophages participating in the pathogenesis of fatty liver disease, including Toll-like receptors (TLRs), NLRP3 inflammasome, lipotoxicity, glucotoxicity, metabolic reprogramming, interaction with surrounding cells in the liver, and iron poisoning. A better understanding of the diverse roles of hepatic macrophages in the development of fatty liver disease may provide a more specific and promising macrophage-targeting therapeutic strategy for inflammatory liver diseases.
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Affiliation(s)
- Liyun Xu
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Cell and Molecular Biology Laboratory, Zhoushan Hospital, Zhoushan, China
| | - Wen Liu
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Basic Medicine Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Fuxiang Bai
- Laboratory for Tissue Engineering and Regeneration, School of Stomatology, Shandong University, Jinan, China
| | - Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Laboratory, Yueyang Hospital, Hunan Normal University, Yueyang, China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
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40
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Arjomandnejad M, Sylvia K, Blackwood M, Nixon T, Tang Q, Muhuri M, Gruntman AM, Gao G, Flotte TR, Keeler AM. Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells. Mol Ther Methods Clin Dev 2021; 23:490-506. [PMID: 34853797 PMCID: PMC8605179 DOI: 10.1016/j.omtm.2021.10.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/13/2021] [Accepted: 10/26/2021] [Indexed: 12/14/2022]
Abstract
Immune responses to adeno-associated virus (AAV) capsids limit the therapeutic potential of AAV gene therapy. Herein, we model clinical immune responses by generating AAV capsid-specific chimeric antigen receptor (AAV-CAR) T cells. We then modulate immune responses to AAV capsid with AAV-CAR regulatory T cells (Tregs). AAV-CAR Tregs in vitro display phenotypical Treg surface marker expression, and functional suppression of effector T cell proliferation and cytotoxicity. In mouse models, AAV-CAR Tregs mediated continued transgene expression from an immunogenic capsid, despite antibody responses, produced immunosuppressive cytokines, and decreased tissue inflammation. AAV-CAR Tregs are also able to bystander suppress immune responses to immunogenic transgenes similarly mediating continued transgene expression, producing immunosuppressive cytokines, and reducing tissue infiltration. Taken together, AAV-CAR T cells and AAV-CAR Tregs are directed and powerful immunosuppressive tools to model and modulate immune responses to AAV capsids and transgenes in the local environment.
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Affiliation(s)
- Motahareh Arjomandnejad
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Katelyn Sylvia
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Meghan Blackwood
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Thomas Nixon
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Qiushi Tang
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Manish Muhuri
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Alisha M Gruntman
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA 01536, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Terence R Flotte
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Allison M Keeler
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.,NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
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41
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Shojaie L, Ali M, Iorga A, Dara L. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm Sin B 2021; 11:3727-3739. [PMID: 35024302 PMCID: PMC8727893 DOI: 10.1016/j.apsb.2021.10.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
The immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1/ligand-1 (PD-1/PD-L1) are vital contributors to immune regulation and tolerance. Recently immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of immune related adverse events involving multiple organs such as the liver. Due to its constant exposure to foreign antigens, the liver has evolved a high capacity for immune tolerance, therefore, blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors. This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors (ILICI) and is more common when CTLA4 and PD-1/PD-L1 are used in combination. The underlying mechanisms of this unique type of hepatotoxicity are not fully understood; however, the contribution of CD8+ cytotoxic T lymphocytes, various CD4+ T cells populations, cytokines, and the secondary activation of the innate immune system leading to liver injury have all been suggested. This review summarizes our current understanding of the underlying mechanisms of liver injury in immunotherapy using animal models of ILICI and available patient data from clinical studies.
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Affiliation(s)
- Layla Shojaie
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Myra Ali
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Andrea Iorga
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- U.S. Food and Drug Administration, Center for Devices and Radiological Health, Silver Spring, MD 20993, USA
- UMBC Center for Accelerated Real Time Analytics, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Lily Dara
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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42
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Rapti K, Grimm D. Adeno-Associated Viruses (AAV) and Host Immunity - A Race Between the Hare and the Hedgehog. Front Immunol 2021; 12:753467. [PMID: 34777364 PMCID: PMC8586419 DOI: 10.3389/fimmu.2021.753467] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
Adeno-associated viruses (AAV) have emerged as the lead vector in clinical trials and form the basis for several approved gene therapies for human diseases, mainly owing to their ability to sustain robust and long-term in vivo transgene expression, their amenability to genetic engineering of cargo and capsid, as well as their moderate toxicity and immunogenicity. Still, recent reports of fatalities in a clinical trial for a neuromuscular disease, although linked to an exceptionally high vector dose, have raised new caution about the safety of recombinant AAVs. Moreover, concerns linger about the presence of pre-existing anti-AAV antibodies in the human population, which precludes a significant percentage of patients from receiving, and benefitting from, AAV gene therapies. These concerns are exacerbated by observations of cellular immune responses and other adverse events, including detrimental off-target transgene expression in dorsal root ganglia. Here, we provide an update on our knowledge of the immunological and molecular race between AAV (the “hedgehog”) and its human host (the “hare”), together with a compendium of state-of-the-art technologies which provide an advantage to AAV and which, thus, promise safer and more broadly applicable AAV gene therapies in the future.
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Affiliation(s)
- Kleopatra Rapti
- Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.,BioQuant Center, BQ0030, University of Heidelberg, Heidelberg, Germany
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.,BioQuant Center, BQ0030, University of Heidelberg, Heidelberg, Germany.,German Center for Infection Research Deutsches Zentrum für Infektionsforschung (DZIF) and German Center for Cardiovascular Research Deutsches Zentrum für Herz-Kreislauf-Erkrankungen (DZHK), Partner Site Heidelberg, Heidelberg, Germany
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43
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Sadanandan P, Payne NL, Sun G, Ashokan A, Gowd SG, Lal A, Satheesh KMK, Pulakkat S, Nair SV, Menon KN, Bernard CCA, Koyakutty M. Exploiting the preferential phagocytic uptake of nanoparticle-antigen conjugates for the effective treatment of autoimmunity. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 40:102481. [PMID: 34748963 DOI: 10.1016/j.nano.2021.102481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/09/2021] [Accepted: 10/23/2021] [Indexed: 10/19/2022]
Abstract
Tolerance induction is central to the suppression of autoimmunity. Here, we engineered the preferential uptake of nano-conjugated autoantigens by spleen-resident macrophages to re-introduce self-tolerance and suppress autoimmunity. The brain autoantigen, myelin oligodendrocyte glycoprotein (MOG), was conjugated to 200 or 500 nm silica nanoparticles (SNP) and delivered to the spleen and liver-resident macrophages of experimental autoimmune encephalomyelitis (EAE) mice model of multiple sclerosis. MOG-SNP conjugates significantly reduced signs of EAE at a very low dose (50 μg) compared to the higher dose (>800 μg) of free-MOG. This was associated with reduced proliferation of splenocytes and pro-inflammatory cytokines secretion, decreased spinal cord inflammation, demyelination and axonal damage. Notably, biodegradable porous SNP showed an enhanced disease suppression assisted by elevated levels of regulatory T cells and programmed-death ligands (PD-L1/2) in splenic and lymph node cells. Our results demonstrate that targeting nano-conjugated autoantigens to tissue-resident macrophages in lymphoid organs can effectively suppress autoimmunity.
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Affiliation(s)
- Prashant Sadanandan
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India; Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Natalie L Payne
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
| | - Guizhi Sun
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
| | - Anusha Ashokan
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Siddaramana G Gowd
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Arsha Lal
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Kumar M K Satheesh
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Sreeranjini Pulakkat
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Shantikumar V Nair
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Krishnakumar N Menon
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.
| | - Claude C A Bernard
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
| | - Manzoor Koyakutty
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.
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44
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The immune niche of the liver. Clin Sci (Lond) 2021; 135:2445-2466. [PMID: 34709406 DOI: 10.1042/cs20190654] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/17/2021] [Accepted: 10/08/2021] [Indexed: 12/19/2022]
Abstract
The liver is an essential organ that is critical for the removal of toxins, the production of proteins, and the maintenance of metabolic homeostasis. Behind each liver functional unit, termed lobules, hides a heterogeneous, complex, and well-orchestrated system. Despite parenchymal cells being most commonly associated with the liver's primary functionality, it has become clear that it is the immune niche of the liver that plays a central role in maintaining both local and systemic homeostasis by propagating hepatic inflammation and orchestrating its resolution. As such, the immunological processes that are at play in healthy and diseased livers are being investigated thoroughly in order to understand the underpinnings of inflammation and the potential avenues for restoring homeostasis. This review highlights recent advances in our understanding of the immune niche of the liver and provides perspectives for how the implementation of new transcriptomic, multimodal, and spatial technologies can uncover the heterogeneity, plasticity, and location of hepatic immune populations. Findings from these technologies will further our understanding of liver biology and create a new framework for the identification of therapeutic targets.
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45
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Macrophage Depletion via Clodronate Pretreatment Reduces Transgene Expression from AAV Vectors In Vivo. Viruses 2021; 13:v13102002. [PMID: 34696433 PMCID: PMC8538323 DOI: 10.3390/v13102002] [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: 08/24/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 01/12/2023] Open
Abstract
Adeno-associated virus is a popular gene delivery vehicle for gene therapy studies. A potential roadblock to widespread clinical adoption is the high vector doses required for efficient transduction in vivo, and the potential for subsequent immune responses that may limit prolonged transgene expression. We hypothesized that the depletion of macrophages via systemic delivery of liposome-encapsulated clodronate would improve transgene expression if given prior to systemic AAV vector administration, as has been shown to be the case with adenoviral vectors. Contrary to our expectations, clodronate liposome pretreatment resulted in significantly reduced transgene expression in the liver and heart, but permitted moderate transduction of the white pulp of the spleen. There was a remarkable localization of transgene expression from the red pulp to the center of the white pulp in clodronate-treated mice compared to untreated mice. Similarly, a greater proportion of transgene expression could be observed in the medulla located in the center of the lymph node in mice treated with clodronate-containing liposomes as compared to untreated mice where transgene expression was localized primarily to the cortex. These results underscore the highly significant role that the immune system plays in influencing the distribution and relative numbers of transduced cells in the context of AAV-mediated gene delivery.
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46
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Toti L, Manzia TM, Sensi B, Blasi F, Baiocchi L, Lenci I, Angelico R, Tisone G. Towards tolerance in liver transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101770. [PMID: 34874844 DOI: 10.1016/j.bpg.2021.101770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/08/2021] [Indexed: 02/08/2023]
Abstract
Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies. This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ: up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.
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Affiliation(s)
- L Toti
- Hepato-Pancreato-Biliary and Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy.
| | - T M Manzia
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - B Sensi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - F Blasi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - L Baiocchi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - I Lenci
- Hepatology and Liver Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
| | - R Angelico
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - G Tisone
- University of Rome Tor Vergata, Department of Surgical Science, Italy
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47
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Wade M, Fausther-Bovendo H, De La Vega MA, Kobinger G. In vivo generation of collagen specific Tregs with AAV8 suppresses autoimmune responses and arthritis in DBA1 mice through IL10 production. Sci Rep 2021; 11:18204. [PMID: 34521922 PMCID: PMC8440515 DOI: 10.1038/s41598-021-97739-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/12/2021] [Indexed: 11/25/2022] Open
Abstract
Available therapeutics for autoimmune disorders focused on mitigating symptoms, rather than treating the cause of the disorder. A novel approach using adeno-associated virus (AAV) could restore tolerance to the autoimmune targets and provide a permanent treatment for autoimmune diseases. Here, we evaluated the ability of collagen II T-cell epitopes packaged in adeno-associated virus serotype 8 (AAV-8) vectors to reduce pathogenic cellular and humoral responses against collagen and to mitigate the disease in the collagen-induced arthritis mouse model. The cytokines and immune cells involved in the immune suppression were also investigated. Mice treated with AAV-8 containing collagen II T-cell epitopes demonstrated a significant reduction in the arthritis symptoms, pathogenic collagen specific antibody and T cell responses. The AAV-8 mediated immune suppression was mediated by increased interleukin-10 expression and regulatory T cells expansion. Altogether, this study strengthens the notion that AAV vectors are promising candidates for the treatment of autoimmune diseases.
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Affiliation(s)
- Matthew Wade
- Department of Microbiology and Immunology, Faculty of Medicine, Laval University, Quebec, Canada
| | - Hugues Fausther-Bovendo
- Department of Microbiology and Immunology, Faculty of Medicine, Laval University, Quebec, Canada
| | - Marc-Antoine De La Vega
- Department of Microbiology and Immunology, Faculty of Medicine, Laval University, Quebec, Canada
| | - Gary Kobinger
- Department of Microbiology and Immunology, Faculty of Medicine, Laval University, Quebec, Canada. .,Department of Pathology and Laboratory Medicine, University of Pennsylvania School 27 of Medicine, Philadelphia, PA, USA.
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48
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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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49
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Muscate F, Woestemeier A, Gagliani N. Functional heterogeneity of CD4 + T cells in liver inflammation. Semin Immunopathol 2021; 43:549-561. [PMID: 34463867 PMCID: PMC8443520 DOI: 10.1007/s00281-021-00881-w] [Citation(s) in RCA: 17] [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: 05/25/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
CD4+ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4+ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4+ T cells as a therapeutic target in both NASH and AIH is discussed.
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Affiliation(s)
- Franziska Muscate
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Woestemeier
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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50
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Bozward AG, Ronca V, Osei-Bordom D, Oo YH. Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy. Front Immunol 2021; 12:711217. [PMID: 34512631 PMCID: PMC8425300 DOI: 10.3389/fimmu.2021.711217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
| | - Daniel Osei-Bordom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
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