|
1
|
Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [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: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
Collapse
Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| |
Collapse
|
|
2
|
Wang H, Yang H, Zhang X, Zhou X. Triptolide promotes differentiation of human monocytes into immunosuppressive MDSCs. Cell Immunol 2024; 401-402:104836. [PMID: 38776753 DOI: 10.1016/j.cellimm.2024.104836] [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: 01/22/2024] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) negatively modulate immune activity. Prior investigations have shown much promise in using MDSCs-assisted immunotherapy for organ transplantation patients. Additionally, owing to its immunosuppressive activity, MDSCs can also be used to manage immune-associated disorders. METHODS Granulocyte-macrophage colony-stimulating factor (GM-CSF) was employed to stimulate myeloid progenitor cell differentiation. Triptolide (PG490) was introduced toward the later phases of in vitro MDSCs induction. Lastly, real-time PCR (RT-PCR) and flow cytometry were used to assess transcript expression and cell phenotype, and a mouse skin transplantation model was established to evaluate the MDSCs-mediated immune suppression in vivo. RESULTS Co-stimulation with PG490 and GM-CSF potently induced myeloid-derived monocytes to form MDSCs, with remarkable immune-suppressive activity. The underlying mechanism involved downregulation of T cell proliferation, activation, enhancement of inflammatory cytokine release, as well as T cell conversion to Treg cells. PG490 strongly enhanced iNOS expression in MDSCs, and iNOS inhibition successfully reversed the immune-suppression. The PG490- and GM-CSF-induced MDSCs substantially extended survival duration of murine skin grafts, thereby validating their strong immune-suppressive activity in vivo. CONCLUSIONS Herein, we presented a new approach involving MDSCs-based immunosuppression in vitro. PG490 and GM-CSF co-treatment strongly induced immuno-suppressive activity in MDSCs both in vitro and in vivo. Our findings highlight the promise of applying MDSCs-based therapy in clinical organ transplantation treatment.
Collapse
Affiliation(s)
- Haozhou Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Hui Yang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xiaodong Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xiaoguang Zhou
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
3
|
Kazuta T, Murakami A, Noda S, Hirano S, Kito H, Tsujikawa K, Nakanishi H, Kimura S, Sahashi K, Koike H, Katsuno M. Clinicopathological features of graft versus host disease-associated myositis. Ann Clin Transl Neurol 2024; 11:508-519. [PMID: 38152056 PMCID: PMC10863911 DOI: 10.1002/acn3.51973] [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: 08/17/2023] [Revised: 12/02/2023] [Accepted: 12/05/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Chronic graft versus host disease (GVHD)-associated myositis targeting skeletal muscle is a relatively rare but potentially debilitating complication following allogeneic hematopoietic stem cell transplantation (HSCT). We reviewed the clinicopathological features of GVHD-associated myositis among patients receiving allogeneic HSCT to elucidate the cellular pathogenesis. METHODS We retrospectively reviewed clinical data and muscle biopsy results from 17 consecutive patients diagnosed with GVHD-associated myositis at our institution between 1995 and 2019. Immunostaining findings of GVHD-associated myositis were compared to those of patients with anti-tRNA-synthetase antibody-associated myopathy (ASM) (n = 13) and dermatomyositis (DM) (n = 12). RESULTS The majority of patients with GVHD-associated myositis showed subacute or chronic progression of mild to moderate limb weakness together with elevated serum creatine kinase. These patients also exhibited mild C-reactive protein elevation but were negative for myositis-related autoantibodies. Programmed death-1 (PD-1)-positive cells were observed in muscle interstitium adjacent to myofibers expressing human leukocyte antigen (HLA)-DR. The interstitium was also HLA-DR-positive, similar to biopsy samples from ASM patients but not DM patients. The proportions of HLA-DR-positive muscle fibers and PD-1-positive interstitial cells were significantly higher in GVHD and ASM samples than DM samples. The PD-1-positive cells were mostly CD-8-positive lymphocytes. DISCUSSION GVHD-associated myositis is characterized by HLA-DR-positive myofibers and infiltration of PD-1-positive lymphocytes. These features distinguish GVHD-associated myositis from DM but not from ASM.
Collapse
Affiliation(s)
- Tomoyuki Kazuta
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- Department of NeurologyChutoen General Medical CenterKakegawaJapan
| | - Ayuka Murakami
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- National Hospital Organization Suzuka National HospitalSuzukaJapan
| | - Seiya Noda
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- National Hospital Organization Suzuka National HospitalSuzukaJapan
| | - Satoko Hirano
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- National Hospital Organization Suzuka National HospitalSuzukaJapan
| | - Hiroshi Kito
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- National Hospital Organization Suzuka National HospitalSuzukaJapan
| | - Koyo Tsujikawa
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
| | | | - Seigo Kimura
- National Hospital Organization Suzuka National HospitalSuzukaJapan
| | - Kentaro Sahashi
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Haruki Koike
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- Division of Neurology, Department of Internal MedicineSaga University Faculty of MedicineSagaJapan
| | - Masahisa Katsuno
- Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
- Department of Clinical Research EducationNagoya University Graduate School of MedicineNagoyaJapan
| |
Collapse
|
|
4
|
Doherty DT, Khambalia HA, van Dellen D, Jennings RE, Piper Hanley K. Unlocking the post-transplant microenvironment for successful islet function and survival. Front Endocrinol (Lausanne) 2023; 14:1250126. [PMID: 37711891 PMCID: PMC10497759 DOI: 10.3389/fendo.2023.1250126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/07/2023] [Indexed: 09/16/2023] Open
Abstract
Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.
Collapse
Affiliation(s)
- Daniel T. Doherty
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Hussein A. Khambalia
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - David van Dellen
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Rachel E. Jennings
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Karen Piper Hanley
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
5
|
Bailey CM, Liu Y, Liu M, Du X, Devenport M, Zheng P, Liu Y, Wang Y. Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues. J Clin Invest 2022; 132:150846. [PMID: 35239514 PMCID: PMC9057613 DOI: 10.1172/jci150846] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 03/01/2022] [Indexed: 11/17/2022] Open
Abstract
Anti-CTLA-4 + anti-PD-1/PD-L1 combination is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAE). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFNγ-dependent mechanism. Targeting the HIF-1α-PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes (TILs) and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated cancer immunotherapeutic effects of anti-CTLA-4 therapy with efficacy comparable to anti-CTLA-4+anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAE triggered by Ipilimumab, echinomycin protected mice against irAE by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1:PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment (TME) to achieve safer and more effective immunotherapy.
Collapse
Affiliation(s)
- Christopher M Bailey
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | - Yan Liu
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | - Mingyue Liu
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | - Xuexiang Du
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | | | - Pan Zheng
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | - Yang Liu
- Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, United States of America
| | - Yin Wang
- University of Maryland School of Medicine, Baltimore, United States of America
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Wang H, Ji J, Zhuang Y, Zhou X, Zhao Y, Zhang X. PMA induces the differentiation of monocytes into immunosuppressive MDSCs. Clin Exp Immunol 2021; 206:216-225. [PMID: 34453319 DOI: 10.1111/cei.13657] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/18/2022] Open
Abstract
The induction of immune tolerance without the use of immunosuppressive drugs is a crucial problem in organ transplantation. The use of myeloid-derived suppressor cells (MDSCs) as a cell-based adjuvant immunosuppressive therapy is a bright clinical prospect in organ transplantation. MDSCs with stable immunosuppressive activities can be used to treat immune-related diseases. In this study, macrophage colony-stimulating factor (M-CSF) was used to promote myeloid progenitor cell differentiation, and phorbol 12-myristate 13-acetate (PMA) was added to induce MDSCs at the later stage of induction in vitro. Cell phenotypes were detected by flow cytometry and mRNA was detected by real-time-polymerase chain reaction (RT-PCR). A mouse skin transplantation model was used to investigate the cell inhibitory function. The combination of PMA and M-CSF induced the differentiation of myeloid-derived monocytes into MDSCs. MDSCs were found to induce immune tolerance by inhibiting the proliferation and activation of T cells, promoting cytokine secretion and inducing T cell transformation to regulatory T cells (Treg ). PMA significantly up-regulated the expression of Arg-1 and the Arg-1 protein expression in MDSCs and arginase 1 (Arg-1) inhibitor nor-NOHA reversed the MDSC immunosuppressive activity, indicating the involvement of the Arg-1 pathway in MDSC-mediated immunosuppression. M-CSF + PMA-induced MDSCs also significantly prolonged the survival time of skin grafts in mice, showing that MDSCs exert immunosuppressive effects in vivo. We describe a novel scheme to induce immunosuppressive MDSCs in vitro. MDSCs induced by M-CSF with PMA showed stable immunosuppression. MDSCs induced by this protocol may benefit patients with organ transplantation through immune regulation.
Collapse
Affiliation(s)
- Haozhou Wang
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - JiaWei Ji
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yuan Zhuang
- Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiaoguang Zhou
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yong Zhao
- Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaodong Zhang
- Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
8
|
Mesenchymal stromal cells for corneal transplantation: Literature review and suggestions for successful clinical trials. Ocul Surf 2021; 20:185-194. [PMID: 33607323 PMCID: PMC9878990 DOI: 10.1016/j.jtos.2021.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 01/28/2023]
Abstract
Corneal transplantation is a routine procedure for patients with corneal blindness. Despite the streamlining of surgical techniques and deeper understanding of the cellular and molecular pathways mediating rejection, corticosteroids are still the main immunosuppressive regimen in corneal transplantation, and the 15-year survival of corneal transplants remains as low as 50%, which is poorer than that for most solid organ transplants. Recently, mesenchymal stromal cells (MSCs) with unique regenerative and immune-modulating properties have emerged as a promising cell therapy to promote transplant tolerance, minimize the use of immunosuppressants, and prevent chronic rejection. Here, we review the literature on preclinical studies of MSCs for corneal transplantation and summarize the key findings from clinical trials with MSCs in solid organ transplantation. Finally, we highlight current issues and challenges regarding MSC therapies and suggest strategies for safe and effective MSC-based therapies in clinical transplantation.
Collapse
|
|
9
|
Ueta H, Xu XD, Yu B, Kitazawa Y, Yu E, Hara Y, Morita-Nakagawa M, Zhou S, Sawanobori Y, Ueha S, Rokutan K, Tanaka T, Tokuda N, Matsushima K, Matsuno K. Suppression of liver transplant rejection by anti-donor MHC antibodies via depletion of donor immunogenic dendritic cells. Int Immunol 2020; 33:261-272. [PMID: 33258927 PMCID: PMC8060989 DOI: 10.1093/intimm/dxaa076] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/29/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, a tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC (MHCI) antigen (DST-antibodies). METHODS We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. RESULTS Preoperative transfer of DST-antibodies or DST pretreatment eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a+CD11b/c+ immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8+ T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the proliferative response of recipient regulatory T cells, DST-primed sera and the anti-donor MHCII antibody did not. CONCLUSION DST-antibodies and anti-donor MHCII antibodies could suppress the CD8+ T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathways of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII- graft cells and recipient cells.
Collapse
Affiliation(s)
- Hisashi Ueta
- Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
| | - Xue-Dong Xu
- Department of General Surgery, Dalian Medical University, The First Affiliated Hospital, Dalian, China
| | - Bin Yu
- Department General Surgery, The First Affiliated Hospital of Soochow University, Jiangsu, China
| | - Yusuke Kitazawa
- Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
| | - Enqiao Yu
- Department General Surgery, The First Affiliated Hospital of Soochow University, Jiangsu, China
| | | | | | - Shu Zhou
- Department of Obstetrics and Gynecology, Dalian Medical University, The First Affiliated Hospital, Dalian, China
| | - Yasushi Sawanobori
- Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
| | - Kazuhito Rokutan
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Toshiya Tanaka
- Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo, Japan
| | - Nobuko Tokuda
- Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
| | - Kenjiro Matsuno
- Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
| |
Collapse
|
|
10
|
Sällberg M, Pasetto A. Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation. Front Immunol 2020; 11:552. [PMID: 32292409 PMCID: PMC7119224 DOI: 10.3389/fimmu.2020.00552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.
Collapse
Affiliation(s)
- Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Pasetto
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
11
|
Why some organ allografts are tolerated better than others: new insights for an old question. Curr Opin Organ Transplant 2020; 24:49-57. [PMID: 30516578 DOI: 10.1097/mot.0000000000000594] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW There is great variability in how different organ allografts respond to the same tolerance induction protocol. Well known examples of this phenomenon include the protolerogenic nature of kidney and liver allografts as opposed to the tolerance-resistance of heart and lung allografts. This suggests there are organ-specific factors which differentially drive the immune response following transplantation. RECENT FINDINGS The specific cells or cell products that make one organ allograft more likely to be accepted off immunosuppression than another are largely unknown. However, new insights have been made in this area recently. SUMMARY The current review will focus on the organ-intrinsic factors that contribute to the organ-specific differences observed in tolerance induction with a view to developing therapeutic strategies to better prevent organ rejection and promote tolerance induction of all organs.
Collapse
|
|
12
|
Chen W, Yan X, Yang A, Xu A, Huang T, You H. miRNA-150-5p promotes hepatic stellate cell proliferation and sensitizes hepatocyte apoptosis during liver fibrosis. Epigenomics 2019; 12:53-67. [PMID: 31833387 DOI: 10.2217/epi-2019-0104] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Aim: To explore the role of miRNA-150-5p (miR-150-5p) in liver fibrosis. Materials & methods: miRNA expression profiles, CCl4-induced liver fibrosis progression and regression rodent models, quantitative real-time PCR, miR-150-5p mimics and inhibitors, cell proliferation and apoptosis detection, RNA sequencing and bioinformatics analysis were employed. Results: Liver tissue miR-150-5p expression was positively associated with liver fibrosis progression and regression; however, miR-150-5p exhibited a cell-specific expression pattern, namely, it was enhanced in hepatocytes but reduced in hepatic stellate cells (HSCs) during liver fibrosis; miR-150-5p overexpression promoted HSC apoptosis and sensitized hepatocyte apoptosis; miR-150-5p mimic had a larger influence on the transcriptomic stability of HSCs than that of hepatocytes; miR-150-5p mediated activation of interferon signaling pathways might be responsible for HSC apoptosis. Conclusion: miR-150-5p exhibited an opposite regulation and function pattern between HSCs and hepatocytes during liver fibrosis.
Collapse
Affiliation(s)
- Wei Chen
- Experimental & Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Tolerance Induction & Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Xuzhen Yan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, PR China
| | - Aiting Yang
- Experimental & Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Tolerance Induction & Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Anjian Xu
- Experimental & Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Tolerance Induction & Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Tao Huang
- Experimental & Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Tolerance Induction & Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
| | - Hong You
- Experimental & Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Tolerance Induction & Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.,Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, PR China
| |
Collapse
|
|
13
|
Deslyper G, Doherty DG, Carolan JC, Holland CV. The role of the liver in the migration of parasites of global significance. Parasit Vectors 2019; 12:531. [PMID: 31703729 PMCID: PMC6842148 DOI: 10.1186/s13071-019-3791-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023] Open
Abstract
Many parasites migrate through different tissues during their life-cycle, possibly with the aim to enhance their fitness. This is true for species of three parasite genera of global importance, Ascaris, Schistosoma and Plasmodium, which cause significant global morbidity and mortality. Interestingly, these parasites all incorporate the liver in their life-cycle. The liver has a special immune status being able to preferentially induce tolerance over immunity. This function may be exploited by parasites to evade host immunity, with Plasmodium spp. in particular using this organ for its multiplication. However, hepatic larval attrition occurs in both ascariasis and schistosomiasis. A better understanding of the molecular mechanisms involved in hepatic infection could be useful in developing novel vaccines and therapies for these parasites.
Collapse
Affiliation(s)
- Gwendoline Deslyper
- Department of Zoology, School of Natural Sciences, Trinity College Dublin, Dublin 2, Ireland.
| | - Derek G Doherty
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
| | - James C Carolan
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Celia V Holland
- Department of Zoology, School of Natural Sciences, Trinity College Dublin, Dublin 2, Ireland
| |
Collapse
|
|
14
|
Hepatic Stellate Cells Enhance Liver Cancer Progression by Inducing Myeloid-Derived Suppressor Cells through Interleukin-6 Signaling. Int J Mol Sci 2019; 20:ijms20205079. [PMID: 31614930 PMCID: PMC6834132 DOI: 10.3390/ijms20205079] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/05/2019] [Accepted: 10/11/2019] [Indexed: 01/07/2023] Open
Abstract
The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.
Collapse
|
|
15
|
Huang WH, Zhou MW, Zhu YF, Xiang JB, Li ZY, Wang ZH, Zhou YM, Yang Y, Chen ZY, Gu XD. The Role Of Hepatic Stellate Cells In Promoting Liver Metastasis Of Colorectal Carcinoma. Onco Targets Ther 2019; 12:7573-7580. [PMID: 31571908 PMCID: PMC6754330 DOI: 10.2147/ott.s214409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 08/31/2019] [Indexed: 01/16/2023] Open
Abstract
Purpose Colorectal cancer (CRC) is the most common malignancy in the gastrointestinal tract. The liver is the most common location of CRC metastases, which are the main causes of CRC-related death. However, the mechanisms underlying metastasis of CRC to the liver have not been characterized, resulting in therapeutic challenges. Methods The effects of hepatic stellate cells (HSCs) on T cells were evaluated using in vitro mixed lymphocyte reactions (MLRs) and cytokine production assays. HSC-induced CT26 cell migration and proliferation were evaluated in vitro and in vivo. Results HSCs induced T cell hypo-responsiveness, promoted T cell apoptosis, and induced regulatory T cell expansion in vitro. IL-2 and IL-4 were significantly lower in MLRs incubated with HSCs. Supernatants of MLRs with HSCs promoted CT26 cell proliferation and migration. Furthermore, the presence of HSCs increased the number of liver metastases and promoted proliferation of liver metastatic tumor cells in vivo. Conclusion HSCs may contribute to an immunosuppressive liver microenvironment, resulting in a favorable environment for the colonization of CRC cells in the liver. These findings highlight a potential strategy for treatment of CRC liver metastases.
Collapse
Affiliation(s)
- Wen-Hai Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Min-Wei Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Yan-Feng Zhu
- Department of Nursing, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Jian-Bin Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Zhen-Yang Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Zi-Hao Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Yi-Ming Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Yi Yang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Zong-You Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Xiao-Dong Gu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| |
Collapse
|
|
16
|
Zhongqi F, Xiaodong S, Yuguo C, Guoyue L. Can Combined Therapy Benefit Immune Checkpoint Blockade Response in Hepatocellular Carcinoma? Anticancer Agents Med Chem 2019; 19:222-228. [PMID: 30426903 DOI: 10.2174/1871520618666181114112431] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 05/24/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
Background:
Hepatocellular Carcinoma (HCC) is one of the most common cancers with high mortality
rate. The effects of most therapies are limited. The Immune Checkpoint Blockade (ICB) improves the prognosis
in multiple malignancies. The application of immune checkpoint blockade to hepatocellular carcinoma
patients has recently started. Early phase clinical trials have shown some benefits to cancer patients.
Methods/Results:
This review focuses on the immune system of liver and clinical trials of ICB. In particular, we
analyze the mechanisms by which immune checkpoint blockade therapies can be used for the treatment of hepatocellular
carcinoma patients, then examine the factors in cancer resistance to the therapies and finally suggest
possible combination therapies for the treatment of hepatocellular carcinoma patients.
Conclusion:
ICB is a promising therapy for advanced HCC patients. Combined therapy exhibits a great potential
to enhance ICB response in these patients. The better understanding of the factors influencing the sensitivity
of ICB and more clinical trials will consolidate the efficiency and minimize the adverse effects of ICB.
Collapse
Affiliation(s)
- Fan Zhongqi
- First Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, China
| | - Sun Xiaodong
- First Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, China
| | - Chen Yuguo
- First Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, China
| | - Lv Guoyue
- First Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|
|
17
|
Engineering human stellate cells for beta cell replacement therapy promotes in vivo recruitment of regulatory T cells. Mater Today Bio 2019; 2:100006. [PMID: 32159143 PMCID: PMC7061575 DOI: 10.1016/j.mtbio.2019.100006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/02/2019] [Accepted: 05/02/2019] [Indexed: 12/25/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β cells. One of the promising therapeutic approaches in T1D is the transplantation of islets; however, it has serious limitations. To address these limitations, immunotherapeutic strategies have focused on restoring immunologic tolerance, preventing transplanted cell destruction by patients’ own immune system. Macrophage-derived chemokines such as chemokine-ligand-22 (CCL22) can be utilized for regulatory T cell (Treg) recruitment and graft tolerance. Stellate cells (SCs) have various immunomodulatory functions: recruitment of Tregs and induction of T-cell apoptosis. Here, we designed a unique immune-privileged microenvironment around implantable islets through overexpression of CCL22 proteins by SCs. We prepared pseudoislets with insulin-secreting mouse insulinoma-6 (MIN6) cells and human SCs as a model to mimic naive islet morphology. Our results demonstrated that transduced SCs can secrete CCL22 and recruit Tregs toward the implantation site in vivo. This study is promising to provide a fundamental understanding of SC-islet interaction and ligand synthesis and transport from SCs at the graft site for ensuring local immune tolerance. Our results also establish a new paradigm for creating tolerable grafts for other chronic diseases such as diabetes, anemia, and central nervous system (CNS) diseases, and advance the science of graft tolerance.
Collapse
|
|
18
|
Liu Z, McMichael EL, Shayan G, Li J, Chen K, Srivastava R, Kane LP, Lu B, Ferris RL. Novel Effector Phenotype of Tim-3 + Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients. Clin Cancer Res 2018; 24:4529-4538. [PMID: 29712685 PMCID: PMC6139056 DOI: 10.1158/1078-0432.ccr-17-1350] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 11/06/2017] [Accepted: 04/24/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA-4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Clin Cancer Res; 24(18); 4529-38. ©2018 AACR.
Collapse
Affiliation(s)
- Zhuqing Liu
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | | | | | - Jing Li
- School of Medicine, Tsinghua University, Beijing, China
| | - Kevin Chen
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Lawrence P Kane
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Binfeng Lu
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
| |
Collapse
|
|
19
|
Cell Therapy as a Tool for Induction of Immunological Tolerance after Liver Transplantation. Bull Exp Biol Med 2018; 165:554-563. [PMID: 30121913 DOI: 10.1007/s10517-018-4213-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Indexed: 12/13/2022]
Abstract
Transplantation of solid organs, including liver, induces a number of serious complications related to immune incompatibility and requiring long-term use of immunosuppressive drugs. Finding the ways to inducing recipient immunological tolerance to the grafts is a top priority in organ transplantation and immunology. Along with the search for immunosupressive therapy, the development of alternative approaches to induction of immunological tolerance based on cell technologies is now in progress. In this regard, studies of the so-called spontaneous operational tolerance observed in ~20% patients after orthotopic liver transplantation is a promising trend. Understanding of this phenomenon can shed light on the mechanisms of immunological tolerance to allografts and will help to identify specific tolerance biomarkers and cell types with the aptitude for the induction of tolerance to liver allografts.
Collapse
|
|
20
|
Qin J, Arakawa Y, Morita M, Fung JJ, Qian S, Lu L. C-C Chemokine Receptor Type 2-Dependent Migration of Myeloid-Derived Suppressor Cells in Protection of Islet Transplants. Transplantation 2017; 101:1793-1800. [PMID: 27755503 PMCID: PMC5393972 DOI: 10.1097/tp.0000000000001529] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Islet transplantation is a promising therapeutic approach to restore the physical response to blood glucose in type 1 diabetes. Current chronic use of immunosuppressive reagents for preventing islet allograft rejection is associated with severe complications. In addition, many of the immunosuppressive drugs are diabetogenic. The induction of transplant tolerance to eliminate the dependency on immunosuppression is ideal, but remains challenging. METHODS Addition of hepatic stellate cells allowed generation of myeloid-derived suppressor cells (MDSC) from precursors in mouse bone marrow. Migration of MDSC was examined in an islet allograft transplant model by tracking the systemic administered MDSC from CD45.1 congenic mice. RESULTS The generated MDSC were expressed C-C chemokine receptor type 2 (CCR2), which was enhanced by exposure to interferon-γ. A single systemic administration of MDSC markedly prolonged survival of islet allografts without requirement of immunosuppression. Tracking the administered MDSC showed that they promptly migrated to the islet graft sites, at which point they exerted potent immune suppressive activity by inhibiting CD8 T cells, enhancing regulatory T cell activity. MDSC generated from CCR2 mice failed to be mobilized and lost tolerogenic activity in vivo, but sustained suppressive activity in vitro. CONCLUSIONS MDSC migration was dependent on expression of CCR2, whereas CCR2 does not directly participate in immune suppression. Expression of CCR2 needs to be closely monitored for quality control purpose when MDSC are generated in vitro for immune therapy.
Collapse
Affiliation(s)
- Jie Qin
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Yusuke Arakawa
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Miwa Morita
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - John J Fung
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| |
Collapse
|
|
21
|
Zhou CL, Kong DL, Liu JF, Lu ZK, Guo HF, Wang W, Qiu JF, Liu XJ, Wang Y. MHC II -, but not MHC II +, hepatic Stellate cells contribute to liver fibrosis of mice in infection with Schistosoma japonicum. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1848-1857. [PMID: 28483578 DOI: 10.1016/j.bbadis.2017.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/12/2017] [Accepted: 05/04/2017] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cells (HSCs) are considered as the main effector cells in vitamin A metabolism and liver fibrosis, as well as in hepatic immune regulation. Recently, researches have revealed that HSCs have plasticity and heterogeneity, which depend on their lobular location and whether liver is normal or injured. This research aimed to explore the biological characteristics and heterogeneity of HSCs in mice with Schistosoma japonicum (S. japonicum) infection, and determine the subpopulation of HSCs in pathogenesis of hepatic fibrosis caused by S. japonicum infection. Results revealed that HSCs significantly increased the expressions of MHC II and fibrogenic genes after S. japonicum infection, and could be classified into MHC II+ HSCs and MHC II- HSCs subsets. Both two HSCs populations suppressed the proliferation of activated CD4+T cells, whereas only MHC II- HSCs displayed a myofibroblast-like phenotype. In response to IFN-γ, HSCs up-regulated the expressions of MHC II and CIITA, while down-regulated the expression of fibrogenic gene Col1. In addition, praziquantel treatment decreased the expressions of fibrogenic genes in MHC II- HSCs. These results confirmed that HSCs from S. japonicum-infected mice have heterogeneity. The MHC II- α-SMA+ HSCs were major subsets of HSCs contributing to liver fibrosis and could be considered as a potential target of praziquantel anti-fibrosis treatment.
Collapse
Affiliation(s)
- Chun-Lei Zhou
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - De-Long Kong
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Jin-Feng Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Zhong-Kui Lu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Hong-Fei Guo
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Wei Wang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Jing-Fan Qiu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Xin-Jian Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China
| | - Yong Wang
- Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.
| |
Collapse
|
|
22
|
Stellate Cell Activation and Imbalanced Expression of TGF- β1/TGF- β3 in Acute Autoimmune Liver Lesions Induced by ConA in Mice. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2540540. [PMID: 28246592 PMCID: PMC5303577 DOI: 10.1155/2017/2540540] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Accepted: 12/13/2016] [Indexed: 01/13/2023]
Abstract
Objective. To study the pathogenic feature of liver injury, activation of hepatic stellate cells, and dynamic expression of TGF-β1/TGF-β3 to reveal their role in liver injury induced by ConA. Methods. Mice were randomly divided into control group and ConA treatment group. ConA (20 mg/kg) was injected through vena caudalis in ConA treatment group; the controls received the same volume of saline injection. After injection for 2 h, 8 h, 24 h, and 48 h, animals were terminated. Blood, liver, and spleen were harvested. Liver function and histopathology were studied. α-SMA, vimentin, TGF-β1, and TGF-β3 were detected. Results. After ConA injection, liver damage started to increase. Expression of α-SMA, vimentin, TGF-β1, and TGF-β3 was significantly enhanced; all above indicators reached peak at 8 h; but from 24 h after ConA injection, TGF-β3 expression began to decline, while the TGF-β1/TGF-β3 ratio at 48 h was significantly lower than control. Conclusion. (1) Autoimmune liver injury induced by ConA showed time-based features, in which the most serious liver lesions happened at 8 h after ConA injection. (2) Early activation of HSC and imbalance expression of TGF-β1 and TGF-β3 existed in ConA-induced acute autoimmune liver injury, which may be associated with liver dysfunction and the mechanisms of progression to fibrosis.
Collapse
|
|
23
|
Oldhafer F, Bock M, Falk CS, Vondran FWR. Immunological aspects of liver cell transplantation. World J Transplant 2016; 6:42-53. [PMID: 27011904 PMCID: PMC4801804 DOI: 10.5500/wjt.v6.i1.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 10/21/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.
Collapse
|
|
24
|
Grakoui A, Crispe IN. Presentation of hepatocellular antigens. Cell Mol Immunol 2016; 13:293-300. [PMID: 26924525 PMCID: PMC4856799 DOI: 10.1038/cmi.2015.109] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/24/2015] [Accepted: 11/25/2015] [Indexed: 12/31/2022] Open
Abstract
The liver is an organ in which antigen-specific T-cell responses manifest a bias toward immune tolerance. This is clearly seen in the rejection of allogeneic liver transplants, and multiple other phenomena suggest that this effect is more general. These include tolerance toward antigens introduced via the portal vein, immune failure to several hepatotropic viruses, the lack of natural liver-stage immunity to malaria parasites, and the frequent metastasis of cancers to the liver. Here we review the mechanisms by which T cells engage with hepatocellular antigens, the context in which such encounters occur, and the mechanisms that act to suppress a full T-cell response. While many mechanisms play a role, we will argue that two important processes are the constraints on the cross-presentation of hepatocellular antigens, and the induction of negative feedback inhibition driven by interferons. The constant exposure of the liver to microbial products from the intestine may drive innate immunity, rendering the local environment unfavorable for specific T-cell responses through this mechanism. Nevertheless, tolerance toward hepatocellular antigens is not monolithic and under specific circumstances allows both effective immunity and immunopathology.
Collapse
Affiliation(s)
- Arash Grakoui
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and Yerkes National Primate Research Center, Atlanta, GA, USA
| | | |
Collapse
|
|
25
|
Dara L, Liu ZX, Kaplowitz N. Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications. Liver Int 2016; 36:158-65. [PMID: 26484420 PMCID: PMC4718752 DOI: 10.1111/liv.12988] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/13/2015] [Indexed: 12/13/2022]
Abstract
In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses.
Collapse
Affiliation(s)
- Lily Dara
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
| | - Zhang-Xu Liu
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
| | - Neil Kaplowitz
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
| |
Collapse
|
|
26
|
Li Y, Lu L, Qian S, Fung JJ, Lin F. Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1. THE JOURNAL OF IMMUNOLOGY 2016; 196:1617-25. [PMID: 26755818 DOI: 10.4049/jimmunol.1501737] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 12/06/2015] [Indexed: 12/24/2022]
Abstract
We demonstrated previously that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but it remains unknown whether they exert any effects on B cells, the other component of the adaptive immune system. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that HSCs inhibited the upregulation of activation markers on activated B cells, as well as the proliferation of activated B cells and their cytokine/Ig production in vitro, and that pharmaceutically or genetically blocking the interaction of PD-L1 with programmed cell death protein 1 impaired the ability of HSCs to inhibit B cells. To test the newly discovered B cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T cell-independent Ag, significantly suppressed Ag-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver's immune homeostasis.
Collapse
Affiliation(s)
- Yan Li
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195
| | - John J Fung
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Feng Lin
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
| |
Collapse
|
|
27
|
Hsieh CC, Hung CH, Lu L, Qian S. Hepatic immune tolerance induced by hepatic stellate cells. World J Gastroenterol 2015; 21:11887-11892. [PMID: 26576077 PMCID: PMC4641110 DOI: 10.3748/wjg.v21.i42.11887] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/27/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells (HpSCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by HpSCs, including the marked expansion of myeloid-derived suppressor cells (MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. HpSC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how HpSCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.
Collapse
|
|
28
|
Lee YS, Yi HS, Suh YG, Byun JS, Eun HS, Kim SY, Seo W, Jeong JM, Choi WM, Kim MH, Kim JH, Park KG, Jeong WI. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells. Mol Cells 2015; 38:998-1006. [PMID: 26537191 PMCID: PMC4673415 DOI: 10.14348/molcells.2015.0218] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 08/30/2015] [Accepted: 08/31/2015] [Indexed: 12/12/2022] Open
Abstract
Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis.
Collapse
Affiliation(s)
- Young-Sun Lee
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705,
Korea
| | - Hyon-Seung Yi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 305-764,
Korea
| | - Yang-Gun Suh
- Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408,
Korea
| | - Jin-Seok Byun
- Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu 41566,
Korea
| | - Hyuk Soo Eun
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - So Yeon Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - Wonhyo Seo
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - Jong-Min Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - Won-Mook Choi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - Myung-Ho Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705,
Korea
| | - Keun-Gyu Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 41566,
Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701,
Korea
| |
Collapse
|
|
29
|
Abstract
PURPOSE OF REVIEW When it comes to tolerance induction, kidney allografts behave differently from heart allografts that behave differently from lung allografts. Here, we examine how and why different organ allografts respond differently to the same tolerance induction protocol. RECENT FINDINGS Allograft tolerance has been achieved in experimental and clinical kidney transplantation. Inducing tolerance in experimental recipients of heart and lung allografts has, however, proven to be more challenging. New protocols being developed in nonhuman primates based on mixed chimerism and cotransplantation of tolerogenic organs may provide mechanistic insights to help overcome these challenges. SUMMARY Tolerance induction protocols that are successful in patients transplanted with 'tolerance-prone' organs such as kidneys and livers will most likely not succeed in recipients of 'tolerance-resistant' organs such as hearts and lungs. Separate clinical trials using more robust tolerance protocols will be required to achieve tolerance in heart and lung recipients.
Collapse
|
|
30
|
Doherty DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun 2015; 66:60-75. [PMID: 26358406 DOI: 10.1016/j.jaut.2015.08.020] [Citation(s) in RCA: 222] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022]
Abstract
The hepatic immune system is constantly exposed to a massive load of harmless dietary and commensal antigens, to which it must remain tolerant. Immune tolerance in the liver is mediated by a number of specialized antigen-presenting cells, including dendritic cells, Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells. These cells are capable of presenting antigens to T cells leading to T cell apoptosis, anergy, or differentiation into regulatory T cells. However, the hepatic immune system must also be able to respond to pathogens and tumours and therefore must be equipped with mechanisms to override immune tolerance. The liver is a site of accumulation of a number of innate lymphocyte populations, including natural killer cells, CD56(+) T cells, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells. Innate lymphocytes recognize conserved metabolites derived from microorganisms and host cells and respond by killing target cells or promoting the differentiation and/or activation of other cells of the immune system. Innate lymphocytes can promote the maturation of antigen-presenting cells from their precursors and thereby contribute to the generation of immunogenic T cell responses. These cells may be responsible for overriding hepatic immune tolerance to autoantigens, resulting in the induction and maintenance of autoreactive T cells that mediate liver injury causing autoimmune liver disease. Some innate lymphocyte populations can also directly mediate liver injury by killing hepatocytes or bile duct cells in murine models of hepatitis, whilst other populations may protect against liver disease. It is likely that innate lymphocyte populations can promote or protect against autoimmune liver disease in humans and that these cells can be targeted therapeutically. Here I review the cellular mechanisms by which hepatic antigen-presenting cells and innate lymphocytes control the balance between immunity, tolerance and autoimmunity in the liver.
Collapse
Affiliation(s)
- Derek G Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Ireland.
| |
Collapse
|
|
31
|
Morita M, Joyce D, Miller C, Fung JJ, Lu L, Qian S. Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice. Hepatology 2015; 62:915-31. [PMID: 25998530 PMCID: PMC4549241 DOI: 10.1002/hep.27909] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 05/19/2015] [Indexed: 12/31/2022]
Abstract
UNLABELLED Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. CONCLUSION MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers.
Collapse
Affiliation(s)
- Miwa Morita
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| | - Daniel Joyce
- Department of General, Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| | - Charles Miller
- Department of General, Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| | - John J. Fung
- Department of General, Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
- Department of General, Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
- Department of General, Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland Ohio, 44195 USA
| |
Collapse
|
|
32
|
Li Y, Kim BG, Qian S, Letterio JJ, Fung JJ, Lu L, Lin F. Hepatic Stellate Cells Inhibit T Cells through Active TGF-β1 from a Cell Surface-Bound Latent TGF-β1/GARP Complex. THE JOURNAL OF IMMUNOLOGY 2015; 195:2648-56. [PMID: 26246140 DOI: 10.4049/jimmunol.1500139] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 07/16/2015] [Indexed: 01/03/2023]
Abstract
Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGF-β1, but the detailed mechanisms by which latent TGF-β1 is activated and whether it plays any role in HSC-mediated T cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells. GARP binds latent TGF-β1 for its activation, which is critical for regulatory T cells to suppress effector T cells; however, it is still unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we found that TGF-β1(+/-) HSCs, which produce reduced levels of TGF-β1, showed decreased potency in inhibiting T cells. We also found that pharmaceutical or genetic inhibition of the TGF-β1 signaling pathway reduced the T cell-inhibiting activity of HSCs. Additionally, using isolated primary HSCs, we demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP function or knocking down GARP expression significantly impaired the potency of HSCs to suppress the proliferation of and IFN-γ production from activated T cells, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the unexpected presence of GARP on HSCs and its significance in regard to the ability of HSCs to activate latent TGF-β1 and thereby inhibit T cells. Our study reveals a new mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC-secreted TGF-β1.
Collapse
Affiliation(s)
- Yan Li
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Byung-Gyu Kim
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106; and
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - John J Letterio
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106; and
| | - John J Fung
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Feng Lin
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
| |
Collapse
|
|
33
|
Maraldi T, Beretti F, Guida M, Zavatti M, De Pol A. Role of hepatocyte growth factor in the immunomodulation potential of amniotic fluid stem cells. Stem Cells Transl Med 2015; 4:539-47. [PMID: 25873747 DOI: 10.5966/sctm.2014-0266] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/23/2015] [Indexed: 01/01/2023] Open
Abstract
UNLABELLED Human amniotic fluid stem cells (hAFSCs) may be useful for regenerative medicine because of their potential to differentiate into all three germ layers and to modulate immune response with different types of secretion molecules. This last issue has not been completely elucidated. The aim of this study was to investigate the secretome profile of the hAFSC, focusing on the role of hepatocyte growth factor (HGF) in immunoregulation through short and long cocultures with human peripheral blood mononuclear cells. We found that HGF produced by hAFSCs exerts a cytoprotective role, inducing an increase in caspase-dependent apoptosis in human immune cells. This study provides evidence supporting the hypothesis that amniotic fluid is an ideal source of stem cells for expansion and banking properties for therapeutic use. hAFSCs not only are less immunogenic but also can secrete immunoregulatory factors that may be useful in autoimmune diseases or allogenic implants. SIGNIFICANCE New information about the secretome pattern is reported in this paper. Human amniotic fluid stem cells (hAFSCs) possess immunomodulatory properties involving hepatocyte growth factor production. hAFSCs could be used in immunotherapies and might be able to avoid allogenic rejection.
Collapse
Affiliation(s)
- Tullia Maraldi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC) Research, Bolzano, Italy
| | - Francesca Beretti
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC) Research, Bolzano, Italy
| | - Marianna Guida
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC) Research, Bolzano, Italy
| | - Manuela Zavatti
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC) Research, Bolzano, Italy
| | - Anto De Pol
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC) Research, Bolzano, Italy
| |
Collapse
|
|
34
|
Wang H, Yang YG. The complex and central role of interferon-γ in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev 2015; 258:30-44. [PMID: 24517424 DOI: 10.1111/imr.12151] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/01/2013] [Accepted: 11/11/2013] [Indexed: 12/22/2022]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly being performed to treat patients with hematologic malignancies. However, separating the beneficial graft-versus-tumor (GVT) or graft-versus-leukemia effects from graft-versus-host disease (GVHD) has been difficult and remains a significant challenge toward improving therapeutic efficacy and reducing toxicity of allo-HCT. GVHD is induced by donor T cells that also mediate potent anti-tumor responses. However, despite the largely shared effector mechanisms, extensive animal studies have demonstrated the potential of dissociating the GVT effect from GVHD. Also in many clinical cases, long-term remission was achieved following allo-HCT, without significant GVHD. A better mechanistic understanding of the immunopathophysiology of GVHD and GVT effects may potentially help to improve allo-HCT as well as maximize the benefit of GVT effects while minimizing GVHD. In this article, we review the role of IFN-γ in regulation of alloresponses following allo-HCT, with a focus on the mechanisms of how this cytokine may separate GVHD from GVT effects.
Collapse
Affiliation(s)
- Hui Wang
- Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | | |
Collapse
|
|
35
|
Chong AS, Alegre ML. Transplantation tolerance and its outcome during infections and inflammation. Immunol Rev 2015; 258:80-101. [PMID: 24517427 DOI: 10.1111/imr.12147] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Much progress has been made toward understanding the mechanistic basis of transplantation tolerance in experimental models, which implicates clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells mediating infectious tolerance and linked suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, although the basis for these challenges is beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus, infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable life-long tolerance in transplant recipients.
Collapse
Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
| | | |
Collapse
|
|
36
|
Schildberg FA, Sharpe AH, Turley SJ. Hepatic immune regulation by stromal cells. Curr Opin Immunol 2015; 32:1-6. [DOI: 10.1016/j.coi.2014.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 10/08/2014] [Indexed: 02/07/2023]
|
|
37
|
Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr 2015; 3:344-63. [PMID: 25568859 DOI: 10.3978/j.issn.2304-3881.2014.11.03] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 10/17/2014] [Indexed: 12/11/2022]
Abstract
The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC), but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancing immunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs) have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity to transdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated the fundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitamin A (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericyte further represents a versatile source of many soluble immunological active factors including cytokines [e.g., interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigen presenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggers via toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediators traditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation. Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatory T cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditions of liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cell activation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Such interactions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signals from natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC. Current directions of research investigate the immune-modulating functions of HSC in the environment of liver tumors, cellular heterogeneity or interactions promoting HSC deactivation during resolution of liver fibrosis. Understanding the role of HSC as central regulators of liver immunology may lead to novel therapeutic strategies for chronic liver diseases.
Collapse
Affiliation(s)
- Ralf Weiskirchen
- 1 Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, 2 Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
| | - Frank Tacke
- 1 Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, 2 Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
| |
Collapse
|
|
38
|
Abstract
UNLABELLED Liver tolerance is manifest as a bias toward immune unresponsiveness, both in the context of a major histocompatibility complex-mismatched liver transplant and in the context of liver infection. Two broad classes of mechanisms account for liver tolerance. The presentation of antigens by different liver cell types results in incomplete activation of CD8(+) T cells, usually leading to initial proliferation followed by either clonal exhaustion or premature death of the T cell. Many liver infections result in relatively poor CD4(+) T-cell activation, which may be because liver antigen-presenting cells express a variety of inhibitory cytokines and coinhibitor ligands. Poor CD4(+) T-cell activation by liver antigens likely contributes to abortive activation, exhaustion, and early death of CD8(+) T cells. In addition, a network of active immunosuppressive pathways in the liver is mediated mostly by myeloid cells. Kupffer cells, myeloid-derived suppressor cells, and liver dendritic cells both promote activation of regulatory T cells and suppress CD8(+) and CD4(+) effector T cells. This suppressive network responds to diverse inputs, including signals from hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells. CONCLUSION Though liver tolerance may be exploited by pathogens, it serves a valuable purpose. Hepatitis A and B infections occasionally elicit a powerful immune response sufficient to cause fatal massive liver necrosis. More commonly, the mechanisms of liver tolerance limit the magnitude of intrahepatic immune responses, allowing the liver to recover. The cost of this adaptive mechanism may be incomplete pathogen eradication, leading to chronic infection.
Collapse
Affiliation(s)
- Ian N Crispe
- Department of Pathology, University of Washington Medical Center, Seattle, WA 98195, USA
| |
Collapse
|
|
39
|
Raicevic G, Najar M, Najimi M, El Taghdouini A, van Grunsven LA, Sokal E, Toungouz M. Influence of inflammation on the immunological profile of adult-derived human liver mesenchymal stromal cells and stellate cells. Cytotherapy 2014; 17:174-85. [PMID: 25455740 DOI: 10.1016/j.jcyt.2014.10.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 10/02/2014] [Accepted: 10/03/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND AIMS Stem cell therapy for liver diseases has recently emerged as a promising alternative to liver transplantation. Eligible cells should have an appropriate immunophenotype. The aim of the present study was to define the immunological profile of two human liver-derived mesenchymal stromal cell populations, namely, stem cells (ADHLSC) and hepatic stellate cells (HSC). METHODS The study was conducted under normal and inflammatory conditions with the use of human bone marrow mesenchymal stromal cells (BM-MSC) as reference. RESULTS Like BM-MSC and ADHLSC, HSC were negative for hematopoietic (CD45) and endothelial (CD34) markers but positive for stromal markers. All cell types were constitutively positive for HLA class I and negative for human leukocyte antigen (HLA) class II and co-stimulatory molecules (CD80, CD86, CD134 and CD252). Inflammation induced the expression of CD40 in all cell types, but the highest values were observed on HSCs; high CD252 expression was only observed on HSC as compared with ADHLSC and BM-MSC. The expression of various adhesion molecules (CD54, CD58, CD106 and CD166) was dissimilar in these three cell types and was differentially influenced by inflammation as well. ADHLSC and HSC constitutively expressed the immunosuppressive molecule HLA-G, whereas CD274 expression was induced by inflammation, as in the case of BM-MSC. Moreover, all cell types expressed the two major natural killer ligands CD112 and CD115. CONCLUSIONS Toll-like receptors (TLR) 1, 3, 4 and 6 messenger RNA was expressed by both cell types, whereas TLR 2, 5, 7, 9 and 10 were only expressed by ADHLSC. Inflammation increased the expression of TLR 2 and 3 by ADHLSC and HSC. Finally, both liver-derived cell types were immunosuppressive because they inhibited the proliferation of mitogen-activated T cells.
Collapse
Affiliation(s)
- Gordana Raicevic
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental & Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Adil El Taghdouini
- Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
| | - Leo A van Grunsven
- Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
| | - Etienne Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental & Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Michel Toungouz
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| |
Collapse
|
|
40
|
Wu T, Zhao Y, Zhao Y. The roles of myeloid-derived suppressor cells in transplantation. Expert Rev Clin Immunol 2014; 10:1385-94. [DOI: 10.1586/1744666x.2014.948424] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
|
|
41
|
Cotransplantation with myeloid-derived suppressor cells protects cell transplants: a crucial role of inducible nitric oxide synthase. Transplantation 2014; 97:740-7. [PMID: 24642686 DOI: 10.1097/01.tp.0000442504.23885.f7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Islet transplantation is an alternative to pancreas transplantation to cure type 1 diabetes, but both require chronic immunosuppression, which is often accompanied by deleterious side effects. The purpose of this study was to explore prolongation of islet allograft survival by cotransplantation with myeloid-derived suppressor cells (MDSCs) without requirement of immunosuppression and determine the role of inducible nitric oxide synthase (iNOS) produced by MDSCs in immune regulation. METHODS Bone marrow cells were isolated from wild-type (WT) or iNOS mice and cultured in the presence of granulocyte-macrophage colony-stimulating factor and hepatic stellate cells (HSCs), resulting in the generation of MDSCs. WT or iNOS MDSCs were cotransplanted with islet allografts under the renal capsule of diabetic recipient mice. RESULTS Addition of HSCs into DC culture promoted generation of MDSCs (instead of DCs). MDSCs had elevated expression of iNOS upon exposure to IFN-γ and inhibited T-cell responses in an MLR culture. Cotransplantation with WT MDSCs markedly prolonged survival of islet allografts, which was associated with reduced infiltration of CD8 T cells resulting from inhibited proliferative response. These effects were significantly attenuated when MDSCs were deficient in iNOS. Furthermore, iNOS MDSCs largely lost their ability to protect islet allografts. CONCLUSIONS Cotransplantation with HSC-induced MDSCs significantly extends islet allograft survival through iNOS-mediated T-cell inhibition. The results demonstrate the potential use of in vitro generated MDSCs as a novel adjunctive immunotherapy for islet transplantation.
Collapse
|
|
42
|
Tonsho M, Michel S, Ahmed Z, Alessandrini A, Madsen JC. Heart transplantation: challenges facing the field. Cold Spring Harb Perspect Med 2014; 4:4/5/a015636. [PMID: 24789875 DOI: 10.1101/cshperspect.a015636] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection. Most, if not all, of these obstacles to long-term survival could be prevented or ameliorated by the induction of transplant tolerance wherein the recipient's immune system is persuaded not to mount a damaging immune response against donor antigens, thus eliminating the need for chronic immunosuppression. However, the heart, as opposed to other allografts like kidneys, appears to be a tolerance-resistant organ. Understanding why organs like kidneys and livers are prone to tolerance induction, whereas others like hearts and lungs are tolerance-resistant, could aid in our attempts to achieve long-term, immunosuppression-free survival in human heart transplant recipients. It could also advance the field of pig-to-human xenotransplantation, which, if successful, would eliminate the organ shortage problem. Of course, there are alternative futures to the field of heart transplantation that may include the application of total mechanical support, stem cells, or bioengineered whole organs. Which modality will be the first to reach the ultimate goal of achieving unlimited, long-term, circulatory support with minimal risk to longevity or lifestyle is unknown, but significant progress in being made in each of these areas.
Collapse
Affiliation(s)
- Makoto Tonsho
- MGH Transplantation Center, Massachusetts General Hospital, Boston, Massachusetts 02114
| | | | | | | | | |
Collapse
|
|
43
|
Liu H, Guan L, Li Z, Wang Z, Li W. Mechanisms of murine spontaneous liver transplant tolerance. EXP CLIN TRANSPLANT 2014; 12:1-8. [PMID: 24471716 DOI: 10.6002/ect.2013.0154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver transplant is associated with the induction of peripheral immune tolerance. Liver allografts are accepted spontaneously in most combinations of mismatch in major histocompatibility complex, without any requirements for immunosuppression. Liver nonparenchymal cells (especially dendritic cells and Kupffer cells), costimulatory pathways, and activated T-cell apoptosis may contribute to the induction of liver tolerance. Therefore, liver tolerance is an active process that includes T-cell activation, proliferation, infiltration of the allograft, and T-cell apoptosis. Liver dendritic cells may modulate the amount of alloreactive T cells in liver graft recipients by expressing the coinhibitory molecule programmed death-ligand 1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Liver dendritic cells also may induce activated T-cell apoptosis and Foxp3+ regulatory T cells. Future studies may clarify the precise function of liver nonparenchymal cells, the interactions between programmed death-ligand 1 and other costimulatory signals, and the contribution of the liver microenvironment to the induction and expansion of Foxp 3 regulatory T cells.
Collapse
Affiliation(s)
- Hongyu Liu
- Department of Hepatobiliary-Pancreatic Surgery, The Third Hospital of Jilin University (China-Japan Union Hospital), Changchun, China
| | | | | | | | | |
Collapse
|
|
44
|
Madariaga ML, Michel SG, Tasaki M, Villani V, La Muraglia GM, Sihag S, Gottschall J, Farkash EA, Shimizu A, Allan JS, Sachs DH, Yamada K, Madsen JC. Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation. Am J Transplant 2013; 13:2558-66. [PMID: 24033991 PMCID: PMC3920984 DOI: 10.1111/ajt.12423] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 06/27/2013] [Accepted: 06/28/2013] [Indexed: 01/25/2023]
Abstract
We have previously shown that tolerance of kidney allografts across a full major histocompatibility complex (MHC) barrier can be induced in miniature swine by a 12-day course of high-dose tacrolimus. However, that treatment did not prolong survival of heart allografts across the same barrier. We have now tested the effect of cotransplanting an allogeneic heart and kidney from the same MHC-mismatched donor using the same treatment regimen. Heart allografts (n = 3) or heart plus kidney allografts (n = 5) were transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. As expected, all isolated heart allografts rejected by postoperative day 40. In contrast, heart and kidney allografts survived for >200 days with no evidence of rejection on serial cardiac biopsies. Heart/kidney recipients lost donor-specific responsiveness in cell-mediated lympholysis and mixed-lymphocyte reaction assays, were free of alloantibody and exhibited prolonged survival of donor, but not third-party skin grafts. Late (>100 days) removal of the kidney allografts did not cause acute rejection of the heart allografts (n = 2) and did not abrogate donor-specific unresponsiveness in vitro. While kidney-induced cardiac allograft tolerance (KICAT) has previously been demonstrated across a Class I disparity, these data demonstrate that this phenomenon can also be observed across the more clinically relevant full MHC mismatch. Elucidating the renal element(s) responsible for KICAT could provide mechanistic information relevant to the induction of tolerance in recipients of isolated heart allografts as well as other tolerance-resistant organs.
Collapse
Affiliation(s)
- M. L. Madariaga
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - S. G. Michel
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA,Department of Cardiac Surgery, Ludwig-Maximilians-Universität, Munich, Germany
| | - M. Tasaki
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - V. Villani
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - G. M. La Muraglia
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - S. Sihag
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - J. Gottschall
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - E. A. Farkash
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - A. Shimizu
- Department of Pathology, Nippon Medical School, Tokyo, Japan
| | - J. S. Allan
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA,Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - D. H. Sachs
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - K. Yamada
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - J. C. Madsen
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA,Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA,Corresponding author: Joren C. Madsen,
| |
Collapse
|
|
45
|
Abstract
BACKGROUND The liver is an immunologic privileged organ; liver allografts are accepted across major histocompatibility complex barriers in many species. However, hepatocyte transplants are acutely rejected, suggesting a role for liver nonparenchymal cells in regulating the immunoresponse. We have shown potent immunoregulatory activity of hepatic stellate cells (HSCs) in mice. The aim of this study was to examine the immunoregulatory activity of human HSCs. METHODS HSCs were isolated from normal human livers for analyses of their impact on T-cell response. RESULTS HSCs expressed low HLA-DR and costimulatory molecules CD40 and CD80 but constitutively expressed high levels of CD54. Interferon-γ stimulated HSCs to express B7-H1 in a dose-dependent manner and produce the suppressive cytokines interleukin-6, interleukin-10, and transforming growth factor-β but did not affect expression of HLA-DR, CD40, and CD80. Human HSCs did not stimulate allogeneic T-cell proliferative response, indicating that they are not professional antigen-presenting cells. HSCs markedly inhibited T-cell response elicited by either allogeneic antigen-presenting cells or CD3/CD28 beads, which was associated with increases in activated CD4 and CD8 T-cell apoptosis. Addition of anti-B7-H1 blocking antibody significantly reversed the inhibitory effect. CONCLUSIONS Human HSCs demonstrate potent immunoregulatory activity via B7-H1-mediated induction of apoptosis in activated T cells. Understanding of the involved mechanisms may lead to development of novel therapeutic approaches for treatment of liver diseases.
Collapse
|
|
46
|
Li F, Tian Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 2013; 10:292-302. [PMID: 23604044 DOI: 10.1038/cmi.2013.7] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 02/21/2013] [Indexed: 12/24/2022] Open
Abstract
Because of its unique blood supply, the liver maintains a special local immune tolerogenic microenvironment. Moreover, the liver can impart this immune tolerogenic effect on other organs, thus inducing systemic immune tolerance. The network of hepatic regulatory cells is an important mechanism underlying liver tolerance. Many types of liver-resident antigen-presenting cells (APCs) have immune regulatory function, and more importantly, they can also induce the differentiation of circulating immune cells into regulatory cells to further extend systemic tolerance. Thus, the liver can be seen as a type of 'school', where liver APCs function as 'teachers' and circulating immune cells function as 'students.'
Collapse
Affiliation(s)
- Fenglei Li
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
| | | |
Collapse
|
|
47
|
Xu XN, Xiao YS, Fan J. Hepatic stellate cells and metastatic liver neoplasms. Shijie Huaren Xiaohua Zazhi 2013; 21:873-879. [DOI: 10.11569/wcjd.v21.i10.873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cells (HSCs) were first described in the 19th century as a type of multi-functional mesenchymal cells. They are considered as the component of liver microenvironment because of their capacity to differentiate into myofibroblasts which are highly proliferative and have collagen secretion capacity. This paper reviews the interactions between tumor cells and HSCs in liver microenvironment and discusses mechanisms by which tumor-derived factors activate HSCs, and in turn, activated HSC promotes metastatic tumor growth. The interactions between tumor cells and HSCs in liver microenvironment can be regarded as an "amplification loop". The activation of HSCs is a complex process that is regulated by multiple pathways, such as the transforming growth factor-β and platelet-derived growth factor signaling pathways. HSCs provide a possible therapeutic target for liver metastases to effectively increase the survival of patients.
Collapse
|
|
48
|
Ravishankar B, McGaha TL. O death where is thy sting? Immunologic tolerance to apoptotic self. Cell Mol Life Sci 2013; 70:3571-89. [PMID: 23377225 DOI: 10.1007/s00018-013-1261-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 12/14/2012] [Accepted: 01/03/2013] [Indexed: 12/22/2022]
Abstract
In higher organisms, innate scavenging cells maintain physiologic homeostasis by removal of the billions of apoptotic cells generated on a daily basis. Apoptotic cell removal requires efficient recognition and uptake by professional and non-professional phagocytic cells, which are governed by an array of soluble and apoptotic cell-integral signals resulting in immunologically silent clearance. While apoptosis is associated with profound suppression of adaptive and innate inflammatory immunity, we have only begun to scratch the surface in understanding how immunologic tolerance to apoptotic self manifest at either the molecular or cellular level. In the last 10 years, data has emerged implicating professional phagocytes, most notably stromal macrophages and CD8α(+)CD103(+) dendritic cells, as critical in initiation of the regulatory cascade that will ultimately lead to long-term whole-animal immune tolerance. Importantly, recent work by our lab and others has shown that alterations in apoptotic cell perception by the innate immune system either by removal of critical phagocytic sentinels in secondary lymphoid organs or blockage of immunosuppressive pathways leads to pronounced inflammation with a breakdown of tolerance towards self. This challenges the paradigm that apoptotic cells are inherently immunosuppressive, suggesting that apoptotic cell tolerance is a "context-dependent" event.
Collapse
Affiliation(s)
- Buvana Ravishankar
- Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Building CN4143, 1120 15th Street, Augusta, GA, 30904, USA
| | | |
Collapse
|
|
49
|
The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 2013; 121:1760-8. [PMID: 23299310 DOI: 10.1182/blood-2012-06-440214] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) play an important role in the regulation of the immune response. MDSC expansion occurs in many circumstances, including cancer, inflammation, stresses, and transplant tolerance. Liver transplants in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected, suggesting the immunoregulatory activities of liver nonparenchymal cells. We have reported that hepatic stellate cells (HpSCs), the stromal cells in the liver, are immensely immunosuppressive and can effectively protect islet transplants via induction of MDSCs. The present study shows that the addition of HpSCs into dendritic cell (DC) culture promoted development of MDSCs, instead of DCs, which was highly dependent on complement component 3 (C3) from HpSCs. The C3(-/-) HpSCs lost their ability to induce MDSCs and, consequently, failed to protect the cotransplanted islet allografts. HpSCs produced complement activation factor B and factor D which then enhanced C3 cleavage to activation products iC3b and C3d. Addition of exogenous iC3b, but not C3d, into the DC culture led to the differentiation of MDSCs with potent immune-inhibitory function. These findings provide novel mechanistic insights into the differentiation of myeloid cells mediated by local tissue cells, and may assist in the development of MDSC-based therapy in clinical settings.
Collapse
|
|
50
|
Kuang P, Zhao W, Su W, Zhang Z, Zhang L, Liu J, Ren G, Yin Z, Wang X. 18β-glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell-mediated immunosuppression in mice. Int J Cancer 2012; 132:1831-41. [PMID: 22991231 DOI: 10.1002/ijc.27852] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 09/05/2012] [Indexed: 01/16/2023]
Abstract
Hepatic stellate cells (HSCs) have immunosuppressive capabilities and contribute to the occurrence and development of hepatocellular carcinoma (HCC). Thus, activated HSCs may be a suitable target for HCC therapy. Our study used mixed leukocyte reactions (MLR) in vitro to demonstrate that 18β-glycyrrhetinic acid (GA) could reverse HSC-mediated immunosuppression by reducing T-cell apoptosis and regulatory T (Treg) cells expression, thereby enhancing the ability of T cells to attack tumor cells and attenuating HCC cell invasiveness. Moreover, we established a HCC orthotopic implantation model in immunocompetent C57BL/6 mice, which suggested that GA played a protective role in HCC development by reducing immunosuppression mediated by HSCs in the tumor microenvironment.
Collapse
Affiliation(s)
- Penghao Kuang
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
| | | | | | | | | | | | | | | | | |
Collapse
|