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Chen SY, Cao JL, Li KP, Wan S, Yang L. BIN1 in cancer: biomarker and therapeutic target. J Cancer Res Clin Oncol 2023; 149:7933-7944. [PMID: 36890396 DOI: 10.1007/s00432-023-04673-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/28/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND The bridging integrator 1 (BIN1) protein was originally identified as a pro-apoptotic tumor suppressor that binds to and inhibits oncogenic MYC transcription factors. BIN1 has complex physiological functions participating in endocytosis, membrane cycling, cytoskeletal regulation, DNA repair deficiency, cell-cycle arrest, and apoptosis. The expression of BIN1 is closely related to the development of various diseases such as cancer, Alzheimer's disease, myopathy, heart failure, and inflammation. PURPOSE Because BIN1 is commonly expressed in terminally differentiated normal tissues and is usually undetectable in refractory or metastatic cancer tissues, this differential expression has led us to focus on human cancers associated with BIN1. In this review, we discuss the potential pathological mechanisms of BIN1 during cancer development and its feasibility as a prognostic marker and therapeutic target for related diseases based on recent findings on its molecular, cellular, and physiological roles. CONCLUSION BIN1 is a tumor suppressor that regulates cancer development through a series of signals in tumor progression and microenvironment. It also makes BIN1 a feasible early diagnostic or prognostic marker for cancer.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
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Mitarotonda R, Giorgi E, Eufrasio-da-Silva T, Dolatshahi-Pirouz A, Mishra YK, Khademhosseini A, Desimone MF, De Marzi M, Orive G. Immunotherapeutic nanoparticles: From autoimmune disease control to the development of vaccines. BIOMATERIALS ADVANCES 2022; 135:212726. [PMID: 35475005 PMCID: PMC9023085 DOI: 10.1016/j.bioadv.2022.212726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 02/09/2022] [Accepted: 02/18/2022] [Indexed: 11/01/2022]
Abstract
The development of nanoparticles (NPs) with potential therapeutic uses represents an area of vast interest in the scientific community during the last years. Recently, the pandemic caused by COVID-19 motivated a race for vaccines creation to overcome the crisis generated. This is a good demonstration that nanotechnology will most likely be the basis of future immunotherapy. Moreover, the number of publications based on nanosystems has significantly increased in recent years and it is expected that most of these developments can go on to experimentation in clinical stages soon. The therapeutic use of NPs to combat different diseases such as cancer, allergies or autoimmune diseases will depend on their characteristics, their targets, and the transported molecules. This review presents an in-depth analysis of recent advances that have been developed in order to obtain novel nanoparticulate based tools for the treatment of allergies, autoimmune diseases and for their use in vaccines. Moreover, it is highlighted that by providing targeted delivery an increase in the potential of vaccines to induce an immune response is expected in the future. Definitively, the here gathered analysis is a good demonstration that nanotechnology will be the basis of future immunotherapy.
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Affiliation(s)
- Romina Mitarotonda
- Laboratorio de Inmunología, Instituto de Ecología y Desarrollo Sustentable (INEDES) CONICET-UNLu, Departamento de Ciencias Básicas, Universidad Nacional de Luján, Ruta 5 y Avenida Constitución (6700) Lujan, Buenos Aires, Argentina
| | - Exequiel Giorgi
- Laboratorio de Inmunología, Instituto de Ecología y Desarrollo Sustentable (INEDES) CONICET-UNLu, Departamento de Ciencias Básicas, Universidad Nacional de Luján, Ruta 5 y Avenida Constitución (6700) Lujan, Buenos Aires, Argentina
| | - Tatiane Eufrasio-da-Silva
- Department of Health Technology, Technical University of Denmark (DTU), 2800 Kgs. Lyngby, Denmark; Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Dentistry - Regenerative Biomaterials, Philips van Leydenlaan 25, 6525EX Nijmegen, the Netherlands
| | | | - Yogendra Kumar Mishra
- Mads Clausen Institute, NanoSYD, University of Southern Denmark, 6400 Sønderborg, Denmark
| | - Ali Khademhosseini
- Department of Bioengineering, Center for Minimally Invasive Therapeutics (C-MIT), California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA; Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, USA; Jonsson Comprehensive Cancer Center, Department of Radiology, University of California, Los Angeles, CA 90095, USA
| | - Martin F Desimone
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de la Química y Metabolismo del Fármaco (IQUIMEFA), Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Mauricio De Marzi
- Laboratorio de Inmunología, Instituto de Ecología y Desarrollo Sustentable (INEDES) CONICET-UNLu, Departamento de Ciencias Básicas, Universidad Nacional de Luján, Ruta 5 y Avenida Constitución (6700) Lujan, Buenos Aires, Argentina.
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore.
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Galanin mediates tumor-induced immunosuppression in head and neck squamous cell carcinoma. Cell Oncol (Dordr) 2022; 45:241-256. [PMID: 35267186 PMCID: PMC9050779 DOI: 10.1007/s13402-021-00631-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2021] [Indexed: 12/14/2022] Open
Abstract
Purpose Galanin receptor 2 (GALR2) plays a significant role in the progression of head and neck squamous cell carcinomas (HNSCC). Since there is virtually no information on immunomodulation mediated by its ligand in the tumor microenvironment, we assessed the effects of galanin on peripheral blood mononuclear cells (PBMCs). Methods After verification of GALR2 expression and it activity in PBMCs we evaluated the effect of galanin and conditioned media from HNSCC cell lines silenced for galanin or antibody-depleted, on proliferation, apoptosis, cytokine expression and activation/differentiation of immune cells. Results We found that galanin alone and as a component of the HNSCC secretome decreased HNSCC cell proliferation and expression of pro-inflammatory cytokines (IFNγ, IL-12, IL-17A, IL-1α, IL-6 and TNF-α), whilst increasing apoptosis and expression of pro-tumoral cytokines/growth factors (IL-10, IL-4, PDGF and GM-CSF). T cell activation (using CD69 as activation marker) and anti-tumoral phenotypes in CD4+ T cells (Th1 and Th17) were found to be suppressed. In vivo, tumor growth was found to be increased in the presence of galanin-stimulated PBMCs. Data from The Cancer Genome Atlas (TCGA) revealed that high expression of galanin was associated with a reduced overall survival of patients with HNSCC. Conclusion Our data indicate that galanin secreted by HNSCC cells exhibits immune-suppressive and pro-tumoral effects. Supplementary Information The online version contains supplementary material available at 10.1007/s13402-021-00631-y.
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Fan Y, Wang Y, Zhang J, Dong X, Gao P, Liu K, Ma C, Zhao G. Breaking Bad: Autophagy Tweaks the Interplay Between Glioma and the Tumor Immune Microenvironment. Front Immunol 2021; 12:746621. [PMID: 34671362 PMCID: PMC8521049 DOI: 10.3389/fimmu.2021.746621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
Though significant strides in tumorigenic comprehension and therapy modality have been witnessed over the past decades, glioma remains one of the most common and malignant brain tumors characterized by recurrence, dismal prognosis, and therapy resistance. Immunotherapy advance holds promise in glioma recently. However, the efficacy of immunotherapy varies among individuals with glioma, which drives researchers to consider the modest levels of immunity in the central nervous system, as well as the immunosuppressive tumor immune microenvironment (TIME). Considering the highly conserved property for sustaining energy homeostasis in mammalian cells and repeatedly reported links in malignancy and drug resistance, autophagy is determined as a cutting angle to elucidate the relations between glioma and the TIME. In this review, heterogeneity of TIME in glioma is outlined along with the reciprocal impacts between them. In addition, controversies on whether autophagy behaves cytoprotectively or cytotoxically in cancers are covered. How autophagy collapses from its homeostasis and aids glioma malignancy, which may depend on the cell type and the cellular context such as reactive oxygen species (ROS) and adenosine triphosphate (ATP) level, are briefly discussed. The consecutive application of autophagy inducers and inhibitors may improve the drug resistance in glioma after overtreatments. It also highlights that autophagy plays a pivotal part in modulating glioma and the TIME, respectively, and the intricate interactions among them. Specifically, autophagy is manipulated by either glioma or tumor-associated macrophages to conform one side to the other through exosomal microRNAs and thereby adjust the interactions. Given that some of the crosstalk between glioma and the TIME highly depend on the autophagy process or autophagic components, there are interconnections influenced by the status and well-being of cells presumably associated with autophagic flux. By updating the most recent knowledge concerning glioma and the TIME from an autophagic perspective enhances comprehension and inspires more applicable and effective strategies targeting TIME while harnessing autophagy collaboratively against cancer.
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Affiliation(s)
- Yuxiang Fan
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Yubo Wang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Jian Zhang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Xuechao Dong
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Pu Gao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Kai Liu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Chengyuan Ma
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Gang Zhao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
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Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 2021; 1:1460-1468. [PMID: 23264892 PMCID: PMC3525601 DOI: 10.4161/onci.21716] [Citation(s) in RCA: 309] [Impact Index Per Article: 77.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-cell tolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integrated stress response kinase GCN2, a sensor of uncharged tRNA that is activated by amino acid deprivation, is recognized as an important effector of the IDO pathway. However, in a mouse model of inflammatory carcinogenesis, ablation of Gcn2 did not promote resistance against tumor development like the absence of IDO does, implying the existence of additional cancer-relevant pathways that operate downstream of IDO. Addressing this gap in knowledge, we report that the IDO-mediated catabolism of tryptophan also inhibits the immunoregulatory kinases mTOR and PKC-Θ, along with the induction of autophagy. These effects were relieved specifically by tryptophan but also by the experimental agent 1-methyl-D-tryptophan (D-1MT, also known as NLG8189), the latter of which reversed the inhibitory signals generated by IDO with higher potency. Taken together, our results implicate mTOR and PKC-Θ in IDO-mediated immunosuppressive signaling, and they provide timely insights into the unique mechanism of action of D-1MT as compared with traditional biochemical inhibitors of IDO. These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO, IDO2 or TDO). Moreover, they define mTOR and PKC-Θ as candidate pharmacodynamic markers for D-1MT responses in patients recruited to ongoing phase IB/II cancer trials, addressing a current clinical need.
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Qi Y, Liu B, Sun Q, Xiong X, Chen Q. Immune Checkpoint Targeted Therapy in Glioma: Status and Hopes. Front Immunol 2020; 11:578877. [PMID: 33329549 PMCID: PMC7729019 DOI: 10.3389/fimmu.2020.578877] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/29/2020] [Indexed: 12/17/2022] Open
Abstract
Glioma is the most malignant primary tumor of the central nervous system and is characterized by an extremely low overall survival. Recent breakthroughs in cancer therapy using immune checkpoint blockade have attracted significant attention. However, despite representing the most promising (immunotherapy) treatment for cancer, the clinical application of immune checkpoint blockade in glioma patients remains challenging due to the "cold phenotype" of glioma and multiple factors inducing resistance, both intrinsic and acquired. Therefore, comprehensive understanding of the tumor microenvironment and the unique immunological status of the brain will be critical for the application of glioma immunotherapy. More sensitive biomarkers to monitor the immune response, as well as combining multiple immunotherapy strategies, may accelerate clinical progress and enable development of effective and safe treatments for glioma patients.
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Affiliation(s)
- Yangzhi Qi
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Baohui Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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Zhang C, Gao J, He J, Liu C, Lv X, Yin X, Deng Y, Lu Z, Tian Z. Regulatory T-cell expansion in oral and maxillofacial Langerhans cell histiocytosis. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 130:547-556. [PMID: 32988807 DOI: 10.1016/j.oooo.2020.08.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 06/22/2020] [Accepted: 08/02/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Langerhans cell histiocytosis (LCH) is a rare myeloid-origin neoplasm characterized by the expansion and dissemination of CD1 a+/CD207+ dendritic cells (LCH cells), but the rarity of its occurrence has long impeded progress in understanding its pathology. We focus on the potentially important role that regulatory T cells (T-reg) play in the oral and maxillofacial LCH tumor microenvironment (TME). STUDY DESIGN Nine cases of oral and maxillofacial LCH, diagnosed from 2009 to 2019, were collected retrospectively from the affiliated hospitals of Southern Medical University. Immunohistochemistry was conducted characterizing T cells and T-reg phenotype. Data were evaluated by 1-sample Wilcoxon's test. RESULTS Significantly increased frequency and abnormal distributions of T-reg were identified in all the LCH lesion sections. Proliferating T-reg account for a mean average of 11.5% of the total T-cell subsets, with significant difference (Wilcoxon's test; P < .05). CONCLUSIONS T-reg expansion in the localized inflammatory TME leads to a failure of immune regulation by suppressing antitumor response, which can be a latent and significant factor contributing to LCH progression. However, T-reg may also acquire the capability for aiding in initiating T-cell responses under the "cytokine storm" at the beginning of LCH onset. T-reg might contribute to the augmentation of tissue repair by transforming growth factor-β (TGF-β), explaining the self-limiting character of LCH.
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Affiliation(s)
- Chuhan Zhang
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jingyi Gao
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jianghai He
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Chundong Liu
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xiaozhi Lv
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xuemin Yin
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Yongjian Deng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhiyun Lu
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Zhihui Tian
- Department of Stomatology, School of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
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Shayesteh Z, Hosseini H, Nasiri V, Haddadi Z, Moradi N, Beikzadeh L, Sezavar M, Heidari A, Zibaei M. Evaluating the preventive and curative effects of Toxocara canis larva in Freund's complete adjuvant-induced arthritis. Parasite Immunol 2020; 42:e12760. [PMID: 32472559 DOI: 10.1111/pim.12760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 05/16/2020] [Accepted: 05/21/2020] [Indexed: 11/29/2022]
Abstract
Helminthic infection and the parallel host immune reactions are the results of a protracted dynamic co-interaction between the host and worms. An assessment of the effect of Toxocara canis infection on arthritis in rats stimulated by Freund's complete adjuvant (FCA) was the main purpose of the investigation. An arthritis model was established by the administration of 0.1 mL FCA in the palmar surface. Cytokine assessment, evaluating oedema and the use of a rheumatoid arthritis (RA) score provided evidence of the protective effects of T canis against adjuvant-induced arthritis (AIA). The cytokines TGF-β, IFN-ɣ, IL-10 and IL-17 were measured to assess the anti-inflammatory effect of T canis infection. Besides, arthritis swelling findings were evaluated in rat paws. The data showed that T canis infection significantly modulated the immune response by alleviating inflammatory cytokines and increasing TGF-β as an anti-inflammatory cytokine. Evaluations of arthritis swelling showed low severity and faster recuperation. These findings suggest that the products derived from T canis eggs might be a potential therapeutic candidate to treat autoimmune diseases like the arthritis.
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Affiliation(s)
- Zahra Shayesteh
- Department of Immunology, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Hamid Hosseini
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Vahid Nasiri
- Protozoology Laboratory, Parasitology Department, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Zeinab Haddadi
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Najmeh Moradi
- Department of Immunology, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Leila Beikzadeh
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Monireh Sezavar
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Aliehsan Heidari
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohammad Zibaei
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
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Yamamoto A, Hester J, Macklin PS, Kawai K, Uchiyama M, Biggs D, Bishop T, Bull K, Cheng X, Cawthorne E, Coleman ML, Crockford TL, Davies B, Dow LE, Goldin R, Kranc K, Kudo H, Lawson H, McAuliffe J, Milward K, Scudamore CL, Soilleux E, Issa F, Ratcliffe PJ, Pugh CW. Systemic silencing of PHD2 causes reversible immune regulatory dysfunction. J Clin Invest 2019; 129:3640-3656. [PMID: 31162141 PMCID: PMC6715380 DOI: 10.1172/jci124099] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 05/29/2019] [Indexed: 12/28/2022] Open
Abstract
Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity.
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Affiliation(s)
- Atsushi Yamamoto
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Joanna Hester
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Philip S. Macklin
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Kento Kawai
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Masateru Uchiyama
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Daniel Biggs
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Tammie Bishop
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Katherine Bull
- Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Xiaotong Cheng
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Eleanor Cawthorne
- Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Mathew L. Coleman
- Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Tanya L. Crockford
- Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ben Davies
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Lukas E. Dow
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York, USA
| | - Rob Goldin
- Department of Cellular Pathology, Imperial College London, London, United Kingdom
| | - Kamil Kranc
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Hiromi Kudo
- Department of Cellular Pathology, Imperial College London, London, United Kingdom
| | - Hannah Lawson
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - James McAuliffe
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Kate Milward
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Cheryl L. Scudamore
- Veterinary Pathology, MRC Harwell, Mary Lyon Centre, Harwell Campus, Oxford, United Kingdom
| | - Elizabeth Soilleux
- Department of Pathology, School of Biological Sciences, University of Cambridge, Cambridge, United Kingdom
| | - Fadi Issa
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Peter J. Ratcliffe
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Chris W. Pugh
- Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Zhao L, Ma M, Wu H, Zhang C, Dai S, Dong P, Huo B, Shan B. p-Hydroxylcinnamaldehyde slows the progression of 4NQO-induced oesophageal tumourigenesis via the RhoA-MAPK signaling pathway. Mol Carcinog 2018; 57:1319-1331. [PMID: 29873419 DOI: 10.1002/mc.22847] [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: 10/09/2017] [Revised: 05/20/2018] [Accepted: 06/01/2018] [Indexed: 12/16/2022]
Abstract
p-Hydroxylcinnamaldehyde isolated from the Cochinchina momordica seed (CMSP) has been identified to inhibit growth and metastasis in oesophageal squamous cell carcinoma (ESCC) by inducing differentiation. The aim of the present study was to evaluate the effect and underlying mechanism of CMSP on 4-nitroquinoline 1-oxide (4NQO)-induced oesophageal tumourigenesis. In the present study, a mouse model of oesophageal preneoplastic lesions was established by providing 4NQO-containing drinking water to C57BL/6 mice. The effect of CMSP on tumourigenesis induced by the chemical mutagen and the effect of CMSP on immune function were investigated. The results showed that the incidence and pathological stage of atypical hyperplasia in oesophageal tissues were significantly reduced in CMSP-treated mice compared with untreated mice. Immunohistochemistry and pull-down assay results revealed that the expression levels of p-ERK1/2, p-SAPK/JNK, and GTP-RhoA were significantly decreased in the oesophageal tissue of CMSP-treated mice. In addition, the proportions of CD4+ T cells, CD8+ T cells, and NK cells were increased, while the proportion of CD4+ CD25+ regulatory T cells (Tregs) was decreased, in the peripheral blood of CMSP-treated mice. These results indicated that CMSP could hamper 4NQO-induced oesophageal tumourigenesis by regulating the RhoA-ERK/JNK signaling pathway and promoting immune system function, thus providing a new potential strategy for treating preneoplastic lesions of the oesophagus.
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Affiliation(s)
- Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Ming Ma
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China.,Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Hao Wu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Cong Zhang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Suli Dai
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Pei Dong
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Bingjie Huo
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Baoen Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China
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11
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Becker W, Nagarkatti M, Nagarkatti PS. miR-466a Targeting of TGF-β2 Contributes to FoxP3 + Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation. Front Immunol 2018; 9:688. [PMID: 29686677 PMCID: PMC5900016 DOI: 10.3389/fimmu.2018.00688] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 03/20/2018] [Indexed: 12/25/2022] Open
Abstract
The promise of inducing immunological tolerance through regulatory T cell (Treg) control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA) regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4+ T cells in the draining lymph node (dLN) of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC) after allogeneic transplantation, in CD4+ T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p), targeting transforming growth factor beta 2 (TGF-β2), as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4+ T cells led to a decreased inducible FoxP3+ Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.
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Affiliation(s)
| | | | - Prakash S. Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
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12
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Ozen M, Zhao H, Kalish F, Yang Y, Folkins A, Burd I, Wong RJ, Stevenson DK. Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation. Am J Reprod Immunol 2018; 79:e12829. [PMID: 29484761 DOI: 10.1111/aji.12829] [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: 12/26/2017] [Accepted: 01/31/2018] [Indexed: 12/28/2022] Open
Abstract
PROBLEM Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. METHOD OF STUDY Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. RESULTS CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. CONCLUSION Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.
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Affiliation(s)
- Maide Ozen
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA.,Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
| | - Hui Zhao
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Flora Kalish
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Yang Yang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ann Folkins
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Irina Burd
- Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ronald J Wong
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - David K Stevenson
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA
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13
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Di Gennaro P, Gerlini G, Caporale R, Sestini S, Brandani P, Urso C, Pimpinelli N, Borgognoni L. T regulatory cells mediate immunosuppresion by adenosine in peripheral blood, sentinel lymph node and TILs from melanoma patients. Cancer Lett 2018; 417:124-130. [PMID: 29306022 DOI: 10.1016/j.canlet.2017.12.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/18/2017] [Accepted: 12/21/2017] [Indexed: 01/23/2023]
Abstract
T regulatory cells (Tregs), involved in tumour tolerance, can generate Adenosine by CD39/CD73 surface enzymes, which identify four Tregs subsets: CD39+CD73- nTregs, CD39+CD73+ iTregs, CD39-CD73+ oTregs and CD39-CD73- xTregs. In melanoma patients, increased Tregs levels are detected in peripheral blood (PB), sentinel lymph node (SLN) and tumour infiltrating lymphocytes (TILs), but Adenosine role was not investigated yet. We examined total Tregs and Adenosine subsets in PB, SLN and TILs from melanoma patients (n = 32) and PB from healthy donors (HD; n = 10) by flow cytometry. Total Tregs significantly increased in stage III-IV patients PB, in SLN and TILs, as compared to HD/stage I-II patients. Tregs subsets analyses showed that: 1) PB nTregs significantly increased in SLN and decreased in TILs; 2) iTregs significantly increased in stage III-IV patients PB and further significantly increased in SLN and TILs; 3) PB oTregs and xTregs significantly decreased in SLN and TILs. Patients clinical features did not significantly influence total Tregs, except SLN excision order. Results confirmed Tregs role in melanoma progression and indicate Adenosine generation as a novel escape mechanism, being nTregs and iTregs increased in PB/SLN/TILs.
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Affiliation(s)
- P Di Gennaro
- Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy.
| | - G Gerlini
- Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy
| | - R Caporale
- Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - S Sestini
- Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy
| | - P Brandani
- Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy
| | - C Urso
- Dept. Anatomic Pathology - Dermatopathology Section, Santa Maria Annunziata Hospital, Florence, Italy
| | - N Pimpinelli
- Dept. Surgery and Translational Medicine, Dermatology Section, University of Florence, Italy
| | - L Borgognoni
- Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy
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14
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Trojan K, Unterrainer C, Weimer R, Bulut N, Morath C, Aly M, Zhu L, Opelz G, Daniel V. Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function. PLoS One 2017; 12:e0173773. [PMID: 28296931 PMCID: PMC5351987 DOI: 10.1371/journal.pone.0173773] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 02/27/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND There is circumstantial evidence that IFNy+ Treg might have clinical relevance in transplantation. IFNy+ Treg express IFNy receptors and are induced by IFNy. In the present study we investigated in kidney transplant recipients with good long-term stable graft function the absolute cell counts of IFNy+ Treg subsets and whether their expression of Foxp3 is stable or transient. METHOD Helios expression determined by eight-color-fluorescence flow cytometry and methylation status of the Foxp3 Treg specific demethylation region (TSDR) served as indicators for stability of Foxp3 expression. Methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations originating from peripheral blood using high resolution melt analysis. A total of 136 transplant recipients and 52 healthy controls were studied. RESULTS Proportions of IFNy+ Treg were similar in patients and healthy controls (0.05% and 0.04% of all CD4+ lymphocytes; p = n.s.). Patients also had similar absolute counts of IFNy producing Helios+ and Helios- Treg (p = n.s.). Most of the IFNy+ and IFNy- Treg in transplant recipients had a methylated Foxp3 TSDR, however, there was a sizeable proportion of IFNy+ and IFNy- Treg with demethylated Foxp3 TSDR. Male and female patients showed more frequently methylated IFNy+ and IFNy- Treg than male and female controls (all p<0.05). CONCLUSIONS Kidney transplant recipients with good long-term stable graft function have similar levels of IFNy+ Treg as healthy controls. IFNy+ and IFNy- Treg subsets in patients consist of cells with stable and cells with transient Foxp3 expression; however, patients showed more frequently methylated IFNy+ and IFNy- Treg than controls. The data show increased levels of Treg subsets with stable as well as transient Foxp3 expression in patients with stable allograft acceptance compared to healthy controls.
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Affiliation(s)
- Karina Trojan
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Unterrainer
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Rolf Weimer
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - Nuray Bulut
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - Christian Morath
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Mostafa Aly
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
- Nephrology unit, Internal Medicine Department, Assiut University, Assiut, Egypt
| | - Li Zhu
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
- Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Gerhard Opelz
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Volker Daniel
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
- * E-mail:
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15
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Trojan K, Zhu L, Aly M, Weimer R, Bulut N, Morath C, Opelz G, Daniel V. Association of peripheral NK cell counts with Helios + IFN-γ - T regs in patients with good long-term renal allograft function. Clin Exp Immunol 2017; 188:467-479. [PMID: 28194759 DOI: 10.1111/cei.12945] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2017] [Indexed: 12/16/2022] Open
Abstract
Little is known about a possible interaction of natural killer (NK) cells with regulatory T cells (Treg ) in long-term stable kidney transplant recipients. Absolute counts of lymphocyte and Treg subsets were studied in whole blood samples of 136 long-term stable renal transplant recipients and 52 healthy controls using eight-colour fluorescence flow cytometry. Patients were 1946 ± 2201 days (153-10 268 days) post-transplant and showed a serum creatinine of 1·7 ± 0·7 mg/dl. Renal transplant recipients investigated > 1·5 years post-transplant showed higher total NK cell counts than recipients studied < 1·5 years after transplantation (P = 0·006). High NK cells were associated with high glomerular filtration rate (P = 0·002) and low serum creatinine (P = 0·005). Interestingly, high NK cells were associated with high CD4+ CD25+ CD127- forkhead box protein 3 (FoxP3+ ) Treg that co-express the phenotype Helios+ interferon (IFN)-γ- and appear to have stable FoxP3 expression and originate from the thymus. Furthermore, high total NK cells were associated with Treg that co-express the phenotypes interleukin (IL)-10- transforming growth factor (TGF)-β+ (P = 0·013), CD183+ CD62L- (P = 0·003), CD183+ CD62+ (P = 0·001), CD183- CD62L+ (P = 0·002), CD252- CD152+ (P < 0·001), CD28+ human leucocyte antigen D-related (HLA-DR- ) (P = 0·002), CD28+ HLA-DR+ (P < 0·001), CD95+ CD178- (P < 0·001) and CD279- CD152+ (P < 0·001), suggesting that these activated Treg home in peripheral tissues and suppress effector cells via TGF-β and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). The higher numbers of NK and Treg cell counts in patients with long-term good allograft function and the statistical association of these two lymphocyte subsets with each other suggest a direct or indirect (via DC) interaction of these cell subpopulations that contributes to good long-term allograft acceptance. Moreover, we speculate that regulatory NK cells are formed late post-transplant that are able to inhibit graft-reactive effector cells.
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Affiliation(s)
- K Trojan
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - L Zhu
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - M Aly
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Nephrology Unit, Internal Medicine Department, Assiut University, Egypt
| | - R Weimer
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - N Bulut
- Department of Internal Medicine, University of Giessen, Giessen, Germany
| | - C Morath
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - G Opelz
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - V Daniel
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
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16
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Zhang X, Zhu S, Li T, Liu YJ, Chen W, Chen J. Targeting immune checkpoints in malignant glioma. Oncotarget 2017; 8:7157-7174. [PMID: 27756892 PMCID: PMC5351697 DOI: 10.18632/oncotarget.12702] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 10/12/2016] [Indexed: 12/31/2022] Open
Abstract
Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the body's anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered "immune privileged" and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma.
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Affiliation(s)
- Xuhao Zhang
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Shan Zhu
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Tete Li
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Yong-Jun Liu
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
- Sanofi Research and Development, Cambridge, MA, USA
| | - Wei Chen
- ADC Biomedical Research Institute, Saint Paul, MN, USA
| | - Jingtao Chen
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
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17
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Eissa MM, Mostafa DK, Ghazy AA, El azzouni MZ, Boulos LM, Younis LK. Anti-Arthritic Activity of Schistosoma mansoni and Trichinella spiralis Derived-Antigens in Adjuvant Arthritis in Rats: Role of FOXP3+ Treg Cells. PLoS One 2016; 11:e0165916. [PMID: 27802332 PMCID: PMC5089557 DOI: 10.1371/journal.pone.0165916] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/19/2016] [Indexed: 12/16/2022] Open
Abstract
A growing body of evidence supports the concept of helminths therapy in a variety of autoimmune diseases. Here, we aimed to investigate the protective effects of autoclaved Schistosoma mansoni antigen (ASMA) and Trichinella spiralis antigen (ATSA) on the clinical and immunopathological features of rheumatoid arthritis (RA). Adjuvant arthritis was induced by subcutaneous and intradermal injections of complete Freund's adjuvant into the plantar surface of the right hind paw and the root of the tail, respectively. Rats were randomly assigned to serve as normal control, untreated arthritis, ASMA or ATSA-treated arthritis groups. Antigens were given by intradermal injection in two doses, two weeks apart. The development, progression of arthritic features, and the impact on animals' gait and body weight were followed up for 4 weeks. The associated changes in serum cytokines (IL-17, IFN-γ and IL-10), joints' histopathology and immunohistochemistry of Foxp3+ T regulatory cells (Tregs) were evaluated at the end of the study. Treatment with either ASMA or ATSA attenuated the progression of clinical features of polyarthritis, improved gait and body weight gain, reduced the elevated serum IL-17 and further increased both IFN-γ and IL-10. Histopathologically, this was associated with a remarkable regression of paws' inflammation that was limited only to the subcutaneous tissue, and a significant increase in the number of Foxp 3+ cells versus the untreated arthritis group. In conclusion, both Schistosoma mansoni and Trichinella spiralis derived antigens exerted protective effect against adjuvant arthritis with better effect achieved by ASMA treatment. This anti-arthritic activity is attributed to upregulation of the Foxp3+ Tregs, with subsequent favorable modulation of both pro- and anti-inflammatory cytokines. The use of autoclaved parasitic antigens excludes the deleterious effects of imposing helminthic infection by using live parasites, which may pave the way to a new therapeutic modality in treating RA.
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Affiliation(s)
- Maha M. Eissa
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Dalia K. Mostafa
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amany A. Ghazy
- Department of Medical microbiology and Immunology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Mervat Z. El azzouni
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Laila M. Boulos
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Layla K. Younis
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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18
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Trojan K, Unterrainer C, Aly M, Zhu L, Weimer R, Bulut N, Morath C, Opelz G, Daniel V. IFNy+ and IFNy- Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function. Transpl Immunol 2016; 39:S0966-3274(16)30124-1. [PMID: 27989714 DOI: 10.1016/j.trim.2016.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 10/25/2016] [Accepted: 10/27/2016] [Indexed: 01/03/2023]
Abstract
BACKGROUND Treg are a heterogenous cell population. In the present study we attempted to identify Treg subsets that might contribute to stable and good long-term graft function. METHOD Lymphocyte and Treg subsets were studied in 136 kidney transplant recipients with good long-term graft function and in 52 healthy control individuals using eight-color-fluorescence flow cytometry. Foxp3 TSDR methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations using high resolution melt analysis. RESULTS Compared with healthy controls, patients showed strong associations of IFNy secreting Helios+ and Helios- Treg with Treg that co-expressed perforin and/or CTLA4 (CD152; p<0.01). Moreover they showed associations of IFNy-Helios+ Treg with Treg that produced TGFβ and/or perforin and of IFNy-Helios- Treg with TGFβ production (all p<0.01). Only in patients, but not in healthy controls, were IFNy- Helios+ and Helios- Treg associated with higher CD45+, CD3+, (CD4+), CD19+ lymphocyte counts (p<0.001). In addition IFNy-Helios+ Treg were associated with CD16+56+ lymphocytes (p<0.001). Enriched IFNy- Treg from female but not male patients showed an association of Foxp3 methylation with higher total Treg and higher Helios+IFNy-, CXCR3+Lselectin+ (CD183+CD62L+), CXCR3-Lselectin+ and CD28+HLADR+ Treg subsets (p<0.01). Enriched IFNy+ Treg from male patients showed an association of demethylated Foxp3 with total Treg and IL10-TFGβ+ Treg counts, and in enriched IFNy- Treg an association of methylated Foxp3 with APO1/FasR+FasL+ (CD95+CD178+) Treg (p<0.01). CONCLUSIONS Kidney recipients with good long-term graft function possess IFNy+ and IFNy- Treg with stable and unstable Foxp3 expression in the blood. They co-express CD28, HLADR, CTLA4, CXCR3, Lselectin, TGFβ, perforin and FasL and might contribute to the establishment and maintenance of good long-term graft function.
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Affiliation(s)
- Karina Trojan
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Christian Unterrainer
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Mostafa Aly
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Li Zhu
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Rolf Weimer
- Department of Internal Medicine, University of Giessen, Klinikstrasse 33, D-35385 Giessen, Germany.
| | - Nuray Bulut
- Department of Internal Medicine, University of Giessen, Klinikstrasse 33, D-35385 Giessen, Germany.
| | - Christian Morath
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
| | - Gerhard Opelz
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Volker Daniel
- Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
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19
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Inic-Kanada A, Stojanovic M, Marinkovic E, Becker E, Stein E, Lukic I, Djokic R, Schuerer N, Hegemann JH, Barisani-Asenbauer T. A Probiotic Adjuvant Lactobacillus rhamnosus Enhances Specific Immune Responses after Ocular Mucosal Immunization with Chlamydial Polymorphic Membrane Protein C. PLoS One 2016; 11:e0157875. [PMID: 27636704 PMCID: PMC5026373 DOI: 10.1371/journal.pone.0157875] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/06/2016] [Indexed: 11/19/2022] Open
Abstract
Recent advances in the development of chlamydia vaccines, using live-attenuated or ultraviolet light-inactivated chlamydia, are paving the way for new possibilities to oppose the societal challenges posed by chlamydia-related diseases, such as blinding trachoma. An effective subunit vaccine would mitigate the risks associated with the use of a whole-cell vaccine. Our rationale for the design of an efficient subunit vaccine against Chlamydia trachomatis (Ct) is based on the membrane proteins involved in the initial Ct-host cell contact and on the route of immunization that mimics the natural infection process (i.e., via the ocular mucosa). The first aim of our study was to characterize the specific conjunctival and vaginal immune responses following eye drop immunization in BALB/c mice, using the N-terminal portion of the Ct serovar E polymorphic membrane protein C (N-PmpC) as the subunit vaccine antigen. Second, we aimed to examine the adjuvant properties of the probiotic Lactobacillus rhamnosus (LB) when formulated with N-PmpC. N-PmpC applied alone stimulated the production of N-PmpC- and Ct serovar B-specific antibodies in serum, tears and vaginal washes, whereas the combination with LB significantly enhanced these responses. The N-PmpC/LB combination initiated a T cell response characterized by an elevated percentage of CD25+ T cells and CD8+ effector T cells, enhanced CD4+ T-helper 1 skewing, and increased regulatory T cell responses. Together, these results show that eye drop vaccination with combined use of N-PmpC and a live probiotic LB stimulates specific cellular and humoral immune responses, not only locally in the conjunctiva but also in the vaginal mucosa, which could be a promising approach in Ct vaccine development.
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Affiliation(s)
- Aleksandra Inic-Kanada
- OCUVAC – Center of Ocular Inflammation and Infection, Laura Bassi Centres of Expertise, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Marijana Stojanovic
- Department of Research and Development, Institute of Virology, Vaccines and Sera – TORLAK, Belgrade, Serbia
| | - Emilija Marinkovic
- Department of Research and Development, Institute of Virology, Vaccines and Sera – TORLAK, Belgrade, Serbia
| | - Elisabeth Becker
- Institut für Funktionelle Genomforschung der Mikroorganismen, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, Gebäude 25.02.U1, 40225, Düsseldorf, Germany
| | - Elisabeth Stein
- OCUVAC – Center of Ocular Inflammation and Infection, Laura Bassi Centres of Expertise, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ivana Lukic
- Department of Research and Development, Institute of Virology, Vaccines and Sera – TORLAK, Belgrade, Serbia
| | - Radmila Djokic
- Department of Research and Development, Institute of Virology, Vaccines and Sera – TORLAK, Belgrade, Serbia
| | - Nadine Schuerer
- OCUVAC – Center of Ocular Inflammation and Infection, Laura Bassi Centres of Expertise, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Johannes H. Hegemann
- Institut für Funktionelle Genomforschung der Mikroorganismen, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, Gebäude 25.02.U1, 40225, Düsseldorf, Germany
| | - Talin Barisani-Asenbauer
- OCUVAC – Center of Ocular Inflammation and Infection, Laura Bassi Centres of Expertise, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- * E-mail:
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Baroja-Mazo A, Revilla-Nuin B, Parrilla P, Martínez-Alarcón L, Ramírez P, Pons JA. Tolerance in liver transplantation: Biomarkers and clinical relevance. World J Gastroenterol 2016; 22:7676-91. [PMID: 27678350 PMCID: PMC5016367 DOI: 10.3748/wjg.v22.i34.7676] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/04/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.
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König M, Rharbaoui F, Aigner S, Dälken B, Schüttrumpf J. Tregalizumab - A Monoclonal Antibody to Target Regulatory T Cells. Front Immunol 2016; 7:11. [PMID: 26834751 PMCID: PMC4724712 DOI: 10.3389/fimmu.2016.00011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 01/11/2016] [Indexed: 12/18/2022] Open
Abstract
Regulatory T cells (Tregs) represent a subpopulation of CD4+ T cells, which are essential for the maintenance of immunological tolerance. The absence or dysfunction of Tregs can lead to autoimmunity and allergies. The restoration of functional Tregs and/or Treg cell numbers represents a novel and attractive approach for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA). The CD4 cell surface receptor is a target for modulation of T cell function. Monoclonal antibodies (mAbs) against CD4 have previously been tested for the treatment of autoimmune diseases, including RA. Furthermore, in model systems, anti-CD4 antibodies are able to induce tolerance and mediate immunomodulatory effects through a variety of mechanisms. Despite the availability of innovative and effective therapies for RA, many patients still have persistently active disease or experience adverse events that can limit use. A growing body of evidence suggests that Treg modulation could offer a new therapeutic strategy in RA and other autoimmune disorders. Here, we describe tregalizumab (BT-061), which is a novel, non-depleting IgG1 mAb that binds to a unique epitope of CD4. Tregalizumab represents the first humanized anti-CD4 mAb that selectively induces Treg activation.
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Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway. J Neuroinflammation 2016; 13:8. [PMID: 26757900 PMCID: PMC4710023 DOI: 10.1186/s12974-016-0475-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 01/03/2016] [Indexed: 12/20/2022] Open
Abstract
Background Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown. Methods Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate-buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3+ cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin-Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin-Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays. Results Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin-Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3-dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97–116 IgG, IgG2a, and IgG2b antibodies. Conclusions Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases.
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Izadi N, Luu M, Ong PY, Tam JS. The Role of Skin Barrier in the Pathogenesis of Food Allergy. CHILDREN (BASEL, SWITZERLAND) 2015; 2:382-402. [PMID: 27417371 PMCID: PMC4928763 DOI: 10.3390/children2030382] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/25/2015] [Accepted: 08/25/2015] [Indexed: 02/08/2023]
Abstract
Food allergy is a serious public health problem with an increasing prevalence. Current management is limited to food avoidance and emergency treatment. Research into the pathogenesis of food allergy has helped to shape our understanding of how patients become sensitized to an allergen. Classically, food sensitization was thought to occur through the gastrointestinal tract, but alternative routes of sensitization are being explored, specifically through the skin. Damaged skin barrier may play a crucial role in the development of food sensitization. Better understanding of how patients initially become sensitized may help lead to the development of a safe and effective treatment for food allergies or better prevention strategies.
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Affiliation(s)
- Neema Izadi
- Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Minnelly Luu
- Department of Dermatology, Keck School of Medicine, University of Southern California.
| | - Peck Y Ong
- Division of Clinical Immunology and Allergy, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California.
| | - Jonathan S Tam
- Division of Clinical Immunology and Allergy, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California.
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Daniel V, Trojan K, Adamek M, Opelz G. IFNγ+ Treg in-vivo and in-vitro represent both activated nTreg and peripherally induced aTreg and remain phenotypically stable in-vitro after removal of the stimulus. BMC Immunol 2015; 16:45. [PMID: 26268522 PMCID: PMC4535851 DOI: 10.1186/s12865-015-0111-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 07/31/2015] [Indexed: 12/30/2022] Open
Abstract
Background IFNγ-producing CD4+CD25+Foxp3+CD127- Treg represent the first line of Treg during an immune response. In the present study we determined whether IFNγ+ Treg in-vivo and in-vitro are Helios-positive representing activated natural (nTreg) or Helios-negative representing adaptive Treg (aTreg) and whether they originate from CD4+CD25+ and/or CD4+CD25- PBL. Furtheron, we investigated whether they are inducible by recombinant IFNγ (rIFNγ) as a single stimulus, decrease in-vitro after elimination of the stimulus, and have a demethylated Foxp3 Treg-specific demethylated region (TSDR) which is associated with stable Foxp3 expression. Method Subsets of IFNγ+ Treg were determined in peripheral blood of healthy controls using eight-color flow cytometry and were further investigated in-vitro. Foxp3 TSDR methylation status was determined using bisulphite polymerase chain reaction (PCR) and high resolution melt (HRM) analysis. Results Nearly all Treg in the peripheral blood were Helios+IFNγ- (1.9 ± 1.1/μl) and only few were Helios+IFNγ+ or Helios-IFNγ+ Treg (both 0.1 ± 0.1/μl). Enriched IFNγ+ Treg subsets showed in part strong Foxp3 TSDR demethylation. In-vitro, rIFNγ was unable to induce Treg. CD4+CD25+ enriched PBL stimulated with PMA/Ionomycin in the presence of rIFNγ were rather resistant to the effect of rIFNγ, in contrast to CD4+CD25- enriched PBL which showed increasing total Treg with Helios+ Treg switching from IFNγ- to IFNγ+ and increasing Helios-IFNγ+ Treg. The data indicate that rIFNγ, in combination with a polyclonal stimulus, activates nTreg and induces aTreg. When phorbol 12-myristate 13-acetate (PMA)/Ionomycin was washed out from the cell culture after 6 h stimulation, Treg induction continued for at least 96 h of cell culture, contradicting the hypothesis that removal of the stimulus results in significant decrease of IFNγ- and IFNγ+ CD4+CD25+Foxp3+CD127- Treg due to loss of Foxp3 expression. Conclusions IFNγ+Helios- aTreg as well as IFNγ+Helios+ nTreg are detectable in the blood of healthy individuals, show in part strong Foxp3 TSDR demethylation and are inducible in-vitro. The present data provide further insight concerning the in-vivo and in-vitro characteristics of IFNγ+ Treg and help to understand their role in immunoregulation. Alloantigen-specific demethylated IFNγ+Helios+ nTreg might represent a suitable marker for monitoring graft-specific immunosuppression in renal transplant recipients.
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Affiliation(s)
- Volker Daniel
- Department of Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
| | - Karina Trojan
- Department of Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
| | - Martina Adamek
- Department of Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
| | - Gerhard Opelz
- Department of Transplantation-Immunology, Institute of Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
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Jia Y, Wang H, Wang Y, Wang T, Wang M, Ma M, Duan Y, Meng X, Liu L. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer 2015; 137:1095-106. [PMID: 25683635 DOI: 10.1002/ijc.29481] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 02/02/2015] [Indexed: 02/06/2023]
Abstract
Indoleamine 2,3-dioxygenase (IDO) has been reported to be involved in esophageal squamous cell cancer (ESCC) progression by promoting immune escape. Previous studies have revealed bridging integrator-1 (Bin1) can inhibit cancer cell growth by suppressing expression of IDO, thus we investigated the correlation between the expression of Bin1 and IDO and their prognostic significances for ESCC patients. Specimens were collected from 196 ESCC patients and detected with flow cytometry, reverse transcription-polymerase chain reaction and immunohistochemistry. We found that in tumor microenvironment (TME) and tumor draining lymph node (TDLN), the proportions of CD3(+) CD4(+) T cell, CD3(+) CD8(+) T cell and CD3(-) CD16(+) CD56(+) NK cell were lower while the proportions of CD3(-) CD19(+) B cell and CD4(+) CD25(+) Treg were higher in specimens with high IDO expression when compared to the specimens with low IDO expression (p < 0.01). In addition, IDO expression was negatively correlated with Bin1 expression at gene and protein level in TME and TDLN. Both the expression of Bin1 and IDO were associated with some clinicopathological parameters including differentiation grade, TNM stage, invasion range, lymph node metastasis (p < 0.05). Moreover, multivariate survival analysis suggested that, along with some other parameters, low expression of Bin1 and high expression of IDO might be independent prognostic factor for ESCC patients. Our results demonstrate that low expression of Bin1, along with high expression of IDO, are predictor for poor prognosis in ESCC and thereby could be used to establish new therapeutic strategies.
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Affiliation(s)
- Yunlong Jia
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China
| | - Hongyan Wang
- Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yu Wang
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China
| | - Tingting Wang
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China
| | - Miao Wang
- Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ming Ma
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China
| | - Yuqing Duan
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China
| | - Xianli Meng
- Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lihua Liu
- Department of Biotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China.,National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China
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26
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The role of FcεRI expressed in dendritic cells and monocytes. Cell Mol Life Sci 2015; 72:2349-60. [PMID: 25715742 DOI: 10.1007/s00018-015-1870-x] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 02/17/2015] [Accepted: 02/20/2015] [Indexed: 01/23/2023]
Abstract
Early studies regarding the function of FcεRI in dendritic cells (DCs) and monocytes have focused on its role in mediating inflammatory signaling and enhancing T cell immunity. It has been the case in part because FcεRI is the major receptor that mediates allergic inflammatory signaling in mast cells and basophils and because DCs and monocytes are antigen presenting cells capable of activating naïve and/or effector T cells. These studies have led to the general belief that FcεRI-mediated DC signaling and antigen presentation promote development and activation of Th2 cells and contribute to allergic inflammatory diseases. However, this belief has long suffered from a lack of evidence. Recently, studies have emerged that provide evidence supporting an opposing role: that FcεRI on DCs instead promotes immune homeostasis and regulation. In this review, we will update the current status of our understanding of FcεRI biology and function, with a specific focus on DCs and monocytes.
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27
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Lemos H, Huang L, McGaha T, Mellor AL. STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy? Expert Rev Clin Immunol 2014; 11:155-65. [PMID: 25521938 DOI: 10.1586/1744666x.2015.995097] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
DNA has potent immunogenic properties that are useful to enhance vaccine efficacy. DNA also incites hyperinflammation and autoimmunity if DNA sensing is not regulated. Paradoxically, DNA regulates immunity and autoimmunity when administered systemically as DNA nanoparticles. DNA nanoparticles regulated immunity via cytosolic DNA sensors that activate the signaling adaptor stimulator of interferon genes. In this review, we describe how DNA sensing to activate stimulator of interferon genes promotes regulatory responses and discuss the biological and clinical implications of these responses for understanding disease progression and designing better therapies for patients with chronic inflammatory diseases, such as autoimmune syndromes or cancer.
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Affiliation(s)
- Henrique Lemos
- Cancer immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, 1120 15th St, Augusta GA 30912, USA
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28
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Hori S. Lineage stability and phenotypic plasticity of Foxp3+regulatory T cells. Immunol Rev 2014; 259:159-72. [DOI: 10.1111/imr.12175] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Shohei Hori
- Laboratory for Immune Homeostasis; RCAI; RIKEN Center for Integrative Medical Sciences; Kanagawa Japan
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29
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Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LMF, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int Immunol 2014; 26:357-67. [PMID: 24402311 DOI: 10.1093/intimm/dxt073] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.
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Affiliation(s)
- Richard Metz
- New Link Genetics Corporation, Ames, IA 50010, USA
| | - Courtney Smith
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
| | | | - Phillip Chandler
- Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA
| | - Babak Baban
- Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA
| | - Lauren M F Merlo
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
| | - Elizabeth Pigott
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
| | - Martin P Keough
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
| | - Sonja Rust
- New Link Genetics Corporation, Ames, IA 50010, USA
| | - Andrew L Mellor
- Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA
| | - Laura Mandik-Nayak
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Alexander J Muller
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - George C Prendergast
- Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA Department of Pathology, Anatomy and Cell Biology, Jefferson Medical School, Thomas Jefferson University, Philadelphia, PA 19107, USA
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30
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Daniel V, Wang H, Sadeghi M, Opelz G. Interferon-gamma producing regulatory T cells as a diagnostic and therapeutic tool in organ transplantation. Int Rev Immunol 2013; 33:195-211. [PMID: 24266365 DOI: 10.3109/08830185.2013.845181] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
There is increasing evidence that IFNg plays a major role in both induction of Tregs as well as immunosuppression mediated by IFNg-producing Tregs. The present review focuses on a small subset of iTregs that produces IFNg, comprises only 0.04% of all CD4(+) T lymphocytes in the blood of healthy individuals, and increases strongly during an immune response. IFNg(+) Tregs are induced by IFNg and IL12, making them sensors for inflammatory cytokines. They develop rapidly during inflammation and represent the first line of Tregs that suppress initial immune responses. The pool of IFNg(+) Tregs consists of activated stable immunosuppressive thymus-derived nTregs as well as peripherally proliferating iTregs with in part only transient immunosuppressive function, which limits their diagnostic and therapeutic usefulness in organ transplantation. Apparently, a part of IFNg(+) Tregs dies during the immune response, whereas others, after efficient immunosuppression with resolution of the immune response, differentiate toward Th1 lymphocytes. Goals of further research are the development of appropriate diagnostic tests for rapid and exact determinination of immunosuppressive IFNg(+) iTregs, as well as the induction and propagation of stable immunosuppressive IFNg(+) Tregs that establish and maintain good long-term graft function in transplant recipients.
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Affiliation(s)
- Volker Daniel
- Department of Transplantation-Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany
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31
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Baban B, Liu JY, Mozaffari MS. Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells. Am J Physiol Regul Integr Comp Physiol 2012; 303:R1136-46. [PMID: 23100028 DOI: 10.1152/ajpregu.00315.2012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The aryl hydrocarbon receptor (AHR) has emerged as a major modulator of inflammatory processes. We tested the hypothesis that AHR activation protects the ischemic-reperfused kidney in association with the suppression of the inflammatory response. Accordingly, male mice were treated with the nondioxin AHR agonist, leflunomide (40 mg/kg ip); vehicle-treated animals served as controls. Thereafter, the right kidney was subjected to an ischemia (45 min)-reperfusion (4 h) insult, while the left kidney served as a sham control. Renal cells prepared from ischemic-reperfused kidneys of leflunomide-treated mice displayed preservation of mitochondrial membrane potential (Ψ(m)) and decreased apoptosis and necrosis compared with vehicle-treated ischemic-reperfused kidneys. Leflunomide treatment increased regulatory T cells (Tregs; forkhead box P3+) and IL-10-positive cells but reduced IL-17- and IL-23-expressing cells in both the peripheral blood and kidney cells, indicative of down-regulation of inflammatory responses. Leflunomide treatment also increased mobilization of stems cells subsets (i.e., mesenchymal and hematopoietic stem cells and endothelial progenitor cells) in the peripheral blood and promoted their recruitment into the ischemic-reperfused kidney. Collectively, the results indicate that AHR stimulation may represent a novel renoprotective mechanism likely involving mobilization and recruitment of Tregs and stem cells into the damaged kidney.
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Affiliation(s)
- Babak Baban
- Dept. of Oral Biology, College of Dental Medicine, Georgia Health Sciences Univ., 1120 15th St., CL-2112, Augusta, GA 30912, USA.
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Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells. J Cereb Blood Flow Metab 2012; 32:1897-908. [PMID: 22739622 PMCID: PMC3463881 DOI: 10.1038/jcbfm.2012.92] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The organic cation transporters OCT1, 2, and 3 (SLC22A1-3) have been implicated in the elimination of biogenic amines such as histamine. Among them, OCT3 was identified as an uptake-2 transporter, responsible for clearance of histamine. Because increasing evidence suggests the involvement of histamine in cerebral ischemia, we investigated the effects of targeted disruption of organic cation transporter-3 (Oct3) on the severity of ischemic brain damage. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery (MCA) of homozygous Oct3-deficient mice and their wild-type (Wt) littermates. Although targeted disruption of Oct3 did not affect physiological parameters after MCA occlusion, this disruption significantly increased histamine content in the ischemic cortex and significantly reduced the infarct volume after cerebral ischemia. Furthermore, targeted disruption of Oct3 prevented the reduction of regulatory T-cell proportion after cerebral ischemia while this disruption did not affect Th1 and Th2 cells proportions after ischemia. Since repeated administration of L-histidine (a precursor of histamine) to Wt mice also showed the same effects, our observations suggested that OCT3 is the molecule responsible for clearance of ischemia-induced histamine in the brain and targeted disruption of Oct3 ameliorated ischemic brain damage through an increase in regulatory T cells.
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Johnson TS, Munn DH. Host Indoleamine 2,3-Dioxygenase: Contribution to Systemic Acquired Tumor Tolerance. Immunol Invest 2012; 41:765-97. [DOI: 10.3109/08820139.2012.689405] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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CD4(+)CD25(+)Foxp3(+)IFNγ(+) Treg are immunosuppressive in vitro and increase with intensity of the alloresponse in pretransplant MLC. Transpl Immunol 2012; 27:114-21. [PMID: 22954802 DOI: 10.1016/j.trim.2012.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 08/17/2012] [Accepted: 08/20/2012] [Indexed: 11/24/2022]
Abstract
IFNγ-producing CD3(+)CD4(+)CD25(+)Foxp3(+) induced Treg are more frequently detectable in patients with good than in patients with impaired long-term kidney graft function. We investigated the in-vitro function of separated CD3(+)CD4(+)CD25(+)Foxp3(+)IFNγ(+) PBL that were induced by phorbol-12-myristate-13-acetate(PMA)/Ionomycin or alloantigenic stimulation. Additionally, we studied iTreg induction and cell proliferation in MLC with pretransplant obtained PBL. CD4(+)CD25(+)IFNγ(+) PBL separated from PMA/Ionomycin-stimulated PBL of healthy controls inhibited secondary cell cultures of autologous PBL. Furthermore, CD4(+)CD25(+)IFNγ(+) PBL separated from primary MLC and added to secondary MLC suppressed allogeneic T-cell activation in secondary MLC unspecifically, irrespective of the stimulator cell. However, the strongest suppression was observed in specific MLC. Patients with poor long-term graft outcome were able to form IFNγ(+) iTreg in pretransplant MLC. Eight patients with a serum creatinine level ranging from 0.9 to 14 mg/dl 18-29 years posttransplant were studied. In MLC with pretransplant obtained recipient and donor cells, strong IFNγ(+) iTreg (p=0.007) and strong blast induction (p=0.047) were associated with impaired long-term graft outcome. Long-term graft outcome was not associated with cell proliferation and iTreg induction in unspecific MLC with third-party cells as stimulator. The data indicate that patients with impaired long-term graft outcome are able to form high numbers of IFNγ(+) iTreg in specific pretransplant MLC. Quantity of induced IFNγ(+) iTreg depends on the strength of the alloresponse and both parameters are inversely associated with long-term graft outcome.
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Wang M, Gou X, Wang L. Protein Kinase B Promotes Radiation-Induced Regulatory T Cell Survival in Bladder Carcinoma. Scand J Immunol 2012; 76:70-4. [DOI: 10.1111/j.1365-3083.2012.02707.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Jin B, Sun T, Yu XH, Yang YX, Yeo AET. The effects of TLR activation on T-cell development and differentiation. Clin Dev Immunol 2012; 2012:836485. [PMID: 22737174 PMCID: PMC3376488 DOI: 10.1155/2012/836485] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 01/26/2012] [Indexed: 02/07/2023]
Abstract
Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.
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Affiliation(s)
- Bo Jin
- Department of Gastroenterology, The 309th Hospital of The People's Liberation Army, Beijing 100091, China
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Tao Sun
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Xiao-Hong Yu
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Ying-Xiang Yang
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
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Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia. J Virol 2012; 86:8461-71. [PMID: 22647697 DOI: 10.1128/jvi.00005-12] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ≥0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor β1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4(+) CD25(+(high)) CD127(-) FoxP3(+) T cell population with an effector memory phenotype (CD103(+)) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4(+) CD25(-) T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV(+) PCa.
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Schmetterer KG, Neunkirchner A, Pickl WF. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation. FASEB J 2012; 26:2253-76. [DOI: 10.1096/fj.11-193672] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Klaus G. Schmetterer
- Institute of ImmunologyCenter for Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria
| | - Alina Neunkirchner
- Institute of ImmunologyCenter for Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for ImmunmodulationViennaAustria
| | - Winfried F. Pickl
- Institute of ImmunologyCenter for Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for ImmunmodulationViennaAustria
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Koguchi Y, Buenafe AC, Thauland TJ, Gardell JL, Bivins-Smith ER, Jacoby DB, Slifka MK, Parker DC. Preformed CD40L is stored in Th1, Th2, Th17, and T follicular helper cells as well as CD4+ 8- thymocytes and invariant NKT cells but not in Treg cells. PLoS One 2012; 7:e31296. [PMID: 22363608 PMCID: PMC3283616 DOI: 10.1371/journal.pone.0031296] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Accepted: 01/05/2012] [Indexed: 01/01/2023] Open
Abstract
CD40L is essential for the development of adaptive immune responses. It is generally thought that CD40L expression in CD4+ T cells is regulated transcriptionally and made from new mRNA following antigen recognition. However, imaging studies show that the majority of cognate interactions between effector CD4+ T cells and APCs in vivo are too short to allow de novo CD40L synthesis. We previously showed that Th1 effector and memory cells store preformed CD40L (pCD40L) in lysosomal compartments and mobilize it onto the plasma membrane immediately after antigenic stimulation, suggesting that primed CD4+ T cells may use pCD40L to activate APCs during brief encounters. Indeed, our recent study showed that pCD40L is sufficient to mediate selective activation of cognate B cells and trigger DC activation in vitro. In this study, we show that pCD40L is present in Th1 and follicular helper T cells developed during infection with lymphocytic choriomeningitis virus, Th2 cells in the airway of asthmatic mice, and Th17 cells from the CNS of animals with experimental autoimmune encephalitis (EAE). pCD40L is nearly absent in both natural and induced Treg cells, even in the presence of intense inflammation such as occurs in EAE. We also found pCD40L expression in CD4 single positive thymocytes and invariant NKT cells. Together, these results suggest that pCD40L may function in T cell development as well as an unexpectedly broad spectrum of innate and adaptive immune responses, while its expression in Treg cells is repressed to avoid compromising their suppressive activity.
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Affiliation(s)
- Yoshinobu Koguchi
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Abigail C. Buenafe
- Department of Neurology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Timothy J. Thauland
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Jennifer L. Gardell
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Elizabeth R. Bivins-Smith
- Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
| | - David B. Jacoby
- Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Mark K. Slifka
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - David C. Parker
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
- * E-mail:
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Modulation of tumor tolerance in primary central nervous system malignancies. Clin Dev Immunol 2012; 2012:937253. [PMID: 22312408 PMCID: PMC3270544 DOI: 10.1155/2012/937253] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Revised: 09/29/2011] [Accepted: 10/03/2011] [Indexed: 12/14/2022]
Abstract
Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance.
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Chang MY, Smith C, DuHadaway JB, Pyle JR, Boulden J, Soler AP, Muller AJ, Laury-Kleintop LD, Prendergast GC. Cardiac and gastrointestinal liabilities caused by deficiency in the immune modulatory enzyme indoleamine 2,3-dioxygenase. Cancer Biol Ther 2011; 12:1050-8. [PMID: 22157149 DOI: 10.4161/cbt.12.12.18142] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) modifies adaptive immunity, in part by determining the character of inflammatory responses in the tissue microenvironment. Small molecule inhibitors of IDO are being developed to treat cancer, chronic infections and other diseases, so the systemic effects of IDO disruption on inflammatory phenomena may influence the design and conduct of early phase clinical investigations of this new class of therapeutic agents. Here, we report cardiac and gastrointestinal phenotypes observed in IDO deficient mice that warrant consideration in planned assessments of the safety risks involved in clinical development of IDO inhibitors. Calcification of the cardiac endometrium proximal to the right ventricle was a sexually dimorphic strain-specific phenotype with ~30% penetrance in BALB/c mice lacking IDO. Administration of complete Freund's adjuvant containing Toll-like receptor ligands known to induce IDO caused acute pancreatitis in IDO deficient mice, with implications for the design of planned combination studies of IDO inhibitors with cancer vaccines. In an established model of hyperlipidemia, IDO deficiency caused a dramatic elevation in levels of serum triglycerides. In the large intestine, IDO loss only slightly increased sensitivity to induction of acute colitis, but it markedly elevated tumor incidence, multiplicity and staging during inflammatory colon carcinogenesis. Together, our findings suggest potential cardiac and gastrointestinal risks of IDO inhibitors that should be monitored in patients as this new class of drugs enter early clinical development.
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Dimova T, Nagaeva O, Stenqvist AC, Hedlund M, Kjellberg L, Strand M, Dehlin E, Mincheva-Nilsson L. Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples. Am J Reprod Immunol 2011; 66 Suppl 1:44-56. [PMID: 21726337 DOI: 10.1111/j.1600-0897.2011.01046.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
PROBLEM Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women. METHOD OF STUDY Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR. RESULTS The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFβ1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells. CONCLUSION (i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.
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Affiliation(s)
- Tanya Dimova
- Department of Clinical Microbiology/Clinical Immunology, Umeå University, Umeå, Sweden
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Xu HT, Ye J, Chen YB, Zhang LX, Huang JX, Xian JC, Liu L, Peng HL, Li L, Lin M, Huang JH. Changes in the proportions of CD4(+)T cell subsets defined by CD127 and CD25 expression during HBV infection. Immunol Invest 2011; 41:290-303. [PMID: 22122423 DOI: 10.3109/08820139.2011.631656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CD4(+)T cell counts are closely related to the progression of HBV infection. Here, we investigated how the proportions of three CD4(+)T cell subsets - CD127(-)CD25(-), CD127(+)CD25(low/-) and CD127(low)CD25(high) - changed during HBV infection, as is little known. Compared with healthy controls, the proportions of CD127(-)CD25(-) in chronic hepatitis B (CHB) patients and HBV carriers significantly increased, while that of CD127(+)CD25(low/-) significantly decreased. The proportion of CD127(low)CD25(high) in CHB patients was significantly higher than those in HBV carriers or healthy controls. Compared with HBV-DNA negative group, the proportion of CD127(-)CD25(-) in positive group significantly decreased and that of CD127(+)CD25(low/-) significantly increased. In the follow-up study for CHB patients treated with interferon-α2b for 12 weeks or 24 weeks, the proportions of CD127(-)CD25(-) significantly decreased, while that of CD127(low/-)CD25(high) significantly increased. The results suggested that specific changes in the fraction of CD4(+)T cell subsets expressing CD127 and/or CD25 were associated with hepatitis B progression.
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Affiliation(s)
- Hong-Tao Xu
- Department of Laboratory Medicine, The Taizhou People's Hospital, Taizhou City, Jiangsu Province 225300, China
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Ha TY. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases. Immune Netw 2011; 11:227-44. [PMID: 22194706 PMCID: PMC3242997 DOI: 10.4110/in.2011.11.5.227] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 08/17/2011] [Accepted: 09/06/2011] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress.
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Affiliation(s)
- Tai-You Ha
- Department of Immunology, Chonbuk National University Medical School, Chonju 561-180, Korea
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Abstract
As Nature Reviews Immunology reaches its 10(th) anniversary, the authors of one of the top-cited articles from each year take a trip down memory lane. We've asked them to look back on the state of research at the time their Review was published, to consider why the article has had the impact it has and to discuss the future directions of their field. This Viewpoint article provides an interesting snapshot of some of the fundamental advances in immunology over the past 10 years. Highlights include our improved understanding of Toll-like receptor signalling, and of immune regulation mediated by regulatory T cells, indoleamine 2,3-dioxygenase, myeloid-derived suppressor cells and interleukin-10. The complexities in the development and heterogeneity of macrophages, dendritic cells and T helper cells continue to engage immunologists, as do the immune processes involved in diseases such as atherosclerosis. We look forward to what the next 10 years of immunology research may bring.
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Sehrawat S, Rouse BT. Tregs and infections: on the potential value of modifying their function. J Leukoc Biol 2011; 90:1079-87. [PMID: 21914856 DOI: 10.1189/jlb.0611271] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
CD4(+) T cells, which express a master transcription factor, Foxp3, have been recognized as bona fide Tregs. These cells are essential to maintain immune homeostasis in healthy as well as infected mice and humans. Extensive investigations in the last decade have provided ways to manipulate the Foxp3(+) Treg response therapeutically so the role of such cells in microbe-induced inflammatory reactions can be evaluated. This review focuses on our current understanding of the mechanisms required for the generation and sustenance of Tregs in vivo and the potential value of modulating Tregs to control microbe-induced immunopathological responses.
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Affiliation(s)
- Sharvan Sehrawat
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
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Baban B, Chandler PR, Johnson BA, Huang L, Li M, Sharpe ML, Francisco LM, Sharpe AH, Blazar BR, Munn DH, Mellor AL. Physiologic control of IDO competence in splenic dendritic cells. THE JOURNAL OF IMMUNOLOGY 2011; 187:2329-35. [PMID: 21813777 DOI: 10.4049/jimmunol.1100276] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4→B7 and PD-1→PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.
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Affiliation(s)
- Babak Baban
- Department of Oral Biology, Georgia Health Sciences University, Augusta, GA 30912, USA
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