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Affiliation(s)
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Cited by Other Article(s) |
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1
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Sureka N, Zaheer S. Regulatory T Cells in Tumor Microenvironment: Therapeutic Approaches and Clinical Implications. Cell Biol Int 2025. [PMID: 40365758 DOI: 10.1002/cbin.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/19/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025]
Abstract
Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.
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Affiliation(s)
- Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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2
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Song Y, Li J, Wu Y. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther 2024; 9:263. [PMID: 39362875 PMCID: PMC11452214 DOI: 10.1038/s41392-024-01952-8] [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: 02/20/2024] [Revised: 07/09/2024] [Accepted: 08/07/2024] [Indexed: 10/05/2024] Open
Abstract
Autoimmune disorders are characterized by aberrant T cell and B cell reactivity to the body's own components, resulting in tissue destruction and organ dysfunction. Autoimmune diseases affect a wide range of people in many parts of the world and have become one of the major concerns in public health. In recent years, there have been substantial progress in our understanding of the epidemiology, risk factors, pathogenesis and mechanisms of autoimmune diseases. Current approved therapeutic interventions for autoimmune diseases are mainly non-specific immunomodulators and may cause broad immunosuppression that leads to serious adverse effects. To overcome the limitations of immunosuppressive drugs in treating autoimmune diseases, precise and target-specific strategies are urgently needed. To date, significant advances have been made in our understanding of the mechanisms of immune tolerance, offering a new avenue for developing antigen-specific immunotherapies for autoimmune diseases. These antigen-specific approaches have shown great potential in various preclinical animal models and recently been evaluated in clinical trials. This review describes the common epidemiology, clinical manifestation and mechanisms of autoimmune diseases, with a focus on typical autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and sjögren's syndrome. We discuss the current therapeutics developed in this field, highlight the recent advances in the use of nanomaterials and mRNA vaccine techniques to induce antigen-specific immune tolerance.
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Affiliation(s)
- Yi Song
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jian Li
- Chongqing International Institute for Immunology, Chongqing, China.
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, China.
- Chongqing International Institute for Immunology, Chongqing, China.
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3
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Gao Q, Li X, Li Y, Long J, Pan M, Wang J, Yang F, Zhang Y. Bibliometric analysis of global research trends on regulatory T cells in neurological diseases. Front Neurol 2023; 14:1284501. [PMID: 37900596 PMCID: PMC10603183 DOI: 10.3389/fneur.2023.1284501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/25/2023] [Indexed: 10/31/2023] Open
Abstract
This bibliometric study aimed to summarize and visualize the current research status, emerging trends, and research hotspots of regulatory T (Treg) cells in neurological diseases. Relevant documents were retrieved from the Web of Science Core Collection. Tableau Public, VOSviewer, and CiteSpace software were used to perform bibliometric analysis and network visualization. A total of 2,739 documents were included, and research on Treg cells in neurological diseases is still in a prolific period. The documents included in the research were sourced from 85 countries/regions, with the majority of them originating from the United States, and 2,811 organizations, with a significant proportion of them coming from Harvard Medical School. Howard E Gendelman was the most prolific author in this research area. Considering the number of documents and citations, impact factors, and JCR partitions, Frontiers in Immunology was the most popular journal in this research area. Keywords "multiple sclerosis," "inflammation," "regulatory T cells," "neuroinflammation," "autoimmunity," "cytokines," and "immunomodulation" were identified as high-frequency keywords. Additionally, "gut microbiota" has recently emerged as a new topic of interest. The study of Treg cells in neurological diseases continues to be a hot topic. Immunomodulation, gut microbiota, and cytokines represent the current research hotspots and frontiers in this field. Treg cell-based immunomodulatory approaches have shown immense potential in the treatment of neurological diseases. Modifying gut microbiota or regulating cytokines to boost the numbers and functions of Treg cells represents a promising therapeutic strategy for neurological diseases.
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Affiliation(s)
- Qian Gao
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinmin Li
- School of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yan Li
- School of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Junzi Long
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Mengyang Pan
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jing Wang
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Fangjie Yang
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yasu Zhang
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
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4
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Robles LM, Reichenberg LH, Grissom Ⅲ JH, Chi RJ, Piller KJ. Recombinant MBP-pσ1 expressed in soybean seeds delays onset and reduces developing disease in an animal model of multiple sclerosis. PLANT BIOTECHNOLOGY (TOKYO, JAPAN) 2022; 39:367-379. [PMID: 37283612 PMCID: PMC10240915 DOI: 10.5511/plantbiotechnology.22.0926a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/26/2022] [Indexed: 06/08/2023]
Abstract
It is estimated that multiple sclerosis (MS) affects over 2.8 million people worldwide, with a prevalence that is expected to continue growing over time. Unfortunately, there is no cure for this autoimmune disease. For several decades, antigen-specific treatments have been used in animal models of experimental autoimmune encephalomyelitis (EAE) to demonstrate their potential for suppressing autoimmune responses. Successes with preventing and limiting ongoing MS disease have been documented using a wide variety of myelin proteins, peptides, autoantigen-conjugates, and mimics when administered by various routes. While those successes were not translatable in the clinic, we have learned a great deal about the roadblocks and hurdles that must be addressed if such therapies are to be useful. Reovirus sigma1 protein (pσ1) is an attachment protein that allows the virus to target M cells with high affinity. Previous studies showed that autoantigens tethered to pσ1 delivered potent tolerogenic signals and diminished autoimmunity following therapeutic intervention. In this proof-of-concept study, we expressed a model multi-epitope autoantigen (human myelin basic protein, MBP) fused to pσ1 in soybean seeds. The expression of chimeric MBP-pσ1 was stable over multiple generations and formed the necessary multimeric structures required for binding to target cells. When administered to SJL mice prophylactically as an oral therapeutic, soymilk formulations containing MBP-pσ1 delayed the onset of clinical EAE and significantly reduced developing disease. These results demonstrate the practicality of soybean as a host for producing and formulating immune-modulating therapies to treat autoimmune diseases.
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Affiliation(s)
| | | | - James H. Grissom Ⅲ
- University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA
| | - Richard J. Chi
- University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA
| | - Kenneth J. Piller
- SoyMeds, Inc., Charlotte, North Carolina 28223, USA
- University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA
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5
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Huldani H, Rashid AI, Turaev KN, Opulencia MJC, Abdelbasset WK, Bokov DO, Mustafa YF, Al-Gazally ME, Hammid AT, Kadhim MM, Ahmadi SH. Concanavalin A as a promising lectin-based anti-cancer agent: the molecular mechanisms and therapeutic potential. Cell Commun Signal 2022; 20:167. [PMID: 36289525 PMCID: PMC9597983 DOI: 10.1186/s12964-022-00972-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 09/17/2022] [Indexed: 11/29/2022] Open
Abstract
Concanavalin A (ConA), the most studied plant lectin, has been known as a potent anti-neoplastic agent for a long time. Since initial reports on its capacity to kill cancer cells, much attention has been devoted to unveiling the lectin's exact molecular mechanism. It has been revealed that ConA can bind to several receptors on cancerous and normal cells and modulate the related signaling cascades. The most studied host receptor for ConA is MT1-MMP, responsible for most of the lectin's modulations, ranging from activating immune cells to killing tumor cells. In this study, in addition to studying the effect of ConA on signaling and immune cell function, we will focus on the most up-to-date advancements that unraveled the molecular mechanisms by which ConA can induce autophagy and apoptosis in various cancer cell types, where it has been found that P73 and JAK/STAT3 are the leading players. Moreover, we further discuss the main signaling molecules causing liver injury as the most significant side effect of the lectin injection. Altogether, these findings may shed light on the complex signaling pathways controlling the diverse responses created via ConA treatment, thereby modulating these complex networks to create more potent lectin-based cancer therapy.
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Video Abstract
- Huldani Huldani
- grid.443126.60000 0001 2193 0299Department of Physiology, Faculty of Medicine, Lambung Mangkurat University, Banjarmasin, South Kalimantan Indonesia
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- Ahmed Ibraheem Rashid
- grid.427646.50000 0004 0417 7786Department of Pharmacology, Collage of Medicine, University of Babylon, Hilla, Iraq
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- Khikmatulla Negmatovich Turaev
- grid.444694.f0000 0004 0403 0119Department of Clinical Pharmacology, Samarkand State Medical Institute, Samarkand, Uzbekistan ,grid.513581.b0000 0004 6356 9173Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, Uzbekistan 100047
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- Walid Kamal Abdelbasset
- grid.449553.a0000 0004 0441 5588Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia ,grid.7776.10000 0004 0639 9286Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
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- Dmitry Olegovich Bokov
- grid.448878.f0000 0001 2288 8774Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., Bldg. 2, Moscow, 119991 Russian Federation ,grid.466474.3Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky Pr, Moscow, 109240 Russian Federation
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- Yasser Fakri Mustafa
- grid.411848.00000 0000 8794 8152Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul-41001, Iraq
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- Ali Thaeer Hammid
- grid.513683.a0000 0004 8495 7394Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja’afar Al-Sadiq University, Baghdad, Iraq
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- Mustafa M. Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit 52001 Iraq ,grid.444971.b0000 0004 6023 831XCollege of Technical Engineering, The Islamic University, Najaf, Iraq ,Department of Pharmacy, Osol Aldeen University College, Baghdad, Iraq
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- Seyed Hossein Ahmadi
- grid.411705.60000 0001 0166 0922Research Center for Cell and Molecular Sciences, School of Medicine, Tehran University of Medical Sciences, PO Box 1417613151, Tehran, Iran
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6
Gertel S, Polachek A, Elkayam O, Furer V. Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatment response in autoimmune diseases.
Autoimmun Rev 2022;
21:103085. [PMID:
35341974 DOI:
10.1016/j.autrev.2022.103085]
[Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/23/2022] [Accepted: 03/23/2022] [Indexed: 11/25/2022]
Abstract
Regulatory T cells (Tregs) comprise a CD4+CD25+Foxp3+ T cell subset for maintaining immune tolerance, and their deficits and/or dysfunction are observed in autoimmune diseases. The lymphocyte activation gene 3 (LAG-3, also known as CD223), which is an immunoglobulin superfamily member expressed on peripheral immune cells, is recognized as an inhibitory regulator of Tregs. LAG-3+ T cells represent a novel protective Tregs subset that produces interleukin-10. Alterations in LAG-3+ Tregs have been reported in several autoimmune diseases, suggesting their potential pathogenic role. Recent studies have indicated that LAG-3+ Tregs may be associated not only with immunopathology but also with response to therapy in several autoimmune and autoinflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis and others. We present a review of Tregs phenotypes and functions, with a focus on LAG-3+ Tregs, and discuss their potential role as biomarkers for treatment response in autoimmune diseases.
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Affiliation(s)
- Smadar Gertel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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- Ari Polachek
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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- Ori Elkayam
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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- Victoria Furer
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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7
Das R, Langou S, Le TT, Prasad P, Lin F, Nguyen TD. Electrical Stimulation for Immune Modulation in Cancer Treatments.
Front Bioeng Biotechnol 2022;
9:795300. [PMID:
35087799 PMCID:
PMC8788921 DOI:
10.3389/fbioe.2021.795300]
[Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/17/2021] [Indexed: 12/17/2022] Open
Abstract
Immunotherapy is becoming a very common treatment for cancer, using approaches like checkpoint inhibition, T cell transfer therapy, monoclonal antibodies and cancer vaccination. However, these approaches involve high doses of immune therapeutics with problematic side effects. A promising approach to reducing the dose of immunotherapeutic agents given to a cancer patient is to combine it with electrical stimulation, which can act in two ways; it can either modulate the immune system to produce the immune cytokines and agents in the patient's body or it can increase the cellular uptake of these immune agents via electroporation. Electrical stimulation in form of direct current has been shown to reduce tumor sizes in immune-competent mice while having no effect on tumor sizes in immune-deficient mice. Several studies have used nano-pulsed electrical stimulations to activate the immune system and drive it against tumor cells. This approach has been utilized for different types of cancers, like fibrosarcoma, hepatocellular carcinoma, human papillomavirus etc. Another common approach is to combine electrochemotherapy with immune modulation, either by inducing immunogenic cell death or injecting immunostimulants that increase the effectiveness of the treatments. Several therapies utilize electroporation to deliver immunostimulants (like genes encoded with cytokine producing sequences, cancer specific antigens or fragments of anti-tumor toxins) more effectively. Lastly, electrical stimulation of the vagus nerve can trigger production and activation of anti-tumor immune cells and immune reactions. Hence, the use of electrical stimulation to modulate the immune system in different ways can be a promising approach to treat cancer.
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Affiliation(s)
- Ritopa Das
- Department of Biomedical Engineering, University of Connecticut, Mansfield, CT, United States
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- Sofia Langou
- Department of Physiology and Neurobiology, University of Connecticut, Mansfield, CT, United States
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- Thinh T. Le
- Department of Mechanical Engineering, University of Connecticut, Mansfield, CT, United States
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- Pooja Prasad
- Department of Cell and Molecular Biology, University of Connecticut, Mansfield, CT, United States
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- Feng Lin
- Department of Mechanical Engineering, University of Connecticut, Mansfield, CT, United States
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- Thanh D. Nguyen
- Department of Biomedical Engineering, University of Connecticut, Mansfield, CT, United States
- Department of Mechanical Engineering, University of Connecticut, Mansfield, CT, United States
- Institute of Materials Science, University of Connecticut, Mansfield, CT, United States
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8
Supriya R, Gao Y, Gu Y, Baker JS. Role of Exercise Intensity on Th1/Th2 Immune Modulations During the COVID-19 Pandemic.
Front Immunol 2021;
12:761382. [PMID:
35003073 PMCID:
PMC8727446 DOI:
10.3389/fimmu.2021.761382]
[Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/07/2021] [Indexed: 12/02/2022] Open
Abstract
The COVID-19 pandemic has led to several pioneering scientific discoveries resulting in no effective solutions with the exception of vaccination. Moderate exercise is a significant non-pharmacological strategy, to reduce the infection-related burden of COVID-19, especially in patients who are obese, elderly, and with additional comorbidities. The imbalance of T helper type 1 (Th1) or T helper type 2 (Th2) cells has been well documented among populations who have suffered as a result of the COVID-19 pandemic, and who are at maximum risk of infection and mortality. Moderate and low intensity exercise can benefit persons at risk from the disease and survivors by favorable modulation in Th1/Th2 ratios. Moreover, in COVID-19 patients, mild to moderate intensity aerobic exercise also increases immune system function but high intensity aerobic exercise may have adverse effects on immune responses. In addition, sustained hypoxia in COVID-19 patients has been reported to cause organ failure and cell death. Hypoxic conditions have also been highlighted to be triggered in COVID-19-susceptible individuals and COVID-19 survivors. This suggests that hypoxia inducible factor (HIF 1α) might be an important focus for researchers investigating effective strategies to minimize the effects of the pandemic. Intermittent hypoxic preconditioning (IHP) is a method of exposing subjects to short bouts of moderate hypoxia interspersed with brief periods of normal oxygen concentrations (recovery). This methodology inhibits the production of pro-inflammatory factors, activates HIF-1α to activate target genes, and subsequently leads to a higher production of red blood cells and hemoglobin. This increases angiogenesis and increases oxygen transport capacity. These factors can help alleviate virus induced cardiopulmonary hemodynamic disorders and endothelial dysfunction. Therefore, during the COVID-19 pandemic we propose that populations should engage in low to moderate exercise individually designed, prescribed and specific, that utilizes IHP including pranayama (yoga), swimming and high-altitude hiking exercise. This would be beneficial in affecting HIF-1α to combat the disease and its severity. Therefore, the promotion of certain exercises should be considered by all sections of the population. However, exercise recommendations and prescription for COVID-19 patients should be structured to match individual levels of capability and adaptability.
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Affiliation(s)
- Rashmi Supriya
- Faculty of Sports Science, Ningbo University, Zhejiang, China
- Centre for Health and Exercise Science Research, Department of Sport, Physical Education and Health, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
- *Correspondence: Rashmi Supriya,
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- Yang Gao
- Faculty of Sports Science, Ningbo University, Zhejiang, China
- Centre for Health and Exercise Science Research, Department of Sport, Physical Education and Health, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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- Yaodong Gu
- Faculty of Sports Science, Ningbo University, Zhejiang, China
- Centre for Health and Exercise Science Research, Department of Sport, Physical Education and Health, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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- Julien S. Baker
- Faculty of Sports Science, Ningbo University, Zhejiang, China
- Centre for Health and Exercise Science Research, Department of Sport, Physical Education and Health, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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9
Pinheiro-Rosa N, Torres L, Oliveira MDA, Andrade-Oliveira MF, Guimarães MADF, Coelho MM, Alves JDL, Maioli TU, Faria AMC. Oral tolerance as antigen-specific immunotherapy.
IMMUNOTHERAPY ADVANCES 2021;
1:ltab017. [PMID:
35919733 PMCID:
PMC9327124 DOI:
10.1093/immadv/ltab017]
[Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 07/23/2021] [Accepted: 08/23/2021] [Indexed: 12/19/2022] Open
Abstract
Summary
Oral tolerance is a physiological phenomenon described more than a century ago as a suppressive immune response to antigens that gain access to the body by the oral route. It is a robust and long-lasting event with local and systemic effects in which the generation of mucosally induced regulatory T cells (iTreg) plays an essential role. The idea of using oral tolerance to inhibit autoimmune and allergic diseases by oral administration of target antigens was an important development that was successfully tested in 1980s. Since then, several studies have shown that feeding specific antigens can be used to prevent and control chronic inflammatory diseases in both animal models and clinically. Therefore, oral tolerance can be classified as an antigen-specific form of oral immunotherapy (OIT). In the light of novel findings on mechanisms, sites of induction and factors affecting oral tolerance, this review will focus on specific characteristics of oral tolerance induction and how they impact in its therapeutic application.
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Affiliation(s)
- Natália Pinheiro-Rosa
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Lícia Torres
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Mariana de Almeida Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Marcos Felipe Andrade-Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Mauro Andrade de Freitas Guimarães
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Monique Macedo Coelho
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Juliana de Lima Alves
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Tatiani Uceli Maioli
- Departamento de Nutrição, Escola de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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- Ana M Caetano Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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10
Richardson N, Wraith DC. Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity.
IMMUNOTHERAPY ADVANCES 2021;
1:ltab009. [PMID:
35919740 PMCID:
PMC9327121 DOI:
10.1093/immadv/ltab009]
[Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/28/2021] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
Targeted restoration of immunological tolerance to self-antigens or innocuous environmental allergens represents the ultimate aim of treatment options in autoimmune and allergic disease. Antigen-specific immunotherapy (ASI) is the only intervention that has proven disease-modifying efficacy as evidenced by induction of long-term remission in a number of allergic conditions. Mounting evidence is now indicating that specific targeting of pathogenic T cells in autoinflammatory and autoimmune settings enables effective restoration of immune homeostasis between effector and regulatory cells and alters the immunological course of disease. Here, we discuss the key lessons learned during the development of antigen-specific immunotherapies and how these can be applied to inform future interventions. Armed with this knowledge and current high-throughput technology to track immune cell phenotype and function, it may no longer be a matter of ‘if’ but ‘when’ this ultimate aim of targeted tolerance restoration is realised.
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Affiliation(s)
- Naomi Richardson
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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- David Cameron Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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11
Derdelinckx J, Cras P, Berneman ZN, Cools N. Antigen-Specific Treatment Modalities in MS: The Past, the Present, and the Future.
Front Immunol 2021;
12:624685. [PMID:
33679769 PMCID:
PMC7933447 DOI:
10.3389/fimmu.2021.624685]
[Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
Antigen-specific therapy for multiple sclerosis may lead to a more effective therapy by induction of tolerance to a wide range of myelin-derived antigens without hampering the normal surveillance and effector function of the immune system. Numerous attempts to restore tolerance toward myelin-derived antigens have been made over the past decades, both in animal models of multiple sclerosis and in clinical trials for multiple sclerosis patients. In this review, we will give an overview of the current approaches for antigen-specific therapy that are in clinical development for multiple sclerosis as well provide an insight into the challenges for future antigen-specific treatment strategies for multiple sclerosis.
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Affiliation(s)
- Judith Derdelinckx
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VaxInfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Division of Neurology, Antwerp University Hospital, Edegem, Belgium
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- Patrick Cras
- Division of Neurology, Antwerp University Hospital, Edegem, Belgium.,Born Bunge Institute, Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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- Zwi N Berneman
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VaxInfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
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- Nathalie Cools
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VaxInfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
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12
Bertolini TB, Biswas M, Terhorst C, Daniell H, Herzog RW, Piñeros AR. Role of orally induced regulatory T cells in immunotherapy and tolerance.
Cell Immunol 2020;
359:104251. [PMID:
33248367 DOI:
10.1016/j.cellimm.2020.104251]
[Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/30/2020] [Accepted: 11/01/2020] [Indexed: 12/24/2022]
Abstract
Oral antigen administration to induce regulatory T cells (Treg) takes advantage of regulatory mechanisms that the gastrointestinal tract utilizes to promote unresponsiveness against food antigens or commensal microorganisms. Recently, antigen-based oral immunotherapies (OITs) have shown efficacy as treatment for food allergy and autoimmune diseases. Similarly, OITs appear to prevent anti-drug antibody responses in replacement therapy for genetic diseases. Intestinal epithelial cells and microbiota possibly condition dendritic cells (DC) toward a tolerogenic phenotype that induces Treg via expression of several mediators, e.g. IL-10, transforming growth factor-β, retinoic acid. Several factors, such as metabolites derived from microbiota or diet, impact the stability and expansion of these induced Treg, which include, but are not limited to, FoxP3+ Treg, LAP+ Treg, and/or Tr1 cells. Here, we review various orally induced Treg, their plasticity and cooperation between the Treg subsets, as well as underlying mechanisms controlling their induction and role in oral tolerance.
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Affiliation(s)
- Thais B Bertolini
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| |
- Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| |
- Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA
| |
- Henry Daniell
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
- Roland W Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
| |
- Annie R Piñeros
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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13
Joo JY, Cha GS, Kim HJ, Lee JY, Choi J. Atheroprotective nasal immunization with a heat shock protein 60 peptide from
Porphyromonas gingivalis.
J Periodontal Implant Sci 2020;
50:159-170. [PMID:
32617181 PMCID:
PMC7321712 DOI:
10.5051/jpis.2020.50.3.159]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 03/13/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose
Immunization with Porphyromonas gingivalis heat shock protein 60 (PgHSP60) may have an immunoregulatory effect on atherogenesis. The aim of this study was to determine whether nasal immunization with a PgHSP60 peptide could reduce atherosclerotic plaque formation in apolipoprotein E knockout (ApoE KO) mice.
Methods
Seven-week-old male ApoE KO mice were assigned to receive a normal diet, a Western diet, a Western diet and challenge with PgHSP60-derived peptide 14 (Pep14) or peptide 19 (Pep19), or a Western diet and immunization with Pep14 or Pep19 before challenge with Pep14 or Pep19.
Results
Atherosclerotic plaques were significantly smaller in mice that received a Western diet with Pep14 nasal immunization than in mice that received a Western diet and no Pep14 immunization with or without Pep14 challenge. An immunoblot profile failed to detect serum reactivity to Pep14 in any of the study groups. Stimulation by either Pep14 or Pep19 strongly promoted the induction of CD4+CD25+forkhead box P3 (FoxP3)+ human regulatory T cells (Tregs) in vitro. However, the expression of mouse splenic CD4+CD25+FoxP3+ Tregs was lower in the Pep14-immunized mice than in the Pep14-challenged or Pep19-immunized mice. Levels of serum interferon gamma (IFN-γ) and transforming growth factor beta were higher and levels of interleukin (IL) 10 were lower in the Pep14-immunized mice than in the other groups. Induction of CD25− IL-17+ T helper 17 (Th17) cells was attenuated in the Pep14-immunized mice.
Conclusions
Nasal immunization with Pep14 may be a mechanism for attenuating atherogenesis by promoting the secretion of IFN-γ and/or suppressing Th17-mediated immunity.
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Affiliation(s)
- Ji-Young Joo
- Periodontal Disease Signaling Network Research Center, Dental and Life Science Institute, Pusan National University School of Dentistry, Yangsan, Korea.,Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry, Yangsan, Korea
| |
- Gil-Sun Cha
- Periodontal Disease Signaling Network Research Center, Dental and Life Science Institute, Pusan National University School of Dentistry, Yangsan, Korea
| |
- Hyun-Joo Kim
- Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry, Yangsan, Korea
| |
- Ju-Youn Lee
- Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry, Yangsan, Korea
| |
- Jeomil Choi
- Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry, Yangsan, Korea
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14
Zhao H, Zhao Q, Zhu S, Huang B, Lv L, Liu G, Li Z, Wang L, Dong H, Han H. Molecular characterization and immune protection of an AN1-like zinc finger protein of Eimeria tenella.
Parasitol Res 2019;
119:623-635. [PMID:
31758298 DOI:
10.1007/s00436-019-06545-x]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 11/06/2019] [Indexed: 11/28/2022]
Abstract
Coccidiosis is caused by multiple species of the apicomplexan protozoa Eimeria. Among them, Eimeria tenella is frequently considered to be the most pathogenic. Zinc finger proteins (ZnFPs) are a type of protein containing zinc finger domains. In the present study, a putative Eimeria tenella AN1-like ZnFP (E. tenella AN1-like zinc finger domain-containing protein, putative partial mRNA, EtAN1-ZnFP) was cloned and characterized, and its immune protective effects were evaluated. The 798-bp ORF sequence of EtAN1-ZnFP that encoded a protein of approximately 27.0 kDa was obtained. The recombinant EtAN1-ZnFP protein (rEtAN1-ZnFP) was expressed in Escherichia coli. Western blot analysis showed that the recombinant protein was recognized by the anti-GST monoclonal antibody and anti-sporozoite protein rabbit serum. qPCR analysis revealed that EtAN1-ZnFP was highly expressed in unsporulated oocysts and sporozoites. Immunostaining with an anti-rEtAN1-ZnFP antibody indicated that EtAN1-ZnFP was uniformly distributed in the cytoplasm of sporozoites, except for the refractive body; furthermore, this protein was evenly distributed in the cytoplasm of immature schizonts but seldom distributed in mature schizonts. The results of the in vitro invasion inhibition assay indicated that the antibodies against rEtAN1-ZnFP efficiently reduced the ability of E. tenella sporozoites to invade host cells. Animal challenge experiments demonstrated that the chickens immunized with rEtAN1-ZnFP protein significantly decreased mean lesion scores and fecal oocyst output compared with challenged control group. The results suggest that EtAN1-ZnFP can induce partial immune protection against infection with E. tenella and could be an effective candidate for the development of new vaccines.
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Affiliation(s)
- Huanzhi Zhao
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
| |
- Qiping Zhao
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
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- Shunhai Zhu
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
| |
- Bing Huang
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
| |
- Ling Lv
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
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- Guiling Liu
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China.,College of Life and Environment Sciences, Shanghai Normal University, Shanghai, 200234, China
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- Zhihang Li
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China.,College of Life and Environment Sciences, Shanghai Normal University, Shanghai, 200234, China
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- Lu Wang
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
| |
- Hui Dong
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China
| |
- Hongyu Han
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, China.
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15
Mowat AM. To respond or not to respond - a personal perspective of intestinal tolerance.
Nat Rev Immunol 2019;
18:405-415. [PMID:
29491358 DOI:
10.1038/s41577-018-0002-x]
[Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research.
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Affiliation(s)
- Allan McI Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK.
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16
Jørgensen N, Persson G, Hviid TVF. The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer.
Front Immunol 2019;
10:911. [PMID:
31134056 PMCID:
PMC6517506 DOI:
10.3389/fimmu.2019.00911]
[Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/09/2019] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms being highly dependent on the balance between immune activation and suppression. As regulatory T cells hold a crucial role in several biological processes, they may also be promising subjects for therapeutic use. Especially in the field of cancer, cell therapy and checkpoint inhibitors have demonstrated that immune-based therapies have a very promising potential in treatment of human malignancies. However, these therapies are often accompanied by adverse autoimmune side effects. Therefore, expanding the knowledge to recognize the complexities of immune regulation pathways shared across different immunological scenarios is extremely important in order to improve and develop new strategies for immune-based therapy. The intent of this review is to highlight the functional characteristics of regulatory T cells in the context of mechanisms of immune regulation in pregnancy and cancer, and how manipulation of these mechanisms potentially may improve therapeutic options.
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Affiliation(s)
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- Thomas Vauvert F. Hviid
- Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Consortium ZUH, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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17
Feng RY, Chen Q, Yang WJ, Tong XG, Sun ZM, Yan H. Immune Tolerance Therapy: A New Method for Treatment of Traumatic Brain Injury.
Chin Med J (Engl) 2018;
131:1990-1998. [PMID:
30082532 PMCID:
PMC6085845 DOI:
10.4103/0366-6999.238147]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective:
Due to the special anatomical structure and pathophysiological mechanism of the central nervous system (CNS), there is a big difference between the repair of brain injury and other systems of the body. More and more evidence shows that targetedly reducing the autoimmune response of brain tissue without affecting the immune function in other parts of the body will be the best optimized treatment for brain injury.
Data Sources:
This review was based on data in articles published in PubMed up to June 5, 2017, with the following keywords: “immune tolerance”, “traumatic brain injury”, and “central nervous system”.
Study Selection:
Original articles and critical reviews on immune tolerance and brain damage were selected for this review. References of the retrieved articles were also screened to search for potentially relevant papers.
Results:
The CNS is isolated from the immune system through the blood-brain barrier. After brain injury, brain antigens are released into the systemic circulation to induce damaging immune responses. Immune tolerance can effectively reduce the brain edema and neurological inflammatory response after brain injury, which is beneficial to the recovery of neurological function. The clinical application prospect and theoretical research value of the treatment of immune tolerance on traumatic brain injury (TBI) is worth attention.
Conclusions:
The establishment of immune tolerance mechanism has a high clinical value in the treatment of TBI. It opens up new opportunities for the treatment of brain damage.
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Affiliation(s)
- Ruo-Yang Feng
- Department of Neurosurgery, Tianjin Medical University, Tianjin 300070, China
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- Qian Chen
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases; Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin 300350, China
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- Wei-Jian Yang
- Department of Neurosurgery, Tianjin Medical University, Tianjin 300070, China
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- Xiao-Guang Tong
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin 300350, China
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- Zhi-Ming Sun
- Department of Spine Surgery, Tianjin Huanhu Hospital, Tianjin 300350, China
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- Hua Yan
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin 300350, China
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18
Tordesillas L, Lozano-Ojalvo D, Dunkin D, Mondoulet L, Agudo J, Merad M, Sampson HA, Berin MC. PDL2
+ CD11b
+ dermal dendritic cells capture topical antigen through hair follicles to prime LAP
+ Tregs.
Nat Commun 2018;
9:5238. [PMID:
30531969 PMCID:
PMC6286332 DOI:
10.1038/s41467-018-07716-7]
[Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 11/21/2018] [Indexed: 12/30/2022] Open
Abstract
The skin immune system must discriminate between innocuous antigens and pathogens. Antigen applied topically using a Viaskin® patch elicits immune tolerance that can suppress colitis and food allergy. Here we show how topical antigen is acquired and presented by dendritic cells in the skin. Topical antigen is acquired by Langerhans cells (LC) and CD11b+ cDC2s but not cDC1s, and both LCs and CD11b+ cDC2s reaching the lymph node can prime T cells and expand LAP+ Tregs. However, LCs are neither required nor sufficient for T cell priming, and have no role in tolerance induction. Conversely, IRF-4-dependent cDC2s are required for T cell priming. Acquisition of antigen in the dermis, delivery to the draining lymph node, and generation of tolerance are all absent in hairless mice. These results indicate an important function for hair follicle niche and CD11b+ cDC2s in antigen acquisition, and in generation of primary immune tolerance to topical antigens.
Antigen present and presented in the structures of the skin can result in immune responses that elicit tolerance, protective immunity or allergy, depending on the immunological context. Here the authors describe a key role for the hair follicle and CD11b+ dendritic cells in the priming of local antigenic tolerance.
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Affiliation(s)
- Leticia Tordesillas
- Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.,Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
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- Daniel Lozano-Ojalvo
- Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.,Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
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- David Dunkin
- Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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- Judith Agudo
- Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
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- Miriam Merad
- Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
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- Hugh A Sampson
- Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.,Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.,DBV Technologies, Montrouge, 90120, France
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- M Cecilia Berin
- Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA. .,Immunology Institute. Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
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19
Kamali AN, Noorbakhsh SM, Hamedifar H, Jadidi-Niaragh F, Yazdani R, Bautista JM, Azizi G. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders.
Mol Immunol 2018;
105:107-115. [PMID:
30502718 DOI:
10.1016/j.molimm.2018.11.015]
[Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/17/2018] [Accepted: 11/21/2018] [Indexed: 12/21/2022]
Abstract
The T helper 17 (Th17) cells contain a dynamic subset of CD4+ T-cells that are able to develop into other different lineage subsets, including the Th1-like Th17 cells. These cells co-express retinoic acid-related orphan receptor gamma t (RORγt) and transcription factor T-box-expressed-in-T-cells (T-bet) and produce both interleukin (IL)-17 and interferon (IFN)-γ. Recent reports have shown that Th1-like Th17 cells play crucial roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, as well as, some primary immunodeficiency with autoimmune features. Here, the actual mechanisms for Th17 cells plasticity to Th1-like Th17 cells are discussed and reviewed in association to the role that Th1-like Th17 cells have on inflammatory and autoimmune disorders.
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Affiliation(s)
- Ali N Kamali
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
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- Haleh Hamedifar
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
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- Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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- Reza Yazdani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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- José M Bautista
- Department of Biochemistry and Molecular Biology, Complutense University of Madrid, Faculty of Veterinary Sciences, 28040, Madrid, Spain; Research Institute Hospital 12 de Octubre, Madrid, 28041, Spain
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- Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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20
Bernaldo de Quiros E, Seoane-Reula E, Alonso-Lebrero E, Pion M, Correa-Rocha R. The role of regulatory T cells in the acquisition of tolerance to food allergens in children.
Allergol Immunopathol (Madr) 2018;
46:612-618. [PMID:
29739687 DOI:
10.1016/j.aller.2018.02.002]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 01/31/2018] [Accepted: 02/09/2018] [Indexed: 01/03/2023]
Abstract
Food allergy is a pathological immune reaction that identifies certain harmless food proteins, usually tolerated by the majority of the people, as a threat. The prevalence of these food allergies is increasing worldwide and currently affects 8% of children. Exacerbated reactions to milk, egg and peanut are the most frequent in the pediatric population. It is well known that allergic diseases are a type 2 T-helper (Th2) immune response, characterized by the elevated production of IgE antibodies. However, little is known about the immune mechanisms responsible for the development of clinical tolerance toward food allergens. Recent studies have suggested the key role of regulatory T cells (Tregs) in controlling allergic inflammation. In this review, we discuss the importance of Tregs in the pathogenesis of food allergy and the acquisition of oral tolerance in children. Further investigation in this area will be crucial for the identification of predictive markers and the development of new therapies, which will represent a clinical and social benefit for these allergic diseases.
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21
Reijmen E, Vannucci L, De Couck M, De Grève J, Gidron Y. Therapeutic potential of the vagus nerve in cancer.
Immunol Lett 2018;
202:38-43. [DOI:
10.1016/j.imlet.2018.07.006]
[Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/06/2018] [Accepted: 07/23/2018] [Indexed: 12/20/2022]
22
Lopes AMM, Michelin MA, Murta EFC. Monocyte-derived dendritic cells from patients with cervical intraepithelial lesions.
Oncol Lett 2017;
13:1456-1462. [PMID:
28454277 DOI:
10.3892/ol.2017.5595]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 11/17/2016] [Indexed: 01/23/2023] Open
Abstract
Immunotherapy with dendritic cells (DCs) is a great promise for the treatment of neoplasms. However, the obtainment and protocol of differentiation of these cells may depend on extrinsic factors such as the tumor itself. The aim of the present study was to verify the influence of cervical neoplasia on different protocols of differentiation of monocyte-derived DCs resulting in an increased maturation phenotype. A total of 83 women were included in the study. The patients were grouped in low-grade squamous intraepithelial lesion (LSIL) (n=30), high-grade squamous intraepithelial lesion (HSIL) (n=22), cervical cancer (n=10) and healthy patients (n=21) groups. The mononuclear cells of patients were subjected to three differentiation protocols. In protocol I (pI), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor (TNF)-α were used for the differentiation of mature DCs (pIDCs). In protocol II (pII), monocytes were stimulated with GM-CSF, IL-4, TNF-α and activated lymphocytes in the absence of non-adherent cells (pIIDCs). In protocol III (pIII), monocytes were stimulated with GM-CSF, IL-4, TNF-α and activated lymphocytes in the presence of non-adherent cells (pIIIDCs). These cells were evaluated by flow cytometry for the expression of maturation markers such as cluster of differentiation (CD)11c, CD86 and human leukocyte antigen-antigen D related (HLA-DR). The main cytokines secreted (IL-4, IL-12 and transforming growth factor-β) were measured by ELISA. Our results indicate a significantly lower mature profile of pIIDCs and a significant increase in CD11c+ pIIIDCs able to produce IL-12 (P=0.0007). Furthermore, a significant reduction in cervical cancer HLA-DR+ pIDCs (P=0.0113) was also observed. HSIL patients exhibited a higher percentage of HLA-DR+ pIIDCs (P=0.0113), while LSIL patients had a lower percentage of CD11c+ pIIIDCs (P=0.0411). These findings suggest that the extent of cervical lesions affects the process of differentiation of DCs. Furthermore, activated lymphocytes may induce a better maturation of monocyte-derived DCs, and the presence of mononuclear cells appears to contribute to the DC differentiation process.
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Affiliation(s)
- Angela Maria Moed Lopes
- Oncology Research Institute, Federal University of The Triângulo Mineiro, Uberaba, MG 38025-440, Brazil
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- Márcia Antoniazi Michelin
- Oncology Research Institute, Federal University of The Triângulo Mineiro, Uberaba, MG 38025-440, Brazil.,Discipline of Immunology, Clinical Hospital of Federal University of The Triângulo Mineiro, Uberaba, MG 38025-440, Brazil
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- Eddie Fernando Cândido Murta
- Oncology Research Institute, Federal University of The Triângulo Mineiro, Uberaba, MG 38025-440, Brazil.,Discipline of Gynecology and Obstetrics, Clinical Hospital of Federal University of The Triângulo Mineiro, Uberaba, MG 38025-440, Brazil
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23
Rezapour-Firouzi S. Herbal Oil Supplement With Hot-Nature Diet for Multiple Sclerosis.
NUTRITION AND LIFESTYLE IN NEUROLOGICAL AUTOIMMUNE DISEASES 2017:229-245. [DOI:
10.1016/b978-0-12-805298-3.00024-4]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
24
Epicutaneous immunotherapy induces gastrointestinal LAP
+ regulatory T cells and prevents food-induced anaphylaxis.
J Allergy Clin Immunol 2016;
139:189-201.e4. [PMID:
27417020 DOI:
10.1016/j.jaci.2016.03.057]
[Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 02/09/2016] [Accepted: 03/22/2016] [Indexed: 11/23/2022]
Abstract
BACKGROUND
The attempt to induce oral tolerance as a treatment for food allergy has been hampered by a lack of sustained clinical protection. Immunotherapy by nonoral routes, such as the skin, may be more effective for the development of maintained tolerance to food allergens.
OBJECTIVE
We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) in a model of food-induced anaphylaxis.
METHODS
C3H/HeJ mice were sensitized to ovalbumin (OVA) orally or through the skin and treated with EPIT using OVA-Viaskin patches or oral immunotherapy using OVA. Mice were orally challenged with OVA to induce anaphylaxis. Antigen-specific regulatory T (Treg)-cell induction was assessed by flow cytometry using a transgenic T-cell transfer model.
RESULTS
By using an adjuvant-free model of food allergy generated by epicutaneous sensitization and reactions triggered by oral allergen challenge, we found that EPIT induced sustained protection against anaphylaxis. We show that the gastrointestinal tract is deficient in de novo generation of Treg cells in allergic mice. This defect was tissue-specific, and epicutaneous application of antigen generated a population of gastrointestinal-homing LAP+Foxp3- Treg cells. The mechanism of protection was found to be a novel pathway of direct TGF-β-dependent Treg-cell suppression of mast cell activation, in the absence of modulation of T- or B-cell responses.
CONCLUSIONS
Our data highlight the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.
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25
Hoeppli RE, MacDonald KG, Levings MK, Cook L. How antigen specificity directs regulatory T-cell function: self, foreign and engineered specificity.
HLA 2016;
88:3-13. [PMID:
27256587 DOI:
10.1111/tan.12822]
[Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 04/29/2016] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) are a suppressive subset of T cells that have important roles in maintaining self-tolerance and preventing immunopathology. The T-cell receptor (TCR) and its antigen specificity play a dominant role in the differentiation of cells to a Treg fate, either in the thymus or in the periphery. This review focuses on the effects of the TCR and its antigen specificity on Treg biology. The role of Tregs with specificity for self-antigen has primarily been studied in the context of autoimmune disease, although recent studies have focused on their role in steady-state conditions. The role of Tregs that are specific for pathogens, dietary antigens and allergens is much less studied, although recent data suggest a significant and previously underappreciated role for Tregs during memory responses to a wide range of foreign antigens. The development of TCR- or chimeric antigen receptor (CAR)-transduced T cells means we are now able to engineer Tregs with disease-relevant antigen specificities, paving the way for ensuring specificity with Treg-based therapies. Understanding the role that antigens play in driving the generation and function of Tregs is critical for defining the pathophysiology of many immune-mediated diseases, and developing new therapeutic interventions.
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Affiliation(s)
- R E Hoeppli
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
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- K G MacDonald
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
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- M K Levings
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
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- L Cook
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
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26
Mohiuddin IH, Pillai V, Baughman EJ, Greenberg BM, Frohman EM, Crawford MP, Sinha S, Karandikar NJ. Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis.
Clin Immunol 2016;
166-167:12-8. [PMID:
27154631 DOI:
10.1016/j.clim.2016.05.001]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 04/27/2016] [Accepted: 05/02/2016] [Indexed: 12/24/2022]
Abstract
Regulatory T-cells (Tregs) are vital for maintaining immunological self-tolerance, and the transcription factor FOXP3 is considered critical for their development and function. Peripheral Treg induction may significantly contribute to the total Treg pool in healthy adults, and this pathway may be enhanced in thymic-deficient conditions like multiple sclerosis (MS). Here, we evaluated iTreg formation from memory versus naïve CD4(+)CD25(-) T-cell precursors. We report the novel finding that memory T-cells readily expressed CD25 and FOXP3, and demonstrated significantly greater suppressive function. Additionally, the CD25(-)FOXP3(-) fraction of stimulated memory T-cells also displayed robust suppression not observed in naïve counterparts or ex vivo resting (CD25(-)) T-cells. This regulatory population was present in both healthy subjects and clinically-quiescent MS patients, but was specifically deficient during disease exacerbation. These studies indicate that iTreg development and function are precursor dependent. Furthermore, MS quiescence appears to correlate with restoration of suppressive function in memory-derived CD4(+)CD25(-)FOXP3(-) iTregs.
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Affiliation(s)
- Imran H Mohiuddin
- Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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- Vinodh Pillai
- Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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- Ethan J Baughman
- Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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- Benjamin M Greenberg
- Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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- Elliot M Frohman
- Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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- Michael P Crawford
- Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA
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- Sushmita Sinha
- Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA
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- Nitin J Karandikar
- Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA.
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27
Berin MC, Shreffler WG. Mechanisms Underlying Induction of Tolerance to Foods.
Immunol Allergy Clin North Am 2016;
36:87-102. [DOI:
10.1016/j.iac.2015.08.002]
[Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
28
Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease.
World J Gastroenterol 2015;
21:11236-45. [PMID:
26523099 PMCID:
PMC4616201 DOI:
10.3748/wjg.v21.i40.11236]
[Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 06/02/2015] [Accepted: 08/28/2015] [Indexed: 02/06/2023] Open
Abstract
Since their discovery two decades ago, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) have become the subject of intense investigation by immunologists. Unlike other T cells, which promote an immune response, Tregs actively inhibit inflammation when activated by their cognate antigen, thus raising hope that these cells could be engineered into a highly targeted, antigen-specific, immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4(+)T cells, they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular, spontaneous intestinal inflammation has been shown to occur in the absence of Tregs, suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease (IBD). However, over the past decade, multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn's disease and ulcerative colitis. In this review, we will discuss the history of Tregs, what is known about them in IBD, and what progress and obstacles have been seen with efforts to employ them for therapeutic benefit.
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29
Azizi G, Rastegar Pouyani M, Navabi SS, Yazdani R, Kiaee F, Mirshafiey A. The Newly Identified T Helper 22 Cells Lodge in Leukemia.
Int J Hematol Oncol Stem Cell Res 2015;
9:143-54. [PMID:
26261700 PMCID:
PMC4529682]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 05/17/2015] [Indexed: 11/28/2022] Open
Abstract
Leukemia is a hematological tumor in which the malignant myeloid or lymphoid subsets play a pivotal role. Newly identified T helper cell 22 (Th22) is a subset of CD4(+) T cells with distinguished gene expression, function and specific properties apart from other known CD4(+) T cell subsets.Th22 cells are characterized by production of a distinct profile of effector cytokines, including interleukin (IL)-22, IL-13, and tumor necrosis factor-α (TNF-α). The levels of Th22 and cytokine IL-22 are increased and positively related to inflammatory and autoimmune disorders. Recently, several studies have reported the changes in frequency and function of Th22 in acute leukemic disorders as AML and ALL. This review discusses the role of Th22 and its cytokine IL-22 in the immunopathogenesis of leukemic disease.
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Affiliation(s)
- Gholamreza Azizi
- Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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- Mohsen Rastegar Pouyani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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- Shadi sadat Navabi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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- Reza Yazdani
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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- Fatemeh Kiaee
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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- Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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30
Abstract
Antigen-specific immunotherapy is expected to be a desirable treatment for allergic diseases. Currently, antigen-specific immunotherapy is performed by administering disease-causing antigens subcutaneously or sublingually. These approaches induce long-term remission in patients with allergic rhinitis or asthma. The oral route is an alternative to subcutaneous and sublingual routes, and can also induce long-term remission, a phenomenon known as "oral tolerance." The effectiveness of oral tolerance has been reported in the context of autoimmune diseases, food allergies, asthma, atopic dermatitis, and allergic rhinitis in both human patients and animal models. However, few studies have examined its efficacy in animal models of allergic conjunctivitis. Previously, we showed that ovalbumin feeding suppressed ovalbumin-induced experimental allergic conjunctivitis, indicating the induction of oral tolerance is effective in treating experimental allergic conjunctivitis. In recent years, transgenic rice has been developed that can induce oral tolerance and reduce the severity of anaphylaxis. The major Japanese cedar pollen antigens in transgenic rice, Cryptomeria japonica 1 and C. japonica 2, were deconstructed by molecular shuffling, fragmentation, and changes in the oligomeric structure. Thus, transgenic rice may be an effective treatment for allergic conjunctivitis.
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31
Ohtsuka Y. Food intolerance and mucosal inflammation.
Pediatr Int 2015;
57:22-9. [PMID:
25442377 DOI:
10.1111/ped.12546]
[Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/28/2014] [Accepted: 11/17/2014] [Indexed: 01/13/2023]
Abstract
Most infants are immunologically active and are able to develop a tolerance to oligoclonal antigens by producing IgA, along with activation of regulatory T cells, in early infancy. Cytokines and their signaling molecules are important mediators in the intestine, regulating both oral tolerance and mucosal inflammation. This system works efficiently in most individuals, but for an as yet undefined reason, some people react to food and other proteins as though they were pathogens, with induction of chronic inflammation in the mucosa. The adverse reaction caused by ingested foods is defined as food intolerance. The clinical features of food intolerance include vomiting, diarrhea, bloody stool, eczema, failure to thrive, and a protean range of other symptoms. Intolerance can be divided into two categories depending on whether or not they are immunologically mediated. Food intolerance and mucosal inflammation are deeply related because tolerance cannot be established when there is an inflammation in the intestinal mucosa. Mast cells, eosinophils, mucosal lymphocytes, and epithelial cells are deeply involved and related to each other in the development of mucosal inflammation. Meanwhile, rectal bleeding in infancy is related to lymphoid hyperplasia with eosinophil infiltration into the colonic mucosa facilitated by C-C motif ligand 11 (CCL11, known as eotaxin-1) and C-X-C motif chemokine ligand 13 (CXCL13). Rectal bleeding in infancy may not be simply caused by allergic reactions against specific antigens, but may be due to migrated lymphocytes developing immunological tolerance; including IgA synthesizing, in the intestinal mucosa.
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Affiliation(s)
- Yoshikazu Ohtsuka
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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32
Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, Lechner-Scott J, Macdonell RAL, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies J, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies. MS Neurology Group of the Australian and New Zealand Association of Neurologists.
J Clin Neurosci 2014;
21:1835-46. [PMID:
24993135 DOI:
10.1016/j.jocn.2014.01.016]
[Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 01/28/2014] [Indexed: 01/05/2023]
Abstract
Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.
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Affiliation(s)
- Simon A Broadley
- School of Medicine, Griffith University, Gold Coast Campus, QLD 4222, Australia; Department of Neurology, Gold Coast University Hospital, Southport, QLD, Australia.
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- Michael H Barnett
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
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- Mike Boggild
- Department of Neurology, The Townsville Hospital, Douglas, QLD, Australia
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- Bruce J Brew
- Department of Neurology and St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, University of New South Wales, Darlinghurst, NSW, Australia
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- Helmut Butzkueven
- Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
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- Robert Heard
- Westmead Clinical School, University of Sydney, NSW, Australia
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- Suzanne Hodgkinson
- South Western Sydney Clinical School, University of New South Wales, NSW, Australia
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- Allan G Kermode
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, WA, Australia; Institute of Immunology and Infectious Diseases, Murdoch University, WA, Australia
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- Mark Marriott
- Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
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- Deborah F Mason
- Department of Neurology, Christchurch Hospital, Christchurch, New Zealand
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- John Parratt
- Central Clinical School, University of Sydney, NSW, Australia
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- Stephen W Reddel
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
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- Mark Slee
- Centre for Neuroscience and Flinders Medical Centre, Flinders University, SA, Australia
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- Judith Spies
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
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- Bruce V Taylor
- Menzies Research Institute, University of Tasmania, TAS, Australia
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- William M Carroll
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, WA, Australia
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- John King
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
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- Pamela A McCombe
- University of Queensland Centre for Clinical Research, QLD, Australia
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- John D Pollard
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
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- Ernest Willoughby
- Department of Neurology, Auckland City Hospital, Auckland, New Zealand
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33
Szczepanik M. Skin-induced tolerance as a new needle free therapeutic strategy.
Pharmacol Rep 2014;
66:192-7. [PMID:
24911069 DOI:
10.1016/j.pharep.2013.09.001]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 08/26/2013] [Accepted: 09/12/2013] [Indexed: 11/29/2022]
Abstract
This article summarizes current knowledge about a new subject called "skin induced tolerance". Suppression is induced via epicutaneous (EC) immunization with a protein antigen and is described in Th1, Tc1 and NK mediated contact hypersensitivity (CHS) reactions. The subject of skin-induced suppression is also described in the regulation of experimental models of autoimmune diseases like experimental autoimmune encephalomyelitis (EAE), collagen induced arthritis (CIA) and inflammatory bowel disease (IBD) and finally in an animal model of graft rejection. The potential clinical use of this approach to regulate human diseases is also discussed.
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Affiliation(s)
- Marian Szczepanik
- Department of Medical Biology, Jagiellonian University College of Medicine, Kraków, Poland.
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34
Li MO, Flavell RA. TGF-β, T-cell tolerance and immunotherapy of autoimmune diseases and cancer.
Expert Rev Clin Immunol 2014;
2:257-65. [DOI:
10.1586/1744666x.2.2.257]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
35
Park KS, Park MJ, Cho ML, Kwok SK, Ju JH, Ko HJ, Park SH, Kim HY. Type II collagen oral tolerance; mechanism and role in collagen-induced arthritis and rheumatoid arthritis.
Mod Rheumatol 2014. [DOI:
10.3109/s10165-009-0210-0]
[Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
36
Downregulation of CD4+LAP+ and CD4+CD25+ regulatory T cells in acute coronary syndromes.
Mediators Inflamm 2013;
2013:764082. [PMID:
24385687 PMCID:
PMC3872438 DOI:
10.1155/2013/764082]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Accepted: 11/05/2013] [Indexed: 12/26/2022] Open
Abstract
Background. Regulatory T (Treg) cells play a protective role in atherosclerosis prone models and are related to the onset of acute coronary syndromes (ACS, including non-ST-elevation ACS (NSTEACS) and ST-elevation acute myocardial infarction (STEAMI)). CD4+LAP+ Treg cells are a novel subset of Tregs that have been found to ameliorate atherosclerosis in ApoE−/− mice, and these cells also exist in humans. The present study was designed to investigate whether CD4+LAP+ Treg cells are involved in the onset of ACS. Methods. The frequencies of CD4+LAP+ and CD4+CD25+ Treg cells were detected using flow cytometric analysis, and the plasma IL-10 and TGF-β1 levels were measured using an ELISA in 29 stable angina (SA) patients, 30 NSTEACS patients, 27 STEAMI patients, and a control group (30 cases).
Results. The results revealed a significant decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells and in the levels of IL-10 and TGF-β1 in patients with ACS compared with those in the SA and control groups. Conclusions. The decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells may play a role in the onset of ACS.
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37
Abstract
Food allergies are increasing in prevalence at a higher rate than can be explained by genetic factors, suggesting a role for as yet unidentified environmental factors. In this review, we summarize the state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in immunoglobulin E (IgE) sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors, such as dietary factors and microbiota, in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Finally, we discuss recent developments in our understanding of immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and the microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy.
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Affiliation(s)
- M Cecilia Berin
- Pediatric Allergy and Immunology, Box 1198, One Gustave L. Levy Place, New York, NY 10029, USA.
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38
Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients.
Complement Ther Med 2013;
21:473-80. [DOI:
10.1016/j.ctim.2013.06.006]
[Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 05/08/2013] [Accepted: 06/16/2013] [Indexed: 11/24/2022] Open
39
Wang X, Sherman A, Liao G, Leong KW, Daniell H, Terhorst C, Herzog RW. Mechanism of oral tolerance induction to therapeutic proteins.
Adv Drug Deliv Rev 2013;
65:759-73. [PMID:
23123293 PMCID:
PMC3578149 DOI:
10.1016/j.addr.2012.10.013]
[Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 10/18/2012] [Accepted: 10/24/2012] [Indexed: 12/20/2022]
Abstract
Oral tolerance is defined as the specific suppression of humoral and/or cellular immune responses to an antigen by administration of the same antigen through the oral route. Due to its absence of toxicity, easy administration, and antigen specificity, oral tolerance is a very attractive approach to prevent unwanted immune responses that cause a variety of diseases or that complicate treatment of a disease. Many researchers have induced oral tolerance to efficiently treat autoimmune and inflammatory diseases in different animal models. However, clinical trials yielded limited success. Thus, understanding the mechanisms of oral tolerance induction to therapeutic proteins is critical for paving the way for clinical development of oral tolerance protocols. This review will summarize progress on understanding the major underlying tolerance mechanisms and contributors, including antigen presenting cells, regulatory T cells, cytokines, and signaling pathways. Potential applications, examples for therapeutic proteins and disease targets, and recent developments in delivery methods are discussed.
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Affiliation(s)
- Xiaomei Wang
- Dept. Pediatrics, University of Florida, Gainesville, FL 32610
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- Gongxian Liao
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
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- Kam W. Leong
- Department of Biomedical Engineering, Duke University, Durham, NC 27708
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- Henry Daniell
- Dept. Molecular Biology and Microbiology, University of Central Florida, Orlando, FL, 32816
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- Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
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- Roland W Herzog
- Dept. Pediatrics, University of Florida, Gainesville, FL 32610
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40
Cobbold SP, Waldmann H. Regulatory cells and transplantation tolerance.
Cold Spring Harb Perspect Med 2013;
3:3/6/a015545. [PMID:
23732858 DOI:
10.1101/cshperspect.a015545]
[Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Transplantation tolerance is a continuing therapeutic goal, and it is now clear that a subpopulation of T cells with regulatory activity (Treg) that express the transcription factor foxp3 are crucial to this aspiration. Although reprogramming of the immune system to donor-specific transplantation tolerance can be readily achieved in adult mouse models, it has yet to be successfully translated in human clinical practice. This requires that we understand the fundamental mechanisms by which donor antigen-specific Treg are induced and function to maintain tolerance, so that we can target therapies to enhance rather than impede these regulatory processes. Our current understanding is that Treg act via numerous molecular mechanisms, and critical underlying components such as mTOR inhibition, are only now emerging.
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Affiliation(s)
- Stephen P Cobbold
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom.
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41
Niedbala W, Besnard AG, Jiang HR, Alves-Filho JC, Fukada SY, Nascimento D, Mitani A, Pushparaj P, Alqahtani MH, Liew FY. Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.
THE JOURNAL OF IMMUNOLOGY 2013;
191:164-70. [PMID:
23720815 DOI:
10.4049/jimmunol.1202580]
[Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of CD4(+)CD25(-) effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs inhibited the expression of retinoic acid-related orphan receptor γt but not T-bet, whereas nTregs suppressed T-bet but not retinoic acid-related orphan receptor γt expression. The NO-Treg-mediated suppression of Th17 was partially cell contact-dependent and was associated with IL-10. In vivo, adoptively transferred NO-Tregs potently attenuated experimental autoimmune encephalomyelitis. The disease suppression was accompanied by a reduction of Th17, but not Th1 cells in the draining lymph nodes, and a decrease in the production of IL-17, but an increase in IL-10 synthesis. Our results therefore demonstrate the differential suppressive function between NO-Tregs and nTregs and indicate specialization of the regulatory mechanism of the immune system.
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Affiliation(s)
- Wanda Niedbala
- Centre of Immunology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
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42
Steele L, Mayer L, Berin MC. Mucosal immunology of tolerance and allergy in the gastrointestinal tract.
Immunol Res 2013;
54:75-82. [PMID:
22447352 DOI:
10.1007/s12026-012-8308-4]
[Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The mucosal immune system typically exists in a state of active tolerance to food antigens and commensal bacteria. Tolerance to food proteins is induced in part by dendritic cells residing in the intestinal mucosa and implemented by regulatory T cells. Food allergy occurs when immune tolerance is disrupted and a sensitizing immune response characterized by food-specific IgE production occurs instead. Experimental food allergy in mice requires use of adjuvant or exploitation of alternate routes of sensitization to induce allergic sensitization, and can aid in understanding the mechanisms of sensitization to food allergens and the pathophysiology of gastrointestinal manifestations of food allergy. Recent work in the understanding of mucosal immunology of tolerance and allergy in the gastrointestinal tract will be discussed.
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Affiliation(s)
- Lauren Steele
- Mount Sinai School of Medicine, Immunology Institute, New York, NY 10029, USA
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43
Can we produce true tolerance in patients with food allergy?
J Allergy Clin Immunol 2013;
131:14-22. [PMID:
23265693 DOI:
10.1016/j.jaci.2012.10.058]
[Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 10/05/2012] [Accepted: 10/05/2012] [Indexed: 11/23/2022]
Abstract
Immune tolerance is defined as nonresponsiveness of the adaptive immune system to antigens. Immune mechanisms preventing inappropriate immune reactivity to innocuous antigens include deletion of reactive lymphocytes and generation of regulatory T (Treg) cells. The normal response to food antigens is the generation of antigen-specific Treg cells. In patients with food allergy, the dominant immune response is a T(H)2-skewed T-cell response and the generation of food-specific IgE antibodies from B cells. It is not known whether a failure of the Treg cell response is behind this inappropriate immune response, but interventions that boost the Treg cell response, such as mucosal immunotherapy, might lead to a restoration of immune tolerance to foods. Tolerance has been notoriously difficult to restore in animal disease models, but limited data from human trials suggest that tolerance (sustained nonresponsiveness) can be re-established in a subset of patients. Furthermore, studies on the natural history of food allergy indicate that spontaneous development of tolerance to foods over time is not uncommon. The current challenge is to understand the mechanisms responsible for restoration of natural or induced tolerance so that interventions can be developed to more successfully induce tolerance in the majority of patients with food allergy.
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44
Meyer T, Ullrich R, Zeitz M. Oral tolerance induction in humans.
Exp Mol Pathol 2012;
93:449-54. [DOI:
10.1016/j.yexmp.2012.10.002]
[Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Accepted: 10/01/2012] [Indexed: 01/03/2023]
45
Abstract
Onset of multiple sclerosis in childhood occurs in 3-5% of patients. There is limited, but growing knowledge about the underlying pathobiology of pediatric MS. It is crucial to better understand this area in order to address central questions in the field: 1) Can pediatric multiple sclerosis inform us about factors related to disease initiation and propagation? 2) What are the biomarkers of disease course in pediatric multiple sclerosis; 3) Does pediatric multiple sclerosis pathogenesis differ from adult-onset multiple sclerosis; 4) How can we optimize treatment in pediatric demyelinating diseases? 5) Can pediatric multiple sclerosis provide insights into the environmental risk factors for multiple sclerosis in general? Here we review the current knowledge of the pathogenesis of multiple sclerosis in children, and address the five questions raised above.
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Affiliation(s)
- David Vargas-Lowy
- Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02114, USA
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46
Forster K, Goethel A, Chan CWT, Zanello G, Streutker C, Croitoru K. An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice.
Gastroenterology 2012;
143:1298-1307. [PMID:
22819863 DOI:
10.1053/j.gastro.2012.07.019]
[Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Revised: 06/11/2012] [Accepted: 07/13/2012] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS
New therapeutic approaches are needed for inflammatory bowel diseases. A monoclonal antibody against CD3 (anti-CD3) suppresses T-cell-mediated autoimmune diseases such as experimental allergic encephalomyelitis. We explored the effects of anti-CD3 in mice with colitis.
METHODS
Severe combined immunodeficient mice were given injections of CD4(+)CD45RB(high) T cells to induce colitis. Four weeks later, the mice were given 2 or 5 μg/day of anti-CD3 or hamster immunoglobulin (Ig)G (control), via gavage, for 5 or 10 days. The effect of oral anti-CD3 on cytokine responses was studied by activating T cells using intraperitoneal injections of anti-CD3 monoclonal antibody 2 days after oral administration of the antibody. We collected intestine samples for histology analysis and cells were analyzed by flow cytometry. Cytokines in sera were analyzed by cytometric bead array.
RESULTS
Oral administration of anti-CD3 protected the mice from wasting disease and intestinal inflammation. Analyses of spleen and mesenteric lymph node cells showed no differences in total cell counts, or percentages of CD4(+) and forkhead box P3(+) regulatory T cells, between mice given anti-CD3 or the control immunoglobulin. Colitis therefore was not suppressed by induction of forkhead box P3(+) regulatory T cells, or depletion or limited expansion of T cells. Oral administration of anti-CD3 ameliorated the enteropathy induced by intraperitoneal injection of the antibody. In mice with enteropathy, oral anti-CD3 reduced levels of inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin (IL)-6; it also increased levels of the anti-inflammatory cytokines IL-10 and transforming growth factor-β. The effects of oral anti-CD3 required IL-10.
CONCLUSIONS
Oral administration of anti-CD3 to mice induces changes in the mucosal immune response that prevent colitis, independent of specific antigen, and reduce T-cell activation in an IL-10-dependent manner. Oral anti-CD3 therefore might be developed for the treatment of patients with inflammatory bowel disease.
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Affiliation(s)
- Katharina Forster
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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- Ashleigh Goethel
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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- Catherine Wing-Tak Chan
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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- Galliano Zanello
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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- Catherine Streutker
- Surgical Pathology, Department of Pathology and Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
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- Kenneth Croitoru
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Zane Cohen Center for Digestive Research, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada.
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47
Rezapour-Firouzi S, Arefhosseini SR, Farhoudi M, Ebrahimi-Mamaghani M, Rashidi MR, Torbati MA, Baradaran B. Association of Expanded Disability Status Scale and Cytokines after Intervention with Co-supplemented Hemp Seed, Evening Primrose Oils and Hot-natured Diet in Multiple Sclerosis Patients(♦).
BIOIMPACTS : BI 2012;
3:43-7. [PMID:
23678469 DOI:
10.5681/bi.2013.001]
[Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 08/23/2012] [Accepted: 09/05/2012] [Indexed: 12/31/2022]
Abstract
INTRODUCTION
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Because of limited efficacy and adverse side effects, identifying novel therapeutic and protective agents is important. The aim of this study is to examine the correlations between expanded disability status scale (EDSS) and cytokines after intervention with co-supplemented hemp seed and evening primrose oils and hot-natured diet in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS
We studied a group of 23 patients with clinically definite RRMS, with EDSS<6 who received co-supplemented hemp seed and evening primrose oils with advising hot-natured diet. Clinically EDSS and immunological factors (plasma cytokines of IL-4, IFN-γ and IL-17) were assessed at baseline and after 6 months.
RESULTS
Mean follow-up was 180±2.9 days (N=23, 7 Male and 16 Females aged 25.0±7.5 years with disease duration 6.26±3.9 years). After 6 months, significant improvements in extended disability status score were found in the patients in agreement with decrease cytokines of IFN-γ and IL-17 and increase cytokines of IL-4. Clinical and immunological parameters showed improvement in the patients after the intervention.
CONCLUSION
Our study shows that co-supplemented hemp seed and evening primrose oils with hot-natured diet can have beneficial effects in improving clinical symptoms in relapsing remitting MS patients and significant correlation was found between EDSS and immunological findings.
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Affiliation(s)
- Soheila Rezapour-Firouzi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ; School of Nutrition and Health, Tabriz University of Medical Sciences, Tabriz, Iran
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48
The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis.
ARTHRITIS 2012;
2012:805875. [PMID:
23133752 PMCID:
PMC3486158 DOI:
10.1155/2012/805875]
[Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Revised: 09/11/2012] [Accepted: 09/20/2012] [Indexed: 02/07/2023]
Abstract
Rheumatoid arthritis (RA) is a common autoimmune disease and a systemic inflammatory disease which is characterized by chronic joint inflammation and variable degrees of bone and cartilage erosion and hyperplasia of synovial tissues. Considering the role of autoreactive T cells (particularly Th1 and Th17 cells) in pathophysiology of RA, it might be assumed that the regulatory T cells (Tregs) will be able to control the initiation and progression of disease. The frequency, function, and properties of various subsets of Tregs including natural Tregs (nTregs), IL-10-producing type 1 Tregs (Tr1 cells), TGF-β-producing Th3 cells, CD8+ Tregs, and NKT regulatory cells have been investigated in various studies associated with RA and collagen-induced arthritis (CIA) as experimental model of this disease. In this paper, we intend to submit the comprehensive information about the immunobiology of various subsets of Tregs and their roles and function in immunopathophysiology of RA and its animal model, CIA.
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Abstract
During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naïve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons β and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56(bright) natural killer cells.
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Affiliation(s)
- R E Gonsette
- Fondation-Charcot-Stichting, Avenue Huart Hamoir 48, 1030 Brussels, Belgium.
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50
Abstract
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.
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Affiliation(s)
- Karolina Palucka
- Baylor Institute for Immunology Research, 3434 Live Oak Avenue, Dallas, Texas 75204, USA.
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