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1
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Weiner HL. Immune mechanisms and shared immune targets in neurodegenerative diseases. Nat Rev Neurol 2025; 21:67-85. [PMID: 39681722 DOI: 10.1038/s41582-024-01046-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2024] [Indexed: 12/18/2024]
Abstract
The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.
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Affiliation(s)
- Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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2
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Dwyer AJ, Shaheen ZR, Fife BT. Antigen-specific T cell responses in autoimmune diabetes. Front Immunol 2024; 15:1440045. [PMID: 39211046 PMCID: PMC11358097 DOI: 10.3389/fimmu.2024.1440045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting β-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.
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Affiliation(s)
- Alexander J. Dwyer
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Zachary R. Shaheen
- Center for Immunology, Department of Pediatrics, Pediatric Rheumatology, Allergy, & Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Brian T. Fife
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
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3
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Tian K, Jing D, Lan J, Lv M, Wang T. Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor. Immun Inflamm Dis 2024; 12:e1316. [PMID: 39023417 PMCID: PMC11256888 DOI: 10.1002/iid3.1316] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND The gastrointestinal tract contains a wide range of microorganisms that have evolved alongside the immune system of the host. The intestinal mucosa maintains balance within the intestines by utilizing the mucosal immune system, which is controlled by the complex gut mucosal immune network. OBJECTIVE This review aims to comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with commensal bacteria. RESULTS The gut mucosal immune network includes gut-associated lymphoid tissue, mucosal immune cells, cytokines, and chemokines. The connection between microbiota and the immune system occurs through the engagement of bacterial components with pattern recognition receptors found in the intestinal epithelium and antigen-presenting cells. This interaction leads to the activation of both innate and adaptive immune responses. The interaction between the microbial community and the host is vital for maintaining the balance and health of the host's mucosal system. CONCLUSION The gut mucosal immune network maintains a delicate equilibrium between active immunity, which defends against infections and damaging non-self antigens, and immunological tolerance, which allows for the presence of commensal microbiota and dietary antigens. This balance is crucial for the maintenance of intestinal health and homeostasis. Disturbance of gut homeostasis leads to enduring or severe gastrointestinal ailments, such as colorectal cancer and inflammatory bowel disease. Utilizing these factors can aid in the development of cutting-edge mucosal vaccines that have the ability to elicit strong protective immune responses at the primary sites of pathogen invasion.
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Affiliation(s)
- Kexin Tian
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Dehong Jing
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Junzhe Lan
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Mingming Lv
- Department of BreastWomen's Hospital of Nanjing Medical University, Nanjing Maternity, and Child Health Care HospitalNanjingChina
| | - Tingting Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
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4
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Muñoz-Melero M, Biswas M. Role of FoxP3 + Regulatory T Cells in Modulating Immune Responses to Adeno-Associated Virus Gene Therapy. Hum Gene Ther 2024; 35:439-450. [PMID: 38450566 PMCID: PMC11302314 DOI: 10.1089/hum.2023.227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/04/2024] [Indexed: 03/08/2024] Open
Abstract
Adeno-associated virus (AAV) gene therapy is making rapid strides owing to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to the viral vector or transgene, although there is no consensus on the best treatment regimen, dosage, or schedule. Regulatory T cells (Tregs) are crucial for maintaining tolerance against self or nonself antigens. Of importance, Tregs also play an important role in dampening immune responses to AAV gene therapy, including tolerance induction to the transgene product. Approaches to harness the tolerogenic effect of Tregs include the use of selective IS drugs that expand existing Tregs, and skew activated conventional T cells into antigen-specific peripherally induced Tregs. In addition, Tregs can be expanded ex vivo and delivered as cellular therapy. Furthermore, receptor engineering can be used to increase the potency and specificity of Tregs allowing for suppression at lower doses and reducing the risk of disrupting protective immunity. Because immune-mediated toxicities to AAV vectors are a concern in the clinic, strategies that can enhance or preserve Treg function should be considered to improve both the safety and efficacy of AAV gene therapy.
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Affiliation(s)
- Maite Muñoz-Melero
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
| | - Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA
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5
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Kustrimovic N, Gallo D, Piantanida E, Bartalena L, Lai A, Zerbinati N, Tanda ML, Mortara L. Regulatory T Cells in the Pathogenesis of Graves' Disease. Int J Mol Sci 2023; 24:16432. [PMID: 38003622 PMCID: PMC10671795 DOI: 10.3390/ijms242216432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/12/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Maintaining a delicate balance between the prompt immune response to pathogens and tolerance towards self-antigens and commensals is crucial for health. T regulatory (Treg) cells are pivotal in preserving self-tolerance, serving as negative regulators of inflammation through the secretion of anti-inflammatory cytokines, interleukin-2 neutralization, and direct suppression of effector T cells. Graves' disease (GD) is a thyroid-specific autoimmune disorder primarily attributed to the breakdown of tolerance to the thyroid-stimulating hormone receptor. Given the limitations of currently available GD treatments, identifying potential pathogenetic factors for pharmacological targeting is of paramount importance. Both functional impairment and frequency reduction of Tregs seem likely in GD pathogenesis. Genome-wide association studies in GD have identified polymorphisms of genes involved in Tregs' functions, such as CD25 (interleukin 2 receptor), and Forkhead box protein P3 (FOXP3). Clinical studies have reported both functional impairment and a reduction in Treg frequency or suppressive actions in GD, although their precise involvement remains a subject of debate. This review begins with an overview of Treg phenotype and functions, subsequently delves into the pathophysiology of GD and into the existing literature concerning the role of Tregs and the balance between Tregs and T helper 17 cells in GD, and finally explores the ongoing studies on target therapies for GD.
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Affiliation(s)
- Natasa Kustrimovic
- Center for Translational Research on Autoimmune and Allergic Disease—CAAD, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Daniela Gallo
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy (M.L.T.)
| | - Eliana Piantanida
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy (M.L.T.)
| | - Luigi Bartalena
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy (M.L.T.)
| | - Adriana Lai
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy (M.L.T.)
| | - Nicola Zerbinati
- Dermatology Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy
| | - Maria Laura Tanda
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy (M.L.T.)
| | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
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6
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Shakya AK, Mallick B, Nandakumar KS. A Perspective on Oral Immunotherapeutic Tools and Strategies for Autoimmune Disorders. Vaccines (Basel) 2023; 11:1031. [PMID: 37376420 DOI: 10.3390/vaccines11061031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/19/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Oral immune tolerance is a physiological process to achieve tolerance against autoimmunity by oral ingestion of self-antigen(s) or other therapeutics. At the cellular level, oral tolerance suppresses autoimmune diseases by activating FoxP-positive and -negative regulatory T cells (Tregs) and/or causing clonal anergy or deletion of autoreactive T cells, affecting B cell tolerance. However, oral delivery of antigens/biologics is challenging due to their instability in the harsh environment of the gastrointestinal (GI) tract. Several antigen/drug delivery tools and approaches, including micro/nanoparticles and transgenic plant-based delivery systems, have been explored to demonstrate oral immune tolerance for different autoimmune diseases successfully. However, despite the effectiveness, variation in results, dose optimization, and undesirable immune system activation are the limitations of the oral approach to further advancement. From this perspective, the current review discusses the oral tolerance phenomenon, cellular mechanisms, antigen delivery tools and strategies, and its challenges.
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Affiliation(s)
| | - Buddhadev Mallick
- Department of Zoology, Raniganj Girls College, Bardhaman 713358, West Bengal, India
| | - Kutty Selva Nandakumar
- Department of Environmental and Biosciences, School of Business, Innovation, and Sustainability, Halmstad University, 301 18 Halmstad, Sweden
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Ghobadinezhad F, Ebrahimi N, Mozaffari F, Moradi N, Beiranvand S, Pournazari M, Rezaei-Tazangi F, Khorram R, Afshinpour M, Robino RA, Aref AR, Ferreira LMR. The emerging role of regulatory cell-based therapy in autoimmune disease. Front Immunol 2022; 13:1075813. [PMID: 36591309 PMCID: PMC9795194 DOI: 10.3389/fimmu.2022.1075813] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Autoimmune disease, caused by unwanted immune responses to self-antigens, affects millions of people each year and poses a great social and economic burden to individuals and communities. In the course of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and multiple sclerosis, disturbances in the balance between the immune response against harmful agents and tolerance towards self-antigens lead to an immune response against self-tissues. In recent years, various regulatory immune cells have been identified. Disruptions in the quality, quantity, and function of these cells have been implicated in autoimmune disease development. Therefore, targeting or engineering these cells is a promising therapeutic for different autoimmune diseases. Regulatory T cells, regulatory B cells, regulatory dendritic cells, myeloid suppressor cells, and some subsets of innate lymphoid cells are arising as important players among this class of cells. Here, we review the roles of each suppressive cell type in the immune system during homeostasis and in the development of autoimmunity. Moreover, we discuss the current and future therapeutic potential of each one of these cell types for autoimmune diseases.
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Affiliation(s)
- Farbod Ghobadinezhad
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran,Universal Scientific Education and Research Network (USERN) Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nasim Ebrahimi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Fatemeh Mozaffari
- Department of Nutrition, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Neda Moradi
- Division of Biotechnology, Department of Cell and Molecular Biology and Microbiology, Nourdanesh Institute of Higher Education, University of Meymeh, Isfahan, Iran
| | - Sheida Beiranvand
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Shahrekord, Iran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maral Afshinpour
- Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, United States
| | - Rob A. Robino
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States,Xsphera Biosciences, Boston, MA, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
| | - Leonardo M. R. Ferreira
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
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8
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Wesley JD, Pagni PP, Bergholdt R, Kreiner FF, von Herrath M. Induction of antigenic immune tolerance to delay type 1 diabetes - challenges for clinical translation. Curr Opin Endocrinol Diabetes Obes 2022; 29:379-385. [PMID: 35776831 DOI: 10.1097/med.0000000000000742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Dissect the field of antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D), highlighting the major barriers currently blocking clinical translation. RECENT FINDINGS ASIT remains a promising approach in T1D to re-establish the proper balance in the immune system to avoid the autoimmune-mediated attack or destruction of beta-cells in the pancreas. Despite some encouraging preclinical results, ASIT has not yet successfully translated into clinical utility, predominantly due to the lack of validated and clinically useful biomarkers. SUMMARY To restore immune tolerance towards self-antigens, ASIT aims to establish a favourable balance between T effector cells and T regulatory cells. Whilst most ASITs, including systemic or oral administration of relevant antigens, have appeared safe in T1D, meaningful and durable preservation of functional beta-cell mass has not been proven clinically. Development, including clinical translation, remains negatively impacted by lack of predictive biomarkers with confirmed correlation between assay readout and clinical outcomes. To be able to address the high unmet medical need in T1D, we propose continued reinforced research to identify such biomarkers, as well efforts to ensure alignment in terms of trial design and conduct.
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Affiliation(s)
- Johnna D Wesley
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | - Philippe P Pagni
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | - Regine Bergholdt
- Type 1 Diabetes & Functional Insulins, Clinical Drug Development
| | | | - Matthias von Herrath
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
- Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, California, USA
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9
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Harkins AL, Kopec AL, Keeler AM. Regulatory T Cell Therapeutics for Neuroinflammatory Disorders. Crit Rev Immunol 2022; 42:1-27. [PMID: 37017285 PMCID: PMC11465901 DOI: 10.1615/critrevimmunol.2022045080] [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] [Indexed: 11/13/2022]
Abstract
A delicate balance of immune regulation exists in the central nervous system (CNS) that is often dysreg-ulated in neurological diseases, making them complicated to treat. With altered immune surveillance in the diseased or injured CNS, signals that are beneficial in the homeostatic CNS can be disrupted and lead to neuroinflammation. Recent advances in niche immune cell subsets have provided insight into the complicated cross-talk between the nervous system and the immune system. Regulatory T cells (Tregs) are a subset of T cells that are capable of suppressing effector T-cell activation and regulating immune tolerance, and play an important role in neuroprotection. Tregs have been shown to be effective therapies in a variety of immune-related disorders including, graft-versus-host disease (GVHD), type 1 diabetes (T1D), and inflammatory bowel disease (IBD), as well as within the CNS. Recently, significant advancements in engineering T cells, such as chimeric antigen receptor (CAR) T cells, have led to several approved therapies suggesting the safety and efficacy for similar engineered Treg therapies. Further, as understanding of the immune system's role in neuroinflammation has progressed, Tregs have recently become a potential therapeutic in the neurology space. In this review, we discuss Tregs and their evolving role as therapies for neuroinflammatory related disorders.
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Affiliation(s)
- Ashley L. Harkins
- Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences
- Horae Gene Therapy Center
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA
| | | | - Allison M. Keeler
- Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences
- Horae Gene Therapy Center
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA
- Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
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10
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Franco-Valencia K, Nóbrega I, Cantaruti T, Barra A, Klein A, Azevedo-Jr G, Costa R, Carvalho C. Subcutaneous injection of an immunologically tolerated protein up to 5 days before skin injuries improves wound healing. Braz J Med Biol Res 2022; 55:e11735. [PMID: 35170683 PMCID: PMC8851940 DOI: 10.1590/1414-431x2021e11735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/19/2021] [Indexed: 11/22/2022] Open
Abstract
Oral tolerance blocks the development of specific immune responses to proteins ingested by the oral route. One of the first registries of oral tolerance showed that guinea pigs fed corn became refractory to hypersensitivity to corn proteins. Mice fed with chow containing corn are tolerant to zein, and parenteral injection of zein plus adjuvant blocks immunization to unrelated proteins injected concomitantly and reduces unspecific inflammation. Extensive and prolonged inflammatory infiltrate in the wound bed is one of the causes of pathological wound healing. Previous research shows that intraperitoneal injection of zein concomitant with skin injuries reduces the inflammatory infiltrate in the wound bed and improves wound healing. Herein, we tested if one subcutaneous injection of zein before skin injury improves wound healing. We also investigated how long the effects triggered by zein could improve skin wound healing. Mice fed zein received two excisional wounds on the interscapular skin under anesthesia. Zein plus Al(OH)3 was injected at the tail base at 10 min, or 3, 5, or 7 days before skin injuries. Wound healing was analyzed at days 7 and 40 after injury. Our results showed that a zein injection up to 5 days before skin injury reduced the inflammatory infiltrate, increased the number of T-cells in the wound bed, and improved the pattern of collagen deposition in the neodermis. These findings could promote the development of new strategies for the treatment and prevention of pathological healing using proteins normally found in the common diet.
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Affiliation(s)
| | | | | | - A. Barra
- Universidade Federal de Minas Gerais, Brasil
| | - A. Klein
- Universidade Federal de Minas Gerais, Brasil
| | | | - R.A. Costa
- Universidade Federal de São João del Rei, Brasil
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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
| | - Lícia Torres
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mariana de Almeida Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Marcos Felipe Andrade-Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro Andrade de Freitas Guimarães
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Monique Macedo Coelho
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Juliana de Lima Alves
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Tatiani Uceli Maioli
- Departamento de Nutrição, Escola de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - 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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12
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Serr I, Drost F, Schubert B, Daniel C. Antigen-Specific Treg Therapy in Type 1 Diabetes - Challenges and Opportunities. Front Immunol 2021; 12:712870. [PMID: 34367177 PMCID: PMC8341764 DOI: 10.3389/fimmu.2021.712870] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/06/2021] [Indexed: 01/16/2023] Open
Abstract
Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.
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Affiliation(s)
- Isabelle Serr
- Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Institute of Diabetes Research, Munich, Germany
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
| | - Felix Drost
- School of Life Sciences Weihenstephan, Technische Universität München, Garching bei München, Germany
| | - Benjamin Schubert
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Mathematics, Technische Universität München, Garching bei München, Germany
| | - Carolin Daniel
- Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Institute of Diabetes Research, Munich, Germany
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
- Division of Clinical Pharmacology, Department of Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany
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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
| | - 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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14
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Yu J, Liu Z, Li C, Wei Q, Zheng S, Saeb-Parsy K, Xu X. Regulatory T Cell Therapy Following Liver Transplantation. Liver Transpl 2021; 27:264-280. [PMID: 37160016 DOI: 10.1002/lt.25948] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/25/2020] [Accepted: 10/31/2020] [Indexed: 12/17/2022]
Abstract
Liver transplantation (LT) is considered the gold standard of curative treatment for patients with end-stage liver disease or nonresectable hepatic malignant tumors. Rejection after LT is the main nontechnical factor affecting the prognosis of recipients. Medical and surgical advances, combined with improved immunosuppression with drugs such as calcineurin inhibitors (CNIs), have contributed to an increase in 1-year graft survival to around 80%. However, medium- and long-term improvements in LT outcomes have lagged behind. Importantly, CNIs and other classical immunosuppressive drugs are associated with significant adverse effects, including malignancies, cardiovascular disease, and severe renal dysfunction. Immunomodulation using regulatory T cells (Tregs) is emerging as a promising alternative to classical immunosuppression. Since their discovery, the immunomodulatory effects of Tregs have been demonstrated in a range of diseases. This has rejuvenated the interest in using Tregs as a therapeutic strategy to induce immune tolerance after LT. In this review, we first summarize the discovery and development of Tregs. We then review the preclinical data supporting their production, mechanism of action, and therapeutic efficacy followed by a summary of relevant clinical trials. Finally, we discuss the outstanding challenges of Treg therapy and its future prospects for routine use in LT.
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Affiliation(s)
- Jiongjie Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Changbiao Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, Cambridge, UK.,Cambridge National Institute of Health Research Biomedical Research Centre, Cambridge, UK
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
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15
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Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, Akilli-Öztürk Ö, Kranz LM, Berger H, Petschenka J, Diken M, Kreiter S, Yogev N, Waisman A, Karikó K, Türeci Ö, Sahin U. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 2021; 371:145-153. [PMID: 33414215 DOI: 10.1126/science.aay3638] [Citation(s) in RCA: 285] [Impact Index Per Article: 71.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 04/27/2020] [Accepted: 11/17/2020] [Indexed: 12/14/2022]
Abstract
The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.
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Affiliation(s)
- Christina Krienke
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
- Research Center for Immunotherapy (FZI), University Medical Center at the Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany
| | - Laura Kolb
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Elif Diken
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Michael Streuber
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Sarah Kirchhoff
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Thomas Bukur
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Özlem Akilli-Öztürk
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
| | - Lena M Kranz
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
| | - Hendrik Berger
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
| | - Jutta Petschenka
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany
| | - Mustafa Diken
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
| | - Sebastian Kreiter
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
| | - Nir Yogev
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
- Clinic and Polyclinic for Dermatology and Venereology, University Hospital Cologne, Kerpenerstr. 62, Cologne 50937, Germany
| | - Ari Waisman
- Research Center for Immunotherapy (FZI), University Medical Center at the Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Katalin Karikó
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
| | - Özlem Türeci
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
- CI3 - Cluster for Individualized Immunointervention e.V., Hölderlinstraße 8, 55131 Mainz, Germany
| | - Ugur Sahin
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany.
- Research Center for Immunotherapy (FZI), University Medical Center at the Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany
- Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, Mainz 55131, Germany
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16
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Eggenhuizen PJ, Ng BH, Ooi JD. Treg Enhancing Therapies to Treat Autoimmune Diseases. Int J Mol Sci 2020; 21:E7015. [PMID: 32977677 PMCID: PMC7582931 DOI: 10.3390/ijms21197015] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/16/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022] Open
Abstract
Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.
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Affiliation(s)
| | | | - Joshua D. Ooi
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia; (P.J.E.); (B.H.N.)
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17
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Qin X, Akter F, Qin L, Cheng J, Guo M, Yao S, Jian Z, Liu R, Wu S. Adaptive Immunity Regulation and Cerebral Ischemia. Front Immunol 2020; 11:689. [PMID: 32477327 PMCID: PMC7235404 DOI: 10.3389/fimmu.2020.00689] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 03/26/2020] [Indexed: 12/22/2022] Open
Abstract
Stroke is a disease that occurs due to a sudden interruption of the blood supply to the brain. It is a leading cause of death and disability worldwide. It is well-known that the immune system drives brain injury following an episode of ischemic stroke. The innate system and the adaptive system play distinct but synergistic roles following ischemia. The innate system can be activated by damage-associated molecular patterns (DAMPs), which are released from cells in the ischemic region. Damaged cells also release various other mediators that serve to increase inflammation and compromise the integrity of the blood–brain barrier (BBB). Within 24 h of an ischemic insult, the adaptive immune system is activated. This involves T cell and B cell-mediated inflammatory and humoral effects. These cells also stimulate the release of various interleukins and cytokines, which can modulate the inflammatory response. The adaptive immune system has been shown to contribute to a state of immunodepression following an ischemic episode, and this can increase the risk of infections. However, this phenomenon is equally important in preventing autoimmunity of the body to brain antigens that are released into the peripheral system as a result of BBB compromise. In this review, we highlight the key components of the adaptive immune system that are activated following cerebral ischemia.
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Affiliation(s)
- Xingping Qin
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States
| | - Farhana Akter
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States.,Faculty of Arts and Sciences, Harvard University, Cambridge, MA, United States
| | - Lingxia Qin
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing Cheng
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mei Guo
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States
| | - Shun Yao
- Department of Neurosurgery, Center for Pituitary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Neurosurgery, Center for Skull Base and Pituitary Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Renzhong Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Songlin Wu
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China
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18
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Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov 2019; 18:749-769. [PMID: 31541224 PMCID: PMC7773144 DOI: 10.1038/s41573-019-0041-4] [Citation(s) in RCA: 333] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2019] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Treg cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As Treg cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of Treg cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR-Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of Treg cells. In this Review, we describe the key advances and prospects in designing and implementing Treg cell-based therapy in autoimmunity and transplantation.
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Affiliation(s)
- Leonardo M R Ferreira
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, USA
| | - Yannick D Muller
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, USA.
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
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19
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Atayde SR, Velosa APP, Catanozi S, Del Bianco V, Andrade PC, Rodrigues JEDCM, dos Santos Filho A, Antonangelo L, de Mello SBV, Capelozzi VL, Teodoro WR. Collagen V oral administration decreases inflammation and remodeling of synovial membrane in experimental arthritis. PLoS One 2018; 13:e0201106. [PMID: 30059520 PMCID: PMC6066207 DOI: 10.1371/journal.pone.0201106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 06/10/2018] [Indexed: 12/18/2022] Open
Abstract
Because collagen type V (Col V) can be exposed in tissue injury, we hypothesized that oral administration of this collagen species modulates the inflammation and remodeling of experimental synovitis, avoiding joint destruction, and that the modulation may differ according to the temporal administration. Arthritis (IA, n = 20) was induced in Lewis rats by intraarticular (ia) injection of 500 μg of methylated bovine serum albumin (mBSA) emulsified in complete Freund’s adjuvant (CFA) (10 μl) followed by an intraarticular booster of mBSA (50 μg) in saline (50 μl) administered at 7 and 14 days. The control group received saline (50 μl, ia). After the first intraarticular injection, ten IA animals were supplemented via gavage with Col V (500 μg/300 μl) daily for 30 days (IA/Suppl). The control group received saline (50 μL) and Col V supplement in the same way (Suppl). Col V oral administration in IA/Suppl led to 1) inhibited edema and severe inflammatory cell infiltration, 2) decreased collagen fiber content, 3) decreased collagen type I, 4) inhibited lymphocyte subpopulations and macrophages, 5) inhibited IL-1β, IL-10, IL-17 and TNF-α production and 6) increased expression of caspase-9 in the synovial tissue. In conclusion, Col V supplementation decreased synovial inflammation and the fibrotic response, possibly by increased the apoptosis of inflammatory cells.
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Affiliation(s)
- Silvana Ramos Atayde
- Department of Pathology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- * E-mail:
| | - Ana Paula Pereira Velosa
- Rheumatology Division, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | - Sergio Catanozi
- Endocrinology Division (LIM 10), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | - Vanessa Del Bianco
- Endocrinology Division (LIM 10), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | - Priscila Cristina Andrade
- Department of Pathology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | | | - Antonio dos Santos Filho
- Rheumatology Division, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | - Leila Antonangelo
- Department of Pathology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | | | - Vera Luiza Capelozzi
- Department of Pathology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
| | - Walcy Rosolia Teodoro
- Rheumatology Division, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
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20
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Paiatto LN, Silva FGD, Yamada ÁT, Tamashiro WMSC, Simioni PU. Adoptive transfer of dendritic cells expressing CD11c reduces the immunological response associated with experimental colitis in BALB/c mice. PLoS One 2018; 13:e0196994. [PMID: 29738575 PMCID: PMC5940207 DOI: 10.1371/journal.pone.0196994] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 04/24/2018] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION In addition to conventional therapies, several new strategies have been proposed for modulating autoimmune diseases, including the adoptive transfer of immunological cells. In this context, dendritic cells (DCs) appear to be one of the most promising treatments for autoimmune disorders. The present study aimed to evaluate the effects of adoptive transfer of DCs obtained from both naïve and ovalbumin (OVA)-tolerant mice on the severity of TNBS induced colitis and analyze the eventual protective mechanisms. METHODS AND RESULTS To induce oral tolerance, BALB/c mice were fed 4mg/mL OVA solution for seven consecutive days. Spleen DCs were isolated from tolerant (tDC) and naïve (nDC) mice, and then adoptively transferred to syngeneic mice. Three days later, colitis was induced in DC treated mice by intrarectal instillation of 100μg2,4,6-trinitrobenzenesulfonic acid (TNBS) dissolved in 50% ethanol. Control subjects received only intrarectal instillation of either TNBS solution or a vehicle. Five days later, mice from all groups were euthanized and examined for physiological and immunological parameters. Regarding the phenotype, we observed that the frequencies of CD11+ MHC II+ and CD11+ MHCII+ CD86+ cells were significantly lower in DCs isolated from tolerant mice than in those from naive mice. However, pretreatment with both types of DCs was able to significantly reduce clinical signs of colitis such as diarrhea, rectal prolapse, bleeding, and cachexia, although only treatment with tDCs was able to prevent weight loss from instillation of TNBS. In vitro proliferation of spleen cells from mice treated with either type of DCs was significantly lower than that observed in splenic cell cultures of naïve mice. Although no significant difference was observed in the frequencies of Treg cells in the experimental groups, the frequency of Th17+CD4+cellsand the secretion of IL-17 were more reduced in the cultures of spleen cells from mice treated with either type of DCs. The levels of IL-9 and IFN-γ were lower in supernatants of cells from mice treated with nDCs. CONCLUSION The results allow us to conclude that the adoptive transfer of cells expressing CD11c is able to reduce the clinical and immunological signs of drug-induced colitis. Adoptive transfer of CD11c+DC isolated from both naive and tolerant mice altered the proliferative and T cell responses. To the best of our knowledge, there is no previously published data showing the protective effects of DCs from naïve or tolerant mice in the treatment of colitis.
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Affiliation(s)
- Lisiery N. Paiatto
- Institute of Biosciences, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Fernanda G. D. Silva
- Faculty of Food Engineering, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
- Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Áureo T. Yamada
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Wirla M. S. C. Tamashiro
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
| | - Patricia U. Simioni
- Institute of Biosciences, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil
- Department of Biomedical Science, Faculty of Americana, FAM, Americana, São Paulo, Brazil
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21
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Janahi EMA, Das S, Bhattacharya SN, Haque S, Akhter N, Jawed A, Wahid M, Mandal RK, Lohani M, Areeshi MY, Ramachandran VG, Almalki S, Dar SA. Cytomegalovirus aggravates the autoimmune phenomenon in systemic autoimmune diseases. Microb Pathog 2018; 120:132-139. [PMID: 29704668 DOI: 10.1016/j.micpath.2018.04.041] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 04/17/2018] [Accepted: 04/23/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Human Cytomegalovirus (CMV), because of its ability to extensively manipulate host immunity during active infection, has been suggested to be involved in autoimmunity. However, its influence on T-cells and cytokines in systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is indistinct. METHODS We investigated the in-vitro response of T lymphocytes from SLE and SSc patients to CMV antigen. Functional activity of T lymphocytes was determined by estimating Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines. RESULTS We observed that CMV antigen stimulation in-vitro resulted in significant increase in CD4:CD8 T-cell ratio in peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients; response dominated by CD4+ than CD8+ memory T-cells. SSc T-cell response was differentiated by aberrant increase in CD4+CD25+ T-cells. CMV antigen caused elevation in IL-4 and IFN-γ production in both patient PBMCs, whereas IL-2 was also raised in SLE PBMCs. The development of large pool of memory T-cells and overproduction of IFN-γ may result in flare-up of autoimmunity in these patients. CONCLUSION Our study provides an insight into the immunopathological potential of CMV-reactive immune cells to develop new potential strategies for targeted therapeutic intervention.
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Affiliation(s)
| | - Shukla Das
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & Guru Teg Bahadur Hospital, Delhi, India.
| | - Sambit Nath Bhattacharya
- Department of Dermatology, University College of Medical Sciences (University of Delhi) & Guru Teg Bahadur Hospital, Delhi, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Naseem Akhter
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Arshad Jawed
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Mohd Wahid
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Raju Kumar Mandal
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Mohtashim Lohani
- Department of EMS, College of Applied Medical Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Mohammed Yahya Areeshi
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia
| | - Vishnampettai G Ramachandran
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & Guru Teg Bahadur Hospital, Delhi, India
| | - Shaia Almalki
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Sajad Ahmad Dar
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & Guru Teg Bahadur Hospital, Delhi, India; Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, University of Jazan, Jazan, Saudi Arabia.
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Cook DP, Gysemans C, Mathieu C. Lactococcus lactis As a Versatile Vehicle for Tolerogenic Immunotherapy. Front Immunol 2018; 8:1961. [PMID: 29387056 PMCID: PMC5776164 DOI: 10.3389/fimmu.2017.01961] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022] Open
Abstract
Genetically modified Lactococcus lactis bacteria have been engineered as a tool to deliver bioactive proteins to mucosal tissues as a means to exert both local and systemic effects. They have an excellent safety profile, the result of years of human consumption in the food industry, as well as a lack of toxicity and immunogenicity. Also, containment strategies have been developed to promote further application as clinical protein-based therapeutics. Here, we review technological advancements made to enhanced the potential of L. lactis as live biofactories and discuss some examples of tolerogenic immunotherapies mediated by mucosal drug delivery via L. lactis. Additionally, we highlight their use to induce mucosal tolerance by targeted autoantigen delivery to the intestine as an approach to reverse autoimmune type 1 diabetes.
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Affiliation(s)
- Dana P Cook
- Laboratory of Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium
| | - Conny Gysemans
- Laboratory of Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium
| | - Chantal Mathieu
- Laboratory of Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium
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Smole U, Schabussova I, Pickl WF, Wiedermann U. Murine models for mucosal tolerance in allergy. Semin Immunol 2017; 30:12-27. [PMID: 28807539 DOI: 10.1016/j.smim.2017.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 07/21/2017] [Indexed: 02/07/2023]
Abstract
Immunity is established by a fine balance to discriminate between self and non-self. In addition, mucosal surfaces have the unique ability to establish and maintain a state of tolerance also against non-self constituents such as those represented by the large numbers of commensals populating mucosal surfaces and food-derived or air-borne antigens. Recent years have seen a dramatic expansion in our understanding of the basic mechanisms and the involved cellular and molecular players orchestrating mucosal tolerance. As a direct outgrowth, promising prophylactic and therapeutic models for mucosal tolerance induction against usually innocuous antigens (derived from food and aeroallergen sources) have been developed. A major theme in the past years was the introduction of improved formulations and novel adjuvants into such allergy vaccines. This review article describes basic mechanisms of mucosal tolerance induction and contrasts the peculiarities but also the interdependence of the gut and respiratory tract associated lymphoid tissues in that context. Particular emphasis is put on delineating the current prophylactic and therapeutic strategies to study and improve mucosal tolerance induction in allergy.
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Affiliation(s)
- Ursula Smole
- Institute of Immunology, Center for Pathophysiology, Infectiology, and Immunology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Irma Schabussova
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Winfried F Pickl
- Institute of Immunology, Center for Pathophysiology, Infectiology, and Immunology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
| | - Ursula Wiedermann
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
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Cantaruti TA, Costa RA, de Souza KS, Vaz NM, Carvalho CR. Indirect effects of immunological tolerance to a regular dietary protein reduce cutaneous scar formation. Immunology 2017; 151:314-323. [PMID: 28295241 DOI: 10.1111/imm.12732] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 02/15/2017] [Accepted: 03/06/2017] [Indexed: 12/20/2022] Open
Abstract
Oral tolerance refers to the specific inhibition of immune responsiveness to T-cell-dependent antigens contacted through the oral route before parenteral immunization. Oral tolerance to one protein does not inhibit immune responses to other unrelated proteins, but parenteral injection of tolerated antigens plus adjuvant into tolerant, but not normal, mice inhibits immune responses to antigens injected concomitantly or soon thereafter. The inhibitory effect triggered by parenteral injection of tolerated proteins is known as bystander suppression or indirect effects of oral tolerance. Intraperitoneal injection of ovalbumin (OVA) plus alum adjuvant in OVA-tolerant mice soon before skin injury inhibits inflammation and improves cutaneous wound healing. However, as OVA is not a regular component of mouse chow, we tested whether indirect effects could be triggered by zein, the main protein of corn that is regularly present in mouse chow. We show that intraperitoneal injection of a single dose (10 μg) of zein plus alum adjuvant soon before skin injury in mice reduces leucocyte infiltration but increase the number of T cells and the expression of resistin-like molecule-α (a marker of alternatively activated macrophages) in the wound bed, increases the expression of transforming growth factor-β3 in the newly formed epidermis and reduces cutaneous scar formation. These results suggest that indirect effects of oral tolerance triggered by parenteral injection of regular dietary components may be further explored as one alternative way to promote scarless wound healing.
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Affiliation(s)
| | | | - Kênia Soares de Souza
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Nelson Monteiro Vaz
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Cláudia Rocha Carvalho
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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de Oliveira SRP, Nomizo A, Frantz FG, Faccioli LH, de Matos APK, Carrilho E, Afonso A, de Freitas Anibal F. Participation of Leukotrienes in the Immune Modulation of Oral Tolerance. Front Microbiol 2017; 8:242. [PMID: 28270799 PMCID: PMC5318402 DOI: 10.3389/fmicb.2017.00242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 02/03/2017] [Indexed: 11/24/2022] Open
Abstract
Oral tolerance (OT) is characterized as a peripheral immune tolerance form, in which, mature lymphocytes in lymphoid tissues associated with mucosa, become non-functional or hypo responsive due to prior oral administration of antigen. OT is an important immunological phenomenon due to its therapeutic potential in inflammatory processes and others diseases. Here we evaluated leukotriene role in the induction of OT, as well as, the production of cytokines IL-5 and IFN-γ in leukotriene deficient animals (knock-out). Our results suggested that even in the presence of OT and leukotrienes absence, cytokine IFN-γ remains being secreted, which gives us an indication of immune system specificity and also that IFN-γ participates in various immune processes.
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Affiliation(s)
- Sandra R P de Oliveira
- Laboratory of Parasitology, Department of Morphology and Pathology, Universidade Federal de São Carlos São Carlos, Brazil
| | - Auro Nomizo
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto - University of São Paulo Ribeirão Preto, Brazil
| | - Fabiani G Frantz
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto - University of São Paulo Ribeirão Preto, Brazil
| | - Lúcia H Faccioli
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto - University of São Paulo Ribeirão Preto, Brazil
| | - Ana Paula Keller de Matos
- Laboratory of Parasitology, Department of Morphology and Pathology, Universidade Federal de São CarlosSão Carlos, Brazil; Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, Ribeirão PretoBrazil
| | - Emanuel Carrilho
- Bioanalytical, Microfabrication, and Separations Group, Instituto de Química de São Carlos, Universidade de São Paulo São Carlos, Brazil
| | - Ana Afonso
- Laboratory of Parasitology, Department of Morphology and Pathology, Universidade Federal de São CarlosSão Carlos, Brazil; Bioanalytical, Microfabrication, and Separations Group, Instituto de Química de São Carlos, Universidade de São PauloSão Carlos, Brazil; Medical Parasitology Unit, Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade Nova de LisboaLisbon, Portugal
| | - Fernanda de Freitas Anibal
- Laboratory of Parasitology, Department of Morphology and Pathology, Universidade Federal de São Carlos São Carlos, Brazil
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Serebrovskaya EO, Yuzhakova DV, Ryumina AP, Druzhkova IN, Sharonov GV, Kotlobay AA, Zagaynova EV, Lukyanov SA, Shirmanova MV. Soluble OX40L favors tumor rejection in CT26 colon carcinoma model. Cytokine 2016; 84:10-16. [PMID: 27203665 DOI: 10.1016/j.cyto.2016.05.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 04/06/2016] [Accepted: 05/02/2016] [Indexed: 12/14/2022]
Abstract
OX40 receptor-expressing regulatory T cells (Tregs) populate tumors and suppress a variety of immune cells, posing a major obstacle for cancer immunotherapy. Different ways to functionally inactivate Tregs by triggering OX40 receptor have been suggested, including anti-OX40 antibodies and Fc:OX40L fusion proteins. To investigate whether the soluble extracellular domain of OX40L (OX40Lexo) is sufficient to enhance antitumor immune response, we generated an OX40Lexo-expressing CT26 colon carcinoma cell line and studied its tumorigenicity in immunocompetent BALB/c and T cell deficient nu/nu mice. We found that soluble OX40L expressed in CT26 colon carcinoma favors the induction of an antitumor response which is not limited just to cells co-expressing EGFP as an antigenic determinant, but also eliminates CT26 cells expressing another fluorescent protein, KillerRed. Tumor rejection required the presence of T lymphocytes, as indicated by the unhampered tumor growth in nu/nu mice. Subsequent re-challenge of tumor-free BALB/c mice with CT26 EGFP cells resulted in no tumor growth, which is indicative of the formation of immunological memory. Adoptive transfer of splenocytes from mice that successfully rejected CT26 OX40Lexo EGFP tumors to naïve mice conferred 100% resistance to subsequent challenge with the CT26 EGFP tumor.
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Affiliation(s)
- Ekaterina O Serebrovskaya
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya St., 16/10, Moscow, Russia.
| | - Diana V Yuzhakova
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia; Lobachevsky State University of Nizhny Novgorod, 603950 Gagarina Ave., 23, Nizhny Novgorod, Russia
| | - Alina P Ryumina
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya St., 16/10, Moscow, Russia
| | - Irina N Druzhkova
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia
| | - George V Sharonov
- Moscow State University, Faculty of Medicine, 119192, Lomonosovsky pr., 31/5, Moscow, Russia
| | - Alexey A Kotlobay
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya St., 16/10, Moscow, Russia
| | - Elena V Zagaynova
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia
| | - Sergey A Lukyanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya St., 16/10, Moscow, Russia; Pirogov Russian National Research Medical University, 117997, Ostrovityanova st., 1, Moscow, Russia
| | - Marina V Shirmanova
- Nizhny Novgorod State Medical Academy, 603005 Minin and Pozharsky Sq., 10/1, Nizhny Novgorod, Russia
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Costa RA, Matos LBO, Cantaruti TA, de Souza KS, Vaz NM, Carvalho CR. Systemic effects of oral tolerance reduce the cutaneous scarring. Immunobiology 2015; 221:475-85. [PMID: 26652243 DOI: 10.1016/j.imbio.2015.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 11/06/2015] [Accepted: 11/07/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immunological tolerance refer to the inhibition of specific immune responsiveness and the ingestion of proteins previous to immunization is a reliable method to induce (oral) tolerance. Parenteral exposure to tolerated antigens, in adjuvant, trigger indirect and systemic effects that inhibits concomitant immune responses to other unrelated antigens and also decrease unrelated inflammatory responses. Interesting, intraperitoneal (i.p.) exposure to orally-tolerated proteins soon before an incisional linear skin wound improves the healing by primary intention in mice. An important clinical and surgical objective is to identify strategies to improve wound healing and reduce scarring. OBJECTIVE To evaluate whether i.p. injection of an orally-tolerated protein improves wound healing by secondary intention and reduce scarring of full-thickness excisional skin injury. METHODS C57Bl/6 mice were turned tolerant to ovalbumin (OVA) by drinking a solution containing OVA; seven days later, they received an i.p. injection of OVA plus Al(OH)3 adjuvant immediately before two full-thickness excisional skin wounds, under anesthesia. The wound healing process was evaluated macro and microscopically after H&E, toluidine blue and Gomori's Trichrome staining. The presence of granulocytes, macrophages, miofibroblasts, fibronectin, collagen I and collagen III was investigated by immunofluorescence and the levels of cytokines by flow cytometry or ELISA. Mice not tolerant to OVA were included as controls. RESULTS The i.p. injection of OVA+Al(OH)3 in mice orally tolerant to OVA reduced the subsequent inflammatory response in the wound bed and the cutaneous scarring. There was a change in the pattern of collagen deposition making it more similar to the pattern observed in intact skin. In tolerant mice, mast cells and granulocytes (Ly-6C/G+), were reduced, while lymphocytes (CD3+) were increased in the wound bed. Time course analysis of Th1/Th2/Th17 cytokines and growth factors showed slightly differences between tolerant and control groups. CONCLUSION Parenteral injection of an orally-tolerated protein has systemic consequences that impair the inflammatory response triggered by skin injury and reduce the cutaneous scarring.
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Affiliation(s)
- Raquel Alves Costa
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil
| | - Liana Biajoli Otoni Matos
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil
| | - Thiago Anselmo Cantaruti
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil
| | - Kênia Soares de Souza
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil
| | - Nelson Monteiro Vaz
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil
| | - Cláudia Rocha Carvalho
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, Belo Horizonte, MG CEP: 31270-901, Brazil.
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Drescher KM, von Herrath M, Tracy S. Enteroviruses, hygiene and type 1 diabetes: toward a preventive vaccine. Rev Med Virol 2014; 25:19-32. [PMID: 25430610 DOI: 10.1002/rmv.1815] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 09/26/2014] [Accepted: 10/02/2014] [Indexed: 12/24/2022]
Abstract
Enteroviruses and humans have long co-existed. Although recognized in ancient times, poliomyelitis and type 1 diabetes (T1D) were exceptionally rare and not epidemic, due in large part to poor sanitation and personal hygiene which resulted in repeated exposure to fecal-oral transmitted viruses and other infectious agents and viruses and the generation of a broad protective immunity. As a function of a growing acceptance of the benefits of hygienic practices and microbiologically clean(er) water supplies, the likelihood of exposure to diverse infectious agents and viruses declined. The effort to vaccinate against poliomyelitis demonstrated that enteroviral diseases are preventable by vaccination and led to understanding how to successfully attenuate enteroviruses. Type 1 diabetes onset has been convincingly linked to infection by numerous enteroviruses including the group B coxsackieviruses (CVB), while studies of CVB infections in NOD mice have demonstrated not only a clear link between disease onset but an ability to reduce the incidence of T1D as well: CVB infections can suppress naturally occurring autoimmune T1D. We propose here that if we can harness and develop the capacity to use attenuated enteroviral strains to induce regulatory T cell populations in the host through vaccination, then a vaccine could be considered that should function to protect against both autoimmune as well as virus-triggered T1D. Such a vaccine would not only specifically protect from certain enterovirus types but more importantly, also reset the organism's regulatory rheostat making the further development of pathogenic autoimmunity less likely.
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Affiliation(s)
- Kristen M Drescher
- Department of Medical Microbiology and Immunology, School of Medicine, Creighton University, Omaha, NE, USA
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Abstract
Foxp3⁺ regulatory T (Treg) cells are critical contributors to the establishment and maintenance of immunological self-tolerance. Autoimmune type 1 diabetes (T1D) is characterized by the loss of self-tolerance to the insulin-producing β cells in the pancreas and the destruction of β cells, resulting in the development of chronic hyperglycemia at diagnosis. The application of strong agonistic T-cell receptor ligands provided under subimmunogenic conditions functions as a critical means for the efficient de novo conversion of naive CD4⁺ T cells into Foxp3⁺ Treg cells. The specific induction of Treg cells upon supply of strong-agonistic variants of certain self-antigens could therefore function as a critical instrument in order to achieve safe and specific prevention of autoimmunity such as T1D via the restoration of self-tolerance. Such immunotherapeutic strategies are being developed, and in the case of T1D aim to restrict autoimmunity and β-cell destruction. In this review, we discuss the requirements and opportunities for Treg-based tolerance approaches with the goal of interfering with autoimmune T1D.
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Robert S, Gysemans C, Takiishi T, Korf H, Spagnuolo I, Sebastiani G, Van Huynegem K, Steidler L, Caluwaerts S, Demetter P, Wasserfall CH, Atkinson MA, Dotta F, Rottiers P, Van Belle TL, Mathieu C. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes 2014; 63:2876-87. [PMID: 24677716 DOI: 10.2337/db13-1236] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65370-575 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional β-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4(+)Foxp3(+)CD25(+) regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D.
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Affiliation(s)
- Sofie Robert
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Conny Gysemans
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Tatiana Takiishi
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Hannelie Korf
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Isabella Spagnuolo
- Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
| | | | | | | | - Pieter Demetter
- Department of Pathology, Université Libre de Bruxelles, Brussels, Belgium
| | - Clive H Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Francesco Dotta
- Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
| | | | - Tom L Van Belle
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
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Vaz NM, Carvalho CR. On the origin of immunopathology. J Theor Biol 2014; 375:61-70. [PMID: 24937801 DOI: 10.1016/j.jtbi.2014.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 06/02/2014] [Accepted: 06/04/2014] [Indexed: 12/19/2022]
Abstract
Stranded between medicine and experimental biology, immunology is buried in its own problems and remains distant from important areas of current biology, such as evolutionary theory, developmental biology and cognitive sciences. Immunology has treated the living system merely as the place or dimension in which immune activity takes place, inserted on a misleading axis (progressive responsiveness versus no response; memory versus tolerance) which neglects the analysis of a robustly stable dynamics which is always present and is neither tolerance nor immunity-a problem currently approached as one of "regulatory" activity. However, a regulatory response also demands regulation, leading to an endless recursion and the adoption of a stimulus-response framework inevitably drives us away from the physiological processes in which lymphocytes are involved. Herein, we propose that immunological physiology, like everything else in the body is dynamic and conservative. Immunopathology, including inherited immunodeficiencies, severe forms of infectious diseases, allergy and autoimmune diseases, are interferences with this stability which frequently include oligoclonal expansions of T lymphocytes. We suggest that this decrease in clonal diversity results from a loss of the stabilizing connectivity among lymphocytes and are not simply markers of immunopathology, but are rather expressions of basic pathogenic mechanisms. The so-called autoimmune diseases are examples of this disequilibrium. In the last decade the characterization of an enormous and diversified commensal microbiota has posed a new and pressing problem: how to explain the harmonic conviviality with trillions of foreign macromolecules. In addition, robustly stable relations towards macromolecular diet can be established by simple ingestion, a state presently labeled as "oral tolerance", a problem that has been buffered for decades as anti-inflammatory protection of the gut. A major change in terminology is necessary to describe this new panorama. We focus on two important gaps in immunological discussions: (a) the organism, seen simultaneously as the medium with which the immune system is constantly in touch and as the entity that mediates the contact with external materials; and (b) the observer, the immunologist, who operates as a human being in human languaging with other human beings, and characterizes immunological specificity. We acknowledge that we are proposing radical departures from current dogma and that we should justify them. Most of what we propose stem form a way of seeing called Biology of Cognition and Language, that derives from ideas of the neurobiologist/philosopher Humberto Maturana, also known as "autopoiesis theory".
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Affiliation(s)
- Nelson M Vaz
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
| | - Claudia R Carvalho
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, MG, Brazil
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Levast B, Berri M, Wilson HL, Meurens F, Salmon H. Development of gut immunoglobulin A production in piglet in response to innate and environmental factors. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2014; 44:235-244. [PMID: 24384471 DOI: 10.1016/j.dci.2013.12.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/20/2013] [Accepted: 12/21/2013] [Indexed: 06/03/2023]
Abstract
The current review focuses on pre- and post-natal development of intestinal immunoglobulin A (IgA) production in pig. IgA production is influenced by intrinsic genetic factors in the foetus as well as extrinsic environmental factors during the post-natal period. At birth, piglets are exposed to new antigens through maternal colostrums/milk as well as exogenous microbiota. This exposure to new antigens is critical for the proper development of the gut mucosal immune system and is characterized mainly by the establishment of IgA response. A second critical period for neonatal intestinal immune system development occurs at weaning time when the gut environment is exposed to new dietary antigens. Neonate needs to establish oral tolerance and in the absence of protective milk need to fight potential new pathogens. To improve knowledge about the immune response in the neonates, it is important to identify intrinsic and extrinsic factors which influence the intestinal immune system development and to elucidate their mechanism of action.
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Affiliation(s)
- Benoît Levast
- Vaccine and Infectious Disease Organization (VIDO), Home of the International Vaccine Centre (InterVac), University of Saskatchewan, 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - Mustapha Berri
- Institut National de la Recherche Agronomique (INRA), UMR1282 ISP, Nouzilly, France; Université de Tours, UMR1282 ISP, Tours, France
| | - Heather L Wilson
- Vaccine and Infectious Disease Organization (VIDO), Home of the International Vaccine Centre (InterVac), University of Saskatchewan, 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada
| | - François Meurens
- Vaccine and Infectious Disease Organization (VIDO), Home of the International Vaccine Centre (InterVac), University of Saskatchewan, 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada
| | - Henri Salmon
- Institut National de la Recherche Agronomique (INRA), UMR1282 ISP, Nouzilly, France; Université de Tours, UMR1282 ISP, Tours, France
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Gordon JR, Ma Y, Churchman L, Gordon SA, Dawicki W. Regulatory dendritic cells for immunotherapy in immunologic diseases. Front Immunol 2014; 5:7. [PMID: 24550907 PMCID: PMC3907717 DOI: 10.3389/fimmu.2014.00007] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 01/07/2014] [Indexed: 12/12/2022] Open
Abstract
We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings.
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Affiliation(s)
- John R Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Yanna Ma
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Laura Churchman
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Sara A Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Wojciech Dawicki
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
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Martin L, Granier A, Lemoine R, Dauba A, Vermeersch S, Aubert-Jacquin C, Baron C, Lebranchu Y, Hoarau C, Velge-Roussel F. Bifidobacteria BbC50 Fermentation Products Induce Human Cd4 + Regulatory T Cells with Antigen-Specific Activation and Bystander Suppression. EUR J INFLAMM 2014. [DOI: 10.1177/1721727x1401200116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Probiotic bacteria have been shown to have health benefits in various situations (inflammation, allergy, infection). We previously showed that a bacteria-free fermentation product of Bifidobacterium breve C50 (BbC50sn) induced high IL-10 secretion by human dendritic cells. As IL-10 is a regulatory cytokine, the aim of the present study was to examine whether DCs cultured in the presence of BbC50sn could induce regulatory T cells in an allogeneic context. Purified CD4+CD25− human T cells were co-cultured with allogeneic BbC50sn-treated dendritic cells for 4 weeks. The T cell population (BbC50sn-T) was analysed both at phenotypical and functional [ability to inhibit a mixed lymphocyte reaction (MLR)] levels. We showed that T lymphocytes acquired phenotype characteristics of regulatory T cells after 4 weeks of co-culture with BbC50sn-DCs, and inhibited in vitro T lymphocyte proliferation and IFN-γ production in an MLR. Transwell experiments demonstrated that this suppressive activity was not T cell contact-dependent but probably mediated by a soluble factor. Although BbC50sn-T cells secreted significant amounts of IL-10 and TGF-β, their suppressive effect is most likely not mediated through these cytokines. This is, to our knowledge, the first demonstration of in vitro regulatory T cell induction by a bacteria-free fermentation product in an allogeneic context.
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Affiliation(s)
- L. Martin
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | - A. Granier
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | - R. Lemoine
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | - A. Dauba
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | - S. Vermeersch
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | | | - C. Baron
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
- Service de Néphrologie et d'Immunologie Clinique, CHRU de Tours, Tours, France
| | - Y. Lebranchu
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
- Service de Néphrologie et d'Immunologie Clinique, CHRU de Tours, Tours, France
| | - C. Hoarau
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
| | - F. Velge-Roussel
- EA 4245 «Cellules Dendritiques, Immunomodulation et Greffes», UFR de Médecine, Université François-Rabelais de Tours, Tours, France
- UFR des Sciences Pharmaceutiques, Tours, France
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Singh UP, Singh NP, Guan H, Busbee B, Price RL, Taub DD, Mishra MK, Fayad R, Nagarkatti M, Nagarkatti PS. Leptin antagonist ameliorates chronic colitis in IL-10⁻/⁻ mice. Immunobiology 2013; 218:1439-51. [PMID: 23726523 PMCID: PMC3778116 DOI: 10.1016/j.imbio.2013.04.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 04/27/2013] [Accepted: 04/27/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-β1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression. AIM We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis. RESULTS Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39⁺ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-β1, -β2 and -β3 expressing CD4⁺ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-β1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis. CONCLUSION This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD.
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Affiliation(s)
- Udai P Singh
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
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Abstract
It is widely accepted that the main common pathogenetic pathway in multiple sclerosis (MS) involves an immune-mediated cascade initiated in the peripheral immune system and targeting CNS myelin. Logically, therefore, the therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunologic cascade. Since the introduction of interferons in 1993, which were the first registered treatments for MS, huge steps have been made in the field of MS immunotherapy. More efficious and specific immunoactive drugs have been introduced and it appears that the increased specificity for MS of these new treatments is paralleled by greater efficacy. Unfortunately, this seemingly increased efficacy has been accompanied by more safety issues. The immunotherapeutic modalities can be divided into two main groups: those affecting the acute stages (relapses) of the disease and the long-term treatments that are aimed at preventing the appearance of relapses and the progression in disability. Immunomodulating treatments may also be classified according to the level of the 'immune axis' where they exert their main effect. Since, in MS, a neurodegenerative process runs in parallel and as a consequence of inflammation, early immune intervention is warranted to prevent progression of relapses of MS and the accumulation of disability. The use of neuroimaging (MRI) techniques that allow the detection of silent inflammatory activity of MS and neurodegeneration has provided an important tool for the substantiation of the clinical efficacy of treatments and the early diagnosis of MS. This review summarizes in detail the existing information on all the available immunotherapies for MS, old and new, classifies them according to their immunologic mechanisms of action and proposes a structured algorithm/therapeutic scheme for the management of the disease.
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Morgan ME, Zheng B, Koelink PJ, van de Kant HJG, Haazen LCJM, van Roest M, Garssen J, Folkerts G, Kraneveld AD. New perspective on dextran sodium sulfate colitis: antigen-specific T cell development during intestinal inflammation. PLoS One 2013; 8:e69936. [PMID: 23936123 PMCID: PMC3723715 DOI: 10.1371/journal.pone.0069936] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 06/12/2013] [Indexed: 12/14/2022] Open
Abstract
CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS-treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens.
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Affiliation(s)
- Mary E Morgan
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov 2013; 12:51-63. [PMID: 23274471 DOI: 10.1038/nrd3683] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Forkhead box P3 (FOXP3)-expressing regulatory T (T(Reg)) cells have a pivotal role in the regulation of immune responses and in the maintenance of immunological self-tolerance. These cells have emerged as attractive targets for strategies that allow the steering of immune responses in desired directions - arming the immune system to destroy infected cells and cancer cells or downregulating it to limit tissue destruction in autoimmunity. Efforts to understand the generation, activation and function of T(Reg) cells should permit the development of therapeutics for reprogramming the immune system. In this Review, we discuss insights into the generation of T(Reg) cells, their involvement in disease and the molecular basis of the dominant tolerance exerted by FOXP3(+) T(Reg) cells that could permit their safe and specific manipulation in humans.
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Bach JF, Chatenoud L. The hygiene hypothesis: an explanation for the increased frequency of insulin-dependent diabetes. Cold Spring Harb Perspect Med 2013; 2:a007799. [PMID: 22355800 DOI: 10.1101/cshperspect.a007799] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The steadily increasing frequency of insulin-dependent diabetes in several countries is best explained today by the decline of infections. Epidemiologic and animal data support this conclusion, which, however, requires confirmation by intervention trials in man. The mechanisms of the protective effect of infections on diabetes onset are diverse including competition for homeostatic factors and stimulation of regulatory T cells and of Toll-like receptors. These considerations might have interesting therapeutic applications for the prevention of the disease.
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Affiliation(s)
- Jean-François Bach
- Université Paris Descartes, 75015 Paris, France; INSERM, Unité 1013, 75015 Paris, France.
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Esmaeili A, Dadkhahfar S, Fadakar K, Rezaei N. Post-stroke immunodeficiency: effects of sensitization and tolerization to brain antigens. Int Rev Immunol 2013; 31:396-409. [PMID: 23083348 DOI: 10.3109/08830185.2012.723078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Acute onset of cerebrovascular diseases seems to be related to a number of immunological alternations. After the initial pro-inflammatory response to brain ischemia accompanied by systemic inflammatory response syndrome, stroke interferes with function of the innate and the adaptive immune cells, resulting in systemic immunosuppression. Although post-stroke immunodeficiency could predispose patients to life-threatening infections, it could potentially protect brain via reducing autoimmune reaction to the brain antigens. In this paper, we review current knowledge on the immunological alterations after brain ischemia, particularly effects of infection for stimulation of autoimmune response against brain antigens.
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Affiliation(s)
- Arash Esmaeili
- Brain and Spinal Injuries Repair Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Castro-Junior AB, Horta BC, Gomes-Santos AC, Cunha AP, Silva Steinberg R, Nascimento DS, Faria AMC, Vaz NM. Oral tolerance correlates with high levels of lymphocyte activity. Cell Immunol 2013; 280:171-81. [PMID: 23399844 DOI: 10.1016/j.cellimm.2012.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 11/21/2012] [Accepted: 12/17/2012] [Indexed: 11/30/2022]
Abstract
Oral tolerance is defined as an inhibition of specific immune responsiveness to a previously ingested antigen. Paradoxically, we found an increased lymphocyte activity in tolerant mice alongside the specific inhibition. Orally-tolerant mice presented higher number of immunoglobulin secreting cells (ISC) in spleen and bone marrow; showed a greater variety of Ig classes being produced: IgM and IgA in the spleen and IgG and IgM in the bone marrow. ISC from immunized mice produced mainly IgG. Despite having the same number of regulatory and activated T cells in the spleen after immunization, these cells appeared earlier in tolerant mice, right after the primary immunization. Also, tolerant mice showed a prompt expression of regulatory cytokines (TGF-β and IL-10) and a transient expression of effector cytokines (IL-2 and IFN-γ). Thus, in addition to an inhibited specific responsiveness, orally-tolerant mice displayed an early and widespread mobilization of activated and regulatory lymphocytes.
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Affiliation(s)
- Archimedes Barbosa Castro-Junior
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
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Staeva TP, Chatenoud L, Insel R, Atkinson MA. Recent lessons learned from prevention and recent-onset type 1 diabetes immunotherapy trials. Diabetes 2013; 62:9-17. [PMID: 23258904 PMCID: PMC3526042 DOI: 10.2337/db12-0562] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
| | - Lucienne Chatenoud
- Université Paris Descartes, INSERM U1013, Hôpital Universitaire Necker-Enfants malades, Paris, France
| | | | - Mark A. Atkinson
- Department of Pathology, University of Florida, Gainesville, Florida
- Corresponding author: Mark A. Atkinson,
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Abstract
Gut mucosal surfaces separate the external environment from the internal sterile environment and so represent a first line of defence system. This barrier faces environments rich in pathogens that have developed effective mechanisms for colonisation of epithelial surfaces and invasion of mucosal tissues, but also harmless antigens such as food, airborne antigens or commensal bacterial flora. The latter represent the vast majority of the encountered antigens and require an appropriate response characterised by either ignorance or active suppression. However, for the former, a robust immune response is needed. Mucosae have developed a complex immune system that is capable of mounting an immune response against pathogenic antigens, while maintaining the required ignorance or active suppression against non-pathogenic antigens. Taking advantage of this knowledge, strategies have been devised to induce oral tolerance to antigens involved in experimental autoimmune disease or human conditions. It is now known that oral tolerance induces the up-regulation and activation of T cells with regulatory properties, a subtype of CD4⁺ T cells whose function is to regulate functions of other T lymphocytes to avoid excessive immune activation. Amongst them, the Th3 cells (cells that express the latency-associated peptide on the surface and secrete transforming growth factor β, a cytokine with immunoregulatory properties) are especially relevant in the induction of oral tolerance. Orally fed antigens seek to generate these types of cells in the treatment of autoimmune diseases in experimental animals or human subjects.
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Affiliation(s)
- Patricia Castro-Sánchez
- Departamento de Inmunología, Facultad de Medicina, Pabellón V: Planta 4, Universidad Complutense de Madrid, 28040 Madrid, Spain
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Buchanan RM, Tetland S, Wilson HL. Low dose antigen exposure for a finite period in newborn rats prevents induction of mucosal tolerance. PLoS One 2012; 7:e51437. [PMID: 23251533 PMCID: PMC3520849 DOI: 10.1371/journal.pone.0051437] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 10/31/2012] [Indexed: 11/18/2022] Open
Abstract
Background In adult rats, initial exposure to antigens by a mucosal route triggers tolerance such that any subsequent re-exposure, even by a systemic route, results in suppression of immunity. The newborn’s gut is semi-permeable for a finite period to allow maternal antibodies to enter the newborn’s circulation. We propose that antigens introduced in extreme early life can readily traverse the gut wall and therefore circumvent induction of mucosal tolerance. Methodology/Principle Findings Rat pups were gavaged with low-doses of ovalbumin (OVA; oral exposure group) or saline (parenteral control group) every second day for several weeks followed by an intraperitoneal (i.p.) injection at 1 month of age. When gavage was initiated the day after birth, newborn oral exposure pups responded with significantly higher anti-OVA IgA, IgM, IgG2a, and IgG1 titres in their serum and anti-OVA IgA, IgG2a and IgG1 titres in their lungs compared to negative control pups. Oral exposure alone failed to induce immunity. Pups exposed to the same treatment regimen starting at 14 days of age showed induction of mucosal tolerance after i.p. immunization. Newborn oral exposure groups subjected to secondary i.p. immunization responded with significantly increased humoral immunity in lung and sera suggesting that once antigen-specific mucosal tolerance if circumvented, it persists. Lymphocytes derived from mesenteric lymph node cells re-simulated with OVA ex vivo, from newborn oral exposure pups exposed to secondary immunization produced significantly higher IFN-γ expression and lymphocyte proliferation relative to control pups indicating prevention of tolerance in the cell-mediated immune system. Conclusions/Significance This work demonstrates that newborns may be uniquely qualified to prevent induction of mucosal tolerance to oral antigens. These results should be further explored to establish whether prevention of tolerance by early life oral vaccination can be exploited to prime for mucosal as well as systemic immunity and thus protect this susceptible population against infectious diseases.
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Affiliation(s)
- Rachelle M. Buchanan
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
| | - Sherry Tetland
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
| | - Heather L. Wilson
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
- * E-mail:
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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
| | - Ashleigh Goethel
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Catherine Wing-Tak Chan
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Galliano Zanello
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Catherine Streutker
- Surgical Pathology, Department of Pathology and Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
| | - 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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Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells. J Autoimmun 2012; 40:45-57. [PMID: 22939403 DOI: 10.1016/j.jaut.2012.07.012] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Revised: 07/31/2012] [Accepted: 07/31/2012] [Indexed: 11/24/2022]
Abstract
Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice.
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Zhou XL, Zhao XD. Specific oral tolerance induction for the treatment of food allergy. Shijie Huaren Xiaohua Zazhi 2012; 20:1433-1438. [DOI: 10.11569/wcjd.v20.i16.1433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The morbidity of food allergy in children has a tendency to increase these years. Double-blind placebo-controlled food challenge (DBPCFC) is the gold standard for the diagnosis of food allergy, and the standard treatment for food allergy is strict food avoidance. However, long-time strict food avoidance is difficult in everyday life, and may lead to malnutrition and even can increase the risk for developing severe anaphylaxis after accidental ingestion. Specific oral tolerance induction (SOTI) is a new and possible way to treat food allergy, which is performed by limited ingestion of the allergen to make the body become unresponsive to it. However, the effectiveness, safety and economic benefit are still controversial, because of the deficiency of DBPCFC. Our paper will introduce the methods and mechanism of SOTI, compare it with traditional treatments for food allergy, and discuss the possibility of clinical use of SOTI.
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NK cells promote Th-17 mediated corneal barrier disruption in dry eye. PLoS One 2012; 7:e36822. [PMID: 22590618 PMCID: PMC3348128 DOI: 10.1371/journal.pone.0036822] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Accepted: 04/13/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The conjunctiva contains a specialized population of lymphocytes that reside in the epithelium, named intraepithelial lymphocytes (IEL). METHODOLOGY/PRINCIPAL FINDINGS Here we characterized the IEL population prior to and after experimental desiccating stress (DS) for 5 or 10 days (DS5, DS10) and evaluated the effect of NK depletion on DS. The frequency of IELs in normal murine conjunctiva was CD3(+)CD103(+) (~22%), CD3(+)γδ(+) (~9.6%), CD3(+)NK(+) (2%), CD3(-)NK(+) (~4.4%), CD3(+)CD8α (~0.9%), and CD4 (~0.6%). Systemic depletion of NK cells prior and during DS led to a decrease in the frequency of total and activated DCs, a decrease in T helper-17(+) cells in the cervical lymph nodes and generation of less pathogenic CD4(+)T cells. B6.nude recipient mice of adoptively transferred CD4(+)T cells isolated from NK-depleted DS5 donor mice showed significantly less corneal barrier disruption, lower levels of IL-17A, CCL20 and MMP-3 in the cornea epithelia compared to recipients of control CD4(+)T cells. CONCLUSIONS/SIGNIFICANCE Taken together, these results show that the NK IELs are involved in the acute immune response to desiccation-induced dry eye by activating DC, which in turn coordinate generation of the pathogenic Th-17 response.
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