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Fan JN, Ho H, Chiang BL. Characterization of novel CD8 + regulatory T cells and their modulatory effects in murine model of inflammatory bowel disease. Cell Mol Life Sci 2024; 81:327. [PMID: 39085655 PMCID: PMC11335251 DOI: 10.1007/s00018-024-05378-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
Dysregulation of mucosal immune system has been proposed to be critical in the pathogenesis of inflammatory bowel diseases (IBDs). Regulatory T cells (Tregs) play an important role in regulating immune responses. Tregs are involved in maintaining intestinal homeostasis and exerting suppressive function in colitis. Our previous studies showed that a novel forkhead box protein P3 (Foxp3) negative Tregs (Treg-of-B cells), induced by culturing naïve CD4+ T cells with B cells, could protect against colitis and downregulate T helper (Th) 1 and Th17 cell cytokines in T cell-mediated colitis. In the present study, we aimed to induce Treg-of-B cells in the CD8+ T-cell population and investigate their characteristics and immunomodulatory functions. Our results showed that CD8+ Treg-of-B cells expressed Treg-associated markers, including lymphocyte-activation gene-3 (LAG3), inducible co-stimulator (ICOS), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), tumor necrosis factor receptor superfamily member-4 (TNFRSF4, OX40), and tumor necrosis factor receptor superfamily member-18 (TNFRSF18, GITR), but did not express Foxp3. CD8+ Treg-of-B cells produced higher concentration of inhibitory cytokine interleukin (IL)-10, and expressed higher levels of cytotoxic factor granzyme B and perforin after stimulation, compared to those of CD8+CD25- T cells. Moreover, CD8+ Treg-of-B cells suppressed T cell proliferation in vitro and alleviated colonic inflammation in chronic dextran sulfate sodium (DSS)-induced colitis. In conclusion, our study identified a novel subpopulation of CD8+ Tregs with suppressive effects through cell contact. These CD8+ Treg-of-B cells might have therapeutic potential for IBDs.
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Affiliation(s)
- Jia-Ning Fan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin Ho
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bor-Luen Chiang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Pediatrics, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan.
- Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University, Taipei, Taiwan.
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2
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Koh CH, Lee S, Kwak M, Kim BS, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med 2023; 55:2287-2299. [PMID: 37907738 PMCID: PMC10689838 DOI: 10.1038/s12276-023-01105-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 11/02/2023] Open
Abstract
CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Suyoung Lee
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Minkyeong Kwak
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Gangwon, 25159, Republic of Korea.
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3
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Ogbechi J, Huang YS, Clanchy FIL, Pantazi E, Topping LM, Darlington LG, Williams RO, Stone TW. Modulation of immune cell function, IDO expression and kynurenine production by the quorum sensor 2-heptyl-3-hydroxy-4-quinolone (PQS). Front Immunol 2022; 13:1001956. [PMID: 36389710 PMCID: PMC9650388 DOI: 10.3389/fimmu.2022.1001956] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/05/2022] [Indexed: 12/29/2023] Open
Abstract
Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS.
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Affiliation(s)
- Joy Ogbechi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Eirini Pantazi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Louise M. Topping
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | | | - Richard O. Williams
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Trevor W. Stone
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
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4
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Rezaei Kahmini F, Shahgaldi S, Azimi M, Mansourabadi AH. Emerging therapeutic potential of regulatory T (Treg) cells for rheumatoid arthritis: New insights and challenges. Int Immunopharmacol 2022; 108:108858. [PMID: 35597122 DOI: 10.1016/j.intimp.2022.108858] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/27/2022] [Accepted: 05/10/2022] [Indexed: 11/05/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune-related disorder characterized by chronic inflammation. Although the etiopathogenesis of RA still remains to be clarified, it is supposed that the breakdown of immune self-tolerance may contribute to the development of RA. Thus, restoring of immune tolerance at the site of inflammation is the ultimate goal of RA treatment. Regulatory T cells (Treg cells) are the main suppressive cells that maintain tolerance and inhibit immunity against auto-antigen. Of note, recent studies demonstrated the efficacy of adoptive transfer of Treg cells in the modulation of the unwanted immune response, which makes them an ideal candidate to maintain immune homeostasis and restore antigen-specific tolerance in the case of RA and other autoimmune diseases. This review intends to submit recent finding of Treg cells-based therapies in RA with a focus on strategies applied to improve the therapeutic value of Treg cells to restore immune tolerance.
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Affiliation(s)
- Fatemeh Rezaei Kahmini
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Shahab Shahgaldi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Azimi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Mansourabadi
- Department of Immunology, School of medicine, Tehran University of Medical Sciences, Tehran, Iran; Immunogenetics Research Network (IgReN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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5
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Han M, Nguyen B, Lee JY, Browning E, Zhang J, Mukhopadhyay A, Gujar R, Salazar J, Hermiz R, Svenson L, Rolig AS, Redmond WL, Algazi AP, Daud AI, Canton DA, Twitty CG. Intratumoral electroporation of plasmid encoded IL-12 and membrane-anchored anti-CD3 increases systemic tumor immunity. Mol Cancer Res 2022; 20:983-995. [PMID: 35302641 DOI: 10.1158/1541-7786.mcr-21-0834] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 02/15/2022] [Accepted: 03/10/2022] [Indexed: 11/16/2022]
Abstract
Intratumoral delivery of plasmid IL 12 via electroporation (IT tavo EP) induces localized expression of IL 12 leading to regression of treated and distant tumors with durable responses and minimal toxicity. A key driver in amplifying this local therapy into a systemic response is the magnitude and composition of immune infiltrate in the treated tumor. While intratumoral IL 12 typically increases the density of CD3+ tumor infiltrating lymphocytes (TIL), this infiltrate is composed of a broad range of T cell subsets, including activated tumor specific T cells, less functional bystander T cells, as well as suppressive T regulatory cells. To encourage a more favorable on treatment tumor microenvironment, we explored combining this IL 12 therapy with an intratumoral polyclonal T cell stimulator membrane anchored anti CD3 to productively engage a diverse subset of lymphocytes including the non reactive and suppressive T cells. This study highlighted that combined intratumoral electroporation of IL 12 and membrane anchored anti CD3 plasmids can enhance cytokine production, T cell cytotoxicity, and proliferation while limiting the suppressive capacity within the TME. These collective anti tumor effects not only improve regression of treated tumors but drive systemic immunity with control of non treated contralateral tumors in vivo. Moreover, combination of IL 12 and anti CD3 restored the function of TIL isolated from a melanoma patient actively progressing on PD 1 checkpoint inhibitor therapy. This DNA encodable polyclonal T cell stimulator (membrane anchored anti CD3 plasmid) may represent a key addition to intratumoral IL-12 therapies in the clinic.
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Affiliation(s)
- Mia Han
- OncoSec Medical Inc., San Diego, United States
| | | | - Jack Y Lee
- OncoSec Medical Inc., San Diego, CA, United States
| | | | - Jun Zhang
- Oncosec Medical Inc., San Diego, CA, United States
| | | | | | - Jon Salazar
- Oncosec Medical Inc., San Diego, CA, United States
| | | | | | - Annah S Rolig
- Providence Cancer Institute, Portland, OR, United States
| | | | - Alain P Algazi
- University of California, San Francisco, San Francisco, CA, United States
| | - Adil I Daud
- University of California, San Francisco, San Francisco, CA, United States
| | - David A Canton
- Oncosec Medical Incorporated, San Diego, CA, United States
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6
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Zhang Z, Li Y, Shi J, Zhu L, Dai Y, Fu P, Liu S, Hong M, Zhang J, Wang J, Jiang C. Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage. Aging Dis 2022; 14:966-991. [PMID: 37191423 DOI: 10.14336/ad.2022.1102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022] Open
Abstract
Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy.
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7
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Niederlova V, Tsyklauri O, Chadimova T, Stepanek O. CD8 + Tregs revisited: A heterogeneous population with different phenotypes and properties. Eur J Immunol 2021; 51:512-530. [PMID: 33501647 DOI: 10.1002/eji.202048614] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/31/2020] [Accepted: 01/21/2021] [Indexed: 12/20/2022]
Abstract
Regulatory T cells (Tregs) play a key role in the peripheral self-tolerance and preventing autoimmunity. While classical CD4+ Foxp3+ Tregs are well established, their CD8+ counterparts are still controversial in many aspects including their phenotypic identity and their mechanisms of suppression. Because of these controversies and because of only a limited number of studies documenting the immunoregulatory function of CD8+ Tregs in vivo, the concept of CD8+ Tregs is still not unanimously accepted. We propose that any T-cell subset considered as true regulatory must be distinguishable from other cell types and must suppress in vivo immune responses via a known mechanism. In this article, we revisit the concept of CD8+ Tregs by focusing on the characterization of individual CD8+ T-cell subsets with proposed regulatory capacity separately. Therefore, we review the phenotype and function of CD8+ FOXP3+ T cells, CD8+ CD122+ T cells, CD8+ CD28low/- T cells, CD8+ CD45RClow T cells, T cells expressing CD8αα homodimer and Qa-1-restricted CD8+ T cells to show whether there is sufficient evidence to establish these subsets as bona fide Tregs. Based on the intrinsic ability of CD8+ Treg subsets to promote immune tolerance in animal models, we elaborate on their potential use in clinics.
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Affiliation(s)
- Veronika Niederlova
- Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Oksana Tsyklauri
- Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.,Faculty of Science, Charles University, Prague, Czech Republic
| | - Tereza Chadimova
- Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.,Institute of Experimental Neuroimmunology, Technical University of Munich, Munich, Germany
| | - Ondrej Stepanek
- Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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8
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Fischer R, Kontermann RE, Pfizenmaier K. Selective Targeting of TNF Receptors as a Novel Therapeutic Approach. Front Cell Dev Biol 2020; 8:401. [PMID: 32528961 PMCID: PMC7264106 DOI: 10.3389/fcell.2020.00401] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 05/01/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor (TNF) is a central regulator of immunity. Due to its dominant pro-inflammatory effects, drugs that neutralize TNF were developed and are clinically used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, despite their clinical success the use of anti-TNF drugs is limited, in part due to unwanted, severe side effects and in some diseases its use even is contraindicative. With gaining knowledge about the signaling mechanisms of TNF and the differential role of the two TNF receptors (TNFR), alternative therapeutic concepts based on receptor selective intervention have led to the development of novel protein therapeutics targeting TNFR1 with antagonists and TNFR2 with agonists. These antibodies and bio-engineered ligands are currently in preclinical and early clinical stages of development. Preclinical data obtained in different disease models show that selective targeting of TNFRs has therapeutic potential and may be superior to global TNF blockade in several disease indications.
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Affiliation(s)
- Roman Fischer
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Roland E Kontermann
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Klaus Pfizenmaier
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
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9
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Flippe L, Bézie S, Anegon I, Guillonneau C. Future prospects for CD8 + regulatory T cells in immune tolerance. Immunol Rev 2019; 292:209-224. [PMID: 31593314 PMCID: PMC7027528 DOI: 10.1111/imr.12812] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
CD8+ Tregs have been long described and significant progresses have been made about their phenotype, their functional mechanisms, and their suppressive ability compared to conventional CD4+ Tregs. They are now at the dawn of their clinical use. In this review, we will summarize their phenotypic characteristics, their mechanisms of action, the similarities, differences and synergies between CD8+ and CD4+ Tregs, and we will discuss the biology, development and induction of CD8+ Tregs, their manufacturing for clinical use, considering open questions/uncertainties and future technically accessible improvements notably through genetic modifications.
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Affiliation(s)
- Léa Flippe
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Séverine Bézie
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Ignacio Anegon
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Carole Guillonneau
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
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10
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Nácher-Juan J, Terencio MC, Alcaraz MJ, Ferrándiz ML. Osteostatin Inhibits Collagen-Induced Arthritis by Regulation of Immune Activation, Pro-Inflammatory Cytokines, and Osteoclastogenesis. Int J Mol Sci 2019; 20:E3845. [PMID: 31394717 PMCID: PMC6721041 DOI: 10.3390/ijms20163845] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/04/2019] [Accepted: 08/05/2019] [Indexed: 01/05/2023] Open
Abstract
In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 μg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1β, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.
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Affiliation(s)
- Josep Nácher-Juan
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain
| | - María Carmen Terencio
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain
| | - María José Alcaraz
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain.
| | - María Luisa Ferrándiz
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain.
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11
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Zhao H, Feng R, Peng A, Li G, Zhou L. The expanding family of noncanonical regulatory cell subsets. J Leukoc Biol 2019; 106:369-383. [DOI: 10.1002/jlb.6ru0918-353rrrr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 03/13/2019] [Accepted: 03/20/2019] [Indexed: 12/13/2022] Open
Affiliation(s)
- Hai Zhao
- Department of NeurosurgeryWest China HospitalSichuan University Chengdu China
| | - Ridong Feng
- Department of NeurosurgeryWest China HospitalSichuan University Chengdu China
| | - Aijun Peng
- Department of NeurosurgeryWest China HospitalSichuan University Chengdu China
| | - Gaowei Li
- Department of NeurosurgeryWest China HospitalSichuan University Chengdu China
| | - Liangxue Zhou
- Department of NeurosurgeryWest China HospitalSichuan University Chengdu China
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12
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Xing E, Guo Y, Feng G, Song H, An G, Zhao X, Wang M. Effects of dioscin on T helper 17 and regulatory T-cell subsets in chicken collagen type II-induced arthritis mice. J Chin Med Assoc 2019; 82:202-208. [PMID: 30913116 DOI: 10.1097/jcma.0000000000000029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND This study was conducted to investigate the treatment efficacies and immunological mechanisms of action of dioscin in mice with chicken collagen type II-induced arthritis (CIA). METHODS The CIA mice was randomly divided into the model group (M), dioscin group (D), and tripterygium group (T); a normal control group (C) was also included. Each group was orally administered with related drugs or an equal volume of solvent (group C) starting on the 21st day of primary immunity, after which the levels of T helper 17 cells (Th17), regulatory T cells (Tregs), and their related factors were detected on the 35th day. RESULTS Compared to group C, group M exhibited significantly increased levels of interleukin 17 (IL-17) and IL-6 and decreased IL-27 (p < 0.05). Group D exhibited significantly decreased levels of IL-17 and IL-6 compared with group M (p < 0.05). Group M showed a significantly increased ratio of Th17 cells (p < 0.05), while dioscin significantly reduced this ratio (p < 0.05). Groups M and C showed no significant difference in the ratio of Tregs (p > 0.05) but dioscin significantly increased this ratio (p < 0.05). Group M significantly increased signal transducer and activator of transcription 3 (STAT3) and STAT5 compared with that in group C (p < 0.05), while the T and D groups showed significantly reduced levels of STAT3 and STAT5 (p < 0.05). CONCLUSION Dioscin may affect the differentiation of Th17 and Tregs and secretion of related factors by regulating CD4 T cell subset-related signal transduction and the expression of transcription-activating factor STAT3 and STAT5, thus exerting useful immunoregulatory roles in CIA mice.
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Affiliation(s)
- Enhong Xing
- Department of Clinical Laboratory, the Affiliated Hospital of Chengde Medical College, Chengde, Hebei, China
| | - Yachun Guo
- Department of Pathogen Biology, Chengde Medical College, Chengde, Hebei, China
| | - Guiying Feng
- Department of Clinical Nursing, Chengde Medical College, Chengde, Hebei, China
| | - Hongru Song
- Department of Immunology, Chengde Medical College, Chengde, Hebei, China
| | - Gao An
- Department of Immunology, Chengde Medical College, Chengde, Hebei, China
| | - Xiaofei Zhao
- Department of Immunology, Chengde Medical College, Chengde, Hebei, China
| | - Mi Wang
- Department of Immunology, Chengde Medical College, Chengde, Hebei, China
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13
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Rouas R, Merimi M, Najar M, El Zein N, Fayyad‐Kazan M, Berehab M, Agha D, Bron D, Burny A, Rachidi W, Badran B, Lewalle P, Fayyad‐Kazan H. Human CD8
+
CD25
+
CD127
low
regulatory T cells: microRNA signature and impact on TGF‐β and IL‐10 expression. J Cell Physiol 2019; 234:17459-17472. [DOI: 10.1002/jcp.28367] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/20/2019] [Accepted: 01/24/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Redouane Rouas
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Makram Merimi
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy Institut Jules Bordet, Université Libre de Bruxelles (ULB) Brussels Belgium
| | - Nabil El Zein
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I Lebanese University Hadath Lebanon
| | - Mohammad Fayyad‐Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I Lebanese University Hadath Lebanon
| | - Mimoune Berehab
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Douaa Agha
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Dominique Bron
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Arsene Burny
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Walid Rachidi
- Univ. Grenoble Alpes, SYMMES/CIBEST UMR 5819 UGA‐CNRS‐CEA, INAC/CEA‐Grenoble Grenoble France
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I Lebanese University Hadath Lebanon
| | - Philippe Lewalle
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
| | - Hussein Fayyad‐Kazan
- Laboratory of Experimental Hematology Institut Jules Bordet, Université Libre de Bruxelles Bruxelles Belgium
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I Lebanese University Hadath Lebanon
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14
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Chakraborty S, Bhattacharjee P, Panda AK, Kajal K, Bose S, Sa G. Providence of the CD25 + KIR + CD127 - FOXP3 - CD8 + T-cell subset determines the dynamics of tumor immune surveillance. Immunol Cell Biol 2018; 96:1035-1048. [PMID: 29768737 DOI: 10.1111/imcb.12166] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 05/05/2018] [Accepted: 05/07/2018] [Indexed: 12/20/2022]
Abstract
CD8+ T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3+ CD8+ Treg cells, similar to CD4+ Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGFβ. At an early stage of tumor development, we have identified a subset of FOXP3- CD8+ CD25+ KIR+ CD127- Treg-like cells, which are IFNγ+ . However, this early-induced CD8+ CD25+ CD127- T-cell subset is certainly distinct from the IFNγ+ CD8+ T-effector cells. These CD8+ CD25+ CD127- T cells express other FOXP3- CD8+ Treg cell signature markers, and can selectively suppress autoreactive HLA-E+ TFH cells as well as tumor-induced CD4+ Treg cells. In contrast to FOXP3+ CD8+ Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E- . Adoptive transfer of this early-CD8+ Treg-like subset restrained tumor growth and inhibited CD4+ Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4+ Treg cells dominate the tumor-microenvironment, CD4+ Tregs mediate the clonal deletion of these tumor-suppressive FOXP3- IFNγ+ CD8+ CD25+ CD127- T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3- CD8+ CD25+ CD127- T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4+ Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.
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Affiliation(s)
- Sreeparna Chakraborty
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
| | - Pushpak Bhattacharjee
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
| | - Abir K Panda
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
| | - Kirti Kajal
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
| | - Sayantan Bose
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
| | - Gaurisankar Sa
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700 054, India
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15
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Guo Y, Wang Y, Shi X, Qin W, Zhang X, Xu J, Liu X, Yang D, Yang Y. A metabolomics study on the immunosuppressive effect of Tripterygium hypoglaucum (Levl.) Hutch in mice: The discovery of pathway differences in serum metabolites. Clin Chim Acta 2018; 483:94-103. [DOI: 10.1016/j.cca.2018.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 03/09/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
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16
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Tai Y, Wang Q, Korner H, Zhang L, Wei W. Molecular Mechanisms of T Cells Activation by Dendritic Cells in Autoimmune Diseases. Front Pharmacol 2018; 9:642. [PMID: 29997500 PMCID: PMC6028573 DOI: 10.3389/fphar.2018.00642] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/29/2018] [Indexed: 12/21/2022] Open
Abstract
The interaction between T cell and dendritic cells (DCs) that leads to T cell activation affects the progression of the immune response including autoimmune diseases. Antigen presentation on immune cell surface, formation of an immunological synapse (IS), and specific identification of complex by T cells including two activating signals are necessary steps that lead to T cell activation. The formation of stimulatory IS involves the inclusion of costimulatory molecules, such as ICAM-1/LFA-1 and CD28/B7-1, and so on. Some fusion proteins and monoclonal antibodies targeting costimulatory molecules have been developed and approved to treat autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I diabetes (T1D), inflammatory bowel disease (IBD), and psoriasis. These biological agents, including CTLA-4- and LFA-3-Ig, anti-CD3 monoclonal antibody, could prevent the successful engagement of DCs by T cell with significant efficacy and safety profile. In this article, we reviewed the molecular mechanisms of T cell activation during the interaction between T cells and DCs, and summarized some biological agents that target costimulatory molecules involved in the regulation of T cell activation.
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Affiliation(s)
- Yu Tai
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Qingtong Wang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Heinrich Korner
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.,Menzies Institute for Medical Research, Hobart, TAS, Australia
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
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17
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Fischer R, Proske M, Duffey M, Stangl H, Martinez GF, Peters N, Kraske A, Straub RH, Bethea JR, Kontermann RE, Pfizenmaier K. Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis. Arthritis Rheumatol 2018; 70:722-735. [PMID: 29342501 DOI: 10.1002/art.40413] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 01/09/2018] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II (TNFRII) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. METHODS A novel mouse TNFRII-selective fusion protein (EHD2-sc-mTNFR2 ) was generated by genetic engineering. Mouse T cells were incubated together with interleukin-2 and/or EHD2-sc-mTNFR2 , and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen-induced arthritis (CIA) were treated with EHD2-sc-mTNFR2 or saline, and the therapeutic effects were monitored and characterized. RESULTS Selective activation of TNFRII was found to expand both CD4+ and CD8+ Treg cells. Moreover, TNFRII activation elevated the number of CD4+CD25+ and CD8+CD25+ Treg cells and increased the number of FoxP3-expressing cells in CD8+, but not CD4+, Treg cells, indicating different mechanisms of TNFRII-induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD2-sc-mTNFR2 led to the expansion of both CD4+ and CD8+ Treg cells in vivo and induced antiinflammatory responses that alleviated arthritis. CONCLUSION Our findings support the use of TNFRII-selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.
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Affiliation(s)
- Roman Fischer
- University of Stuttgart, Stuttgart, Germany.,Drexel University, Philadelphia, Pennsylvania
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18
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Ilan Y, Ben Ya'acov A, Shabbat Y, Gingis-Velitski S, Almon E, Shaaltiel Y. Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis. World J Gastroenterol 2016; 22:8760-8769. [PMID: 27818591 PMCID: PMC5075550 DOI: 10.3748/wjg.v22.i39.8760] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/21/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model. METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant anti-tumor necrosis factor alpha fusion protein (PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS. RESULTS The orally administered non-absorbable PRX-106 was biologically active. Altered distribution of CD4+CD25+FoxP3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+FoxP3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+FoxP3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice. CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.
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19
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Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. Sci Rep 2016; 6:31441. [PMID: 27511630 PMCID: PMC4980610 DOI: 10.1038/srep31441] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/20/2016] [Indexed: 11/08/2022] Open
Abstract
Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
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20
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Abstract
CD8(+) T cells are key players in the body's defence against viral infections and cancer. To date, data on the role of CD8(+) T cells in autoimmune diseases have been scarce, especially when compared with the wealth of research on CD4(+) T cells. However, growing evidence suggests that CD8(+) T-cell homeostasis is impaired in human autoimmune diseases. The contribution of CD8(+) T cells to autoimmune arthritis is indicated by the close association of MHC class I polymorphisms with disease risk, as well as the correlation between CD8(+) T-cell phenotype and disease outcome. The heterogeneous phenotype, resistance to regulation and impaired regulatory function of CD8(+) T cells - especially at the target organ - might contribute to the persistence of autoimmune inflammation. Moreover, newly identified populations of tissue-resident CD8(+) T cells and their interaction with antigen-presenting cells might have a key role in disease pathology. In this Review, we assess the link between CD8(+) T cells, autoimmune arthritis and the basis of their homeostatic changes under inflammatory conditions. Improved insight into CD8(+) T cell-specific pathogenicity will be essential for a better understanding of autoimmune arthritis and the identification of new therapeutic targets.
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21
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König M, Rharbaoui F, Aigner S, Dälken B, Schüttrumpf J. Tregalizumab - A Monoclonal Antibody to Target Regulatory T Cells. Front Immunol 2016; 7:11. [PMID: 26834751 PMCID: PMC4724712 DOI: 10.3389/fimmu.2016.00011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 01/11/2016] [Indexed: 12/18/2022] Open
Abstract
Regulatory T cells (Tregs) represent a subpopulation of CD4+ T cells, which are essential for the maintenance of immunological tolerance. The absence or dysfunction of Tregs can lead to autoimmunity and allergies. The restoration of functional Tregs and/or Treg cell numbers represents a novel and attractive approach for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA). The CD4 cell surface receptor is a target for modulation of T cell function. Monoclonal antibodies (mAbs) against CD4 have previously been tested for the treatment of autoimmune diseases, including RA. Furthermore, in model systems, anti-CD4 antibodies are able to induce tolerance and mediate immunomodulatory effects through a variety of mechanisms. Despite the availability of innovative and effective therapies for RA, many patients still have persistently active disease or experience adverse events that can limit use. A growing body of evidence suggests that Treg modulation could offer a new therapeutic strategy in RA and other autoimmune disorders. Here, we describe tregalizumab (BT-061), which is a novel, non-depleting IgG1 mAb that binds to a unique epitope of CD4. Tregalizumab represents the first humanized anti-CD4 mAb that selectively induces Treg activation.
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22
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Win SJ, Kühl AA, Sparwasser T, Hünig T, Kamradt T. In vivo activation of Treg cells with a CD28 superagonist prevents and ameliorates chronic destructive arthritis in mice. Eur J Immunol 2016; 46:1193-202. [PMID: 26711629 DOI: 10.1002/eji.201546104] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/01/2015] [Accepted: 12/22/2015] [Indexed: 01/29/2023]
Abstract
Although regulatory T (Treg) cells are necessary to prevent autoimmune diseases, including arthritis, whether Treg cells can ameliorate established inflammatory disease is controversial. Using the glucose-6-phosphate isomerase (G6PI)-induced arthritis model in mice, we aimed to determine the therapeutic efficacy of increasing Treg cell number and function during chronic destructive arthritis. Chronic destructive arthritis was induced by transient depletion of Treg cells prior to immunization with G6PI. At different time points after disease induction, mice were treated with a CD28 superagonistic antibody (CD28SA). CD28SA treatment during the induction phase of arthritis ameliorated the acute signs of arthritis and completely prevented the development of chronic destructive arthritis. CD28SA treatment of mice with fully developed arthritis induced a significant reduction in clinical and histological signs of arthritis. When given during the chronic destructive phase of arthritis, 56 days after disease induction, CD28SA treatment resulted in a modest reduction of clinical signs of arthritis and a reduction in histopathological signs of joint inflammation. Our data show that increasing the number and activation of Treg cells by a CD28SA is therapeutically effective in experimental arthritis.
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Affiliation(s)
- Stephanie J Win
- Institute of Immunology, Universitätsklinikum Jena, Jena, Germany
| | - Anja A Kühl
- Department of Medicine 1-Gastroenterology, Infectious Diseases and Rheumatology and Research Centre ImmunoSciences, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Tim Sparwasser
- Institute for Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany
| | - Thomas Hünig
- Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Thomas Kamradt
- Institute of Immunology, Universitätsklinikum Jena, Jena, Germany
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23
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Zhang S, Ke X, Zeng S, Wu M, Lou J, Wu L, Huang P, Huang L, Wang F, Pan S. Analysis of CD8+ Treg cells in patients with ovarian cancer: a possible mechanism for immune impairment. Cell Mol Immunol 2015; 12:580-91. [PMID: 26166762 PMCID: PMC4579658 DOI: 10.1038/cmi.2015.57] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 05/21/2015] [Accepted: 05/22/2015] [Indexed: 01/02/2023] Open
Abstract
Regulatory T (Treg) cells may participate in mediating a suppressive microenvironment that blunts successful anti-tumor immunotherapy. Recent studies show that CD8+ Treg cells might impede effective immune responses to established tumors. However, there is limited research regarding CD8+ Treg cells in ovarian cancer (OC) patients. Here, we investigated CD8+ Treg cells in OC patients and their in vitro induction. The immunohistochemistry of tumor-infiltrating lymphocytes revealed a significant correlation between the intratumoral CD8+ T cells and the forkhead box p3 (Foxp3)+ cells in the intraepithelial and stromal areas of advanced OC tissues. We examined the expression of Treg markers in CD8+ T cells from the peripheral blood and fresh tumor tissues of OC patients using flow cytometry. Our results indicated an increase in the CD8+ Treg cell subsets of OC patients compared with those in patients with benign ovarian tumors and healthy controls, including an increased expression of CD25, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and Foxp3 and decreased CD28 expression. To demonstrate whether the tumor microenvironment could convert CD8+ effector T cells into suppressor cells, we used an in vitro transwell culturing system. Compared with the CD8+ T cells cultured alone, the CD8+ Treg cells induced in vitro by coculture with SK-OV-3/A2780 showed increased CTLA-4 and Foxp3 expression and decreased CD28 expression. In addition, the in vitro-induced CD8+ Treg cells inhibited naïve CD4+ T-cell proliferation, which was partially mediated through TGF-β1 and IFN-γ. Our study suggests that CD8+ Treg cells were increased in OC patients and could be induced in vitro, which may be the way that tumors limit antitumor immunity and evade immune surveillance.
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Affiliation(s)
- Shuping Zhang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Xing Ke
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Suyun Zeng
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.,Department of Obstetrics and Gynecology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Meng Wu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Jianfang Lou
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Lei Wu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Peijun Huang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Lei Huang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Fang Wang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Shiyang Pan
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
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24
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Byng-Maddick R, Ehrenstein MR. The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology (Oxford) 2015; 54:768-75. [PMID: 25667434 DOI: 10.1093/rheumatology/keu487] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Indexed: 12/31/2022] Open
Abstract
Regulatory T cells (Treg) are functionally defective in patients with RA. Restoring their function may not only control inflammation but also restore tolerance in these patients. Biologic therapies have been tremendously successful in treating RA. Here we review numerous reports suggesting that these immunomodulatory therapies have an impact on Treg and that this may contribute to their beneficial effects. Better understanding of their mode of action may not only lead to improvements in therapies and sustained remission but also enable the development of biomarkers of response, which would be the first steps towards personalized medicine.
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25
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26
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Ellis SDP, McGovern JL, van Maurik A, Howe D, Ehrenstein MR, Notley CA. Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86. Arthritis Rheumatol 2014; 66:2694-705. [PMID: 24980778 DOI: 10.1002/art.38761] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 06/24/2014] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Limiting the severity of inflammation and promoting its eventual resolution are vital for protecting host tissues both in autoimmunity and chronic infection. The aim of this study was to determine the suitability of repurposing anti-CD3 monoclonal antibody (mAb) therapy for rheumatoid arthritis (RA) by analyzing its ability to induce CD8+FoxP3+ Treg cells from peripheral blood mononuclear cells (PBMCs). METHODS Anti-CD3 mAb was cultured with RA PBMCs to induce CD8+FoxP3+ Treg cells, which were analyzed by flow cytometry to determine their phenotype. Treg cell induction was investigated via neutralization or blocking antibodies, cellular depletion, or ImageStream technology. Blotting was used to determine the signaling pathways involved in CD8+FoxP3+ Treg cell induction. Suppression of CD4+ T cell effector responses was assessed by Treg cell suppression assays and Mosaic enzyme-linked immunosorbent assay. RESULTS Potent CD8+FoxP3+ Treg cells were induced from RA PBMCs by anti-CD3 mAb. Unlike their CD4+ counterparts, CD8+FoxP3+ Treg cells inhibited Th17 responses in a contact-dependent manner, thereby functioning to limit a wider range of inflammatory pathways. CD8+FoxP3+ Treg cell induction was supported both by p38 phosphorylation intrinsic to naive CD8+ T cells and by monocytes via CD86 and membrane tumor necrosis factor α (TNFα). Artificially increasing monocyte membrane TNFα or inhibiting CD8+ T cell p38 phosphorylation drove FoxP3 expression in a subset of initially unresponsive CD8+ T cells. CONCLUSION These data define an unknown mechanism of CD8+FoxP3+ Treg cell induction by anti-CD3 mAb, which could be combined with a p38 inhibitor to improve therapeutic efficacy in RA patients and resolve chronic inflammation via the restoration of tolerance.
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27
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Fessler J, Felber A, Duftner C, Dejaco C. Therapeutic potential of regulatory T cells in autoimmune disorders. BioDrugs 2014; 27:281-91. [PMID: 23580095 DOI: 10.1007/s40259-013-0026-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Regulatory T cells (Tregs) play a dominant role in the regulation of immune responses. Quantitative and/or qualitative abnormalities of Tregs were observed in patients with autoimmune diseases and therapeutic interventions focusing Tregs are an attractive new target with the potential to cure these disorders. Biological agents approved for treatment of inflammatory rheumatic diseases transiently influence Treg prevalences and function and experimental therapies including novel biological agents, gene therapy, activation and ex vivo expansion of purified Tregs as well as substances influencing tolerogenic dendritic cells will be developed for selective Treg therapy. Although many of these interventions are effective in vitro, in animal models as well as in early clinical trials, significant concerns exist regarding the stability of Treg modifications as well as the long-term safety of Treg-based therapies.
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Affiliation(s)
- Johannes Fessler
- Department of Rheumatology and Immunology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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28
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Havari E, Turner MJ, Campos-Rivera J, Shankara S, Nguyen TH, Roberts B, Siders W, Kaplan JM. Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology 2014; 141:123-31. [PMID: 24116901 DOI: 10.1111/imm.12178] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 09/27/2013] [Accepted: 09/30/2013] [Indexed: 12/20/2022] Open
Abstract
Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon-β in relapsing-remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25(hi) T-cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell-cell contact and interleukin-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Treg cells may play a role in promoting the long-term efficacy of alemtuzumab in patients with multiple sclerosis.
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Affiliation(s)
- Evis Havari
- Neuroimmunology Research, Genzyme, a Sanofi Company, Framingham, MA, USA
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OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis. Proc Natl Acad Sci U S A 2014; 111:2289-94. [PMID: 24469824 DOI: 10.1073/pnas.1321071111] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the "therapeutic window" and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans.
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High-dose cholecalciferol supplementation significantly increases peripheral CD4⁺ Tregs in healthy adults without negatively affecting the frequency of other immune cells. Eur J Nutr 2013; 53:751-9. [PMID: 23999998 DOI: 10.1007/s00394-013-0579-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 08/22/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND Regulatory T cells (Tregs) play a central role in the maintenance of self-tolerance. Animal and in vitro studies suggest that vitamin D is involved in reducing the risk of autoimmunity by modulating Tregs. METHODS In a double-blind, placebo controlled study in 60 healthy volunteers, we assessed the effect of a 12-week high-dose oral cholecalciferol supplementation (140,000 IU/month) on the number and function of CD4(pos)CD25(high)FoxP3(pos)CD127(dim) Tregs. We also assessed the clinical safety of the supplementation and the effect on the frequency of other immune cells such as monocytes, dendritic cells, natural killer cells, natural killer T cells, B cells and subgroups of T cells. We also tested the in vitro effect of cholecalciferol on Tregs in human cell cultures. RESULTS By using FACS analysis, ex vivo suppressive co-cultures and apoptosis assays, we were able to show that a cholecalciferol supplementation leads to significantly increased numbers of peripheral Tregs in vivo. Tregs function and the frequency of other immune cells remained unchanged, and no clinically relevant safety concerns were found. The in vitro exposure of human peripheral blood mononuclear cells to cholecalciferol also supported our in vivo findings. CONCLUSIONS Our results indicate a substantial effect of a supplementation with inactive vitamin D on the immune system of healthy humans in vivo and provide a rationale for future studies to investigate the immunomodulatory effects of vitamin D in autoimmune diseases.
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Dépis F, Hatterer E, Ballet R, Daubeuf B, Cons L, Glatt S, Reith W, Kosco-Vilbois M, Dean Y. Characterization of a surrogate murine antibody to model anti-human CD3 therapies. MAbs 2013; 5:555-64. [PMID: 23751612 DOI: 10.4161/mabs.24736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.
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Wang XJ, Leveson-Gower D, Golab K, Wang LJ, Marek-Trzonkowska N, Krzystyniak A, Wardowska A, Millis JM, Trzonkowski P, Witkowski P. Influence of pharmacological immunomodulatory agents on CD4(+)CD25(high)FoxP3(+) T regulatory cells in humans. Int Immunopharmacol 2013; 16:364-70. [PMID: 23499512 DOI: 10.1016/j.intimp.2013.02.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Accepted: 02/18/2013] [Indexed: 12/24/2022]
Abstract
T regulatory cells (Tregs) play a critical role in the immunologic tolerance to the graft in transplantation. Thus, due to their immunosuppressive capability, ex vivo expanded Tregs may be used as a cellular therapy and an attractive novel strategy to control chronic rejection and eliminate need for lifelong pharmacological immunosuppression. Since Treg therapy is still in its infancy, initially Tregs still need to be applied in combination with pharmacological agents to prevent rejection. Fortunately, some of the medications have been shown to enhance the function and number of Tregs. In the clinic, different immunosuppressive regimens are used for individual patients for different types of organ transplantation. In this review, we present the most commonly used pharmacological agents for immunosuppression and discuss how they affect the Treg population. It is extremely difficult to dissect the effect of single agent on Tregs population in clinical settings since usually the combination of several medications is applied at the same time for graft protection. Nevertheless, experimental and clinical data indicate that thymoglobulin as immunosuppressive induction and mTOR inhibitors as immunosuppressive maintenance agents have the most beneficial effect on Treg population in the blood. Among supplemental agents promoting Tregs, anti-TNFα preparations have been in clinical use (in autoimmune diseases) for many years, so they are optimal candidates for testing in transplant settings in combination with Treg based cellular therapy.
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Affiliation(s)
- Xiao-Jun Wang
- Department of Surgery, Section of Transplantation, University of Chicago, IL 60637, USA
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Carvalheiro H, da Silva JAP, Souto-Carneiro MM. Potential roles for CD8+ T cells in rheumatoid arthritis. Autoimmun Rev 2013; 12:401-9. [DOI: 10.1016/j.autrev.2012.07.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 07/18/2012] [Indexed: 02/06/2023]
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Dépis F, Hatterer E, Lamacchia C, Waldburger JM, Gabay C, Reith W, Kosco-Vilbois M, Dean Y. Long-term amelioration of established collagen-induced arthritis achieved with short-term therapy combining anti-CD3 and anti-tumor necrosis factor treatments. ACTA ACUST UNITED AC 2012; 64:3189-98. [DOI: 10.1002/art.34497] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Moots RJ, Naisbett-Groet B. The efficacy of biologic agents in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors: a systematic review. Rheumatology (Oxford) 2012; 51:2252-61. [PMID: 22942404 DOI: 10.1093/rheumatology/kes217] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE To assess the relative efficacy of subsequent biologic therapies in patients with RA who have had an inadequate response to prior therapy with a TNF-α inhibitor. METHODS A systematic review was conducted using the MEDLINE, Embase and Cochrane Library databases and abstract lists from the European League Against Rheumatism, American College of Rheumatology and British Society of Rheumatology congresses. Searches covered the period from May 2009 (August 2009 for MEDLINE) to January 2011. Therapies considered were abatacept, adalimumab, etanercept, infliximab and rituximab, used at European licensed standard dose regimens. RESULTS Four full publications and 41 congress abstracts met the criteria for inclusion. Significant improvements in RA signs and symptoms were reported for TNF inhibitors (individual agents or groups of agents, depending on the study) and for abatacept and rituximab. Rituximab was also associated with significantly improved radiographic outcomes. No head-to-head randomized controlled trials directly comparing different agents were published during the search period. Comparative data from registries and other observational studies suggest that rituximab is at least as effective as an alternative TNF inhibitor, and in some studies significantly more effective, in TNF inadequate responders. CONCLUSIONS RA patients with an inadequate response to one or more TNF inhibitors derive significant clinical benefit from subsequent therapy with an alternative TNF inhibitor or with rituximab or abatacept. Prospective randomized controlled trials are needed to help physicians in the best choice of further therapy for their patients.
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Affiliation(s)
- Robert J Moots
- Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
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Abstract
Experimental models of rheumatoid arthritis have contributed immensely to our understanding of the pathogenesis as well as the treatment of this debilitating autoimmune disease. Significant progress has been made in the past few years in defining the role of newer cytokines and regulatory T cells, of inflammation-mediated bone and cartilage damage, and of the cholinergic anti-inflammatory pathway in modulating the disease process in arthritis. Furthermore, new therapeutic targets, including specific tyrosine kinases and proteasome subunits, have been explored. These advances offer renewed optimism for continued improvements in the management of rheumatoid arthritis.
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Affiliation(s)
- Kamal D Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Clark AK, Grist J, Al-Kashi A, Perretti M, Malcangio M. Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. ACTA ACUST UNITED AC 2011; 64:2038-47. [PMID: 22213084 DOI: 10.1002/art.34351] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain. METHODS Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization. RESULTS Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA. CONCLUSION The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX(3) CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA.
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Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR. Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels. J Biol Chem 2011; 286:41530-41538. [PMID: 21987572 DOI: 10.1074/jbc.m111.248856] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Protein ubiquitination is a key regulatory process essential to life at a cellular level; significant efforts have been made to identify ubiquitinated proteins through proteomics studies, but the level of success has not reached that of heavily studied post-translational modifications, such as phosphorylation. HRD1, an E3 ubiquitin ligase, has been implicated in rheumatoid arthritis, but no disease-relevant substrates have been identified. To identify these substrates, we have taken both peptide and protein level approaches to enrich for ubiquitinated proteins in the presence and absence of HRD1. At the protein level, a two-step strategy was taken using cells expressing His(6)-tagged ubiquitin, enriching proteins first based on their ubiquitination and second based on the His tag with protein identification by LC-MS/MS. Application of this method resulted in identification and quantification of more than 400 ubiquitinated proteins, a fraction of which were found to be sensitive to HRD1 and were therefore deemed candidate substrates. In a second approach, ubiquitinated peptides were enriched after tryptic digestion by peptide immunoprecipitation using an antibody specific for the diglycine-labeled internal lysine residue indicative of protein ubiquitination, with peptides and ubiquitination sites identified by LC-MS/MS. Peptide immunoprecipitation resulted in identification of over 1800 ubiquitinated peptides on over 900 proteins in each study, with several proteins emerging as sensitive to HRD1 levels. Notably, significant overlap exists between the HRD1 substrates identified by the protein-based and the peptide-based strategies, with clear cross-validation apparent both qualitatively and quantitatively, demonstrating the effectiveness of both strategies and furthering our understanding of HRD1 biology.
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Affiliation(s)
- Kimberly A Lee
- Department of Molecular Sciences, Amgen, Seattle, Washington 98119
| | - Lisa P Hammerle
- Department of Inflammation, Amgen, Seattle, Washington 98119
| | - Paul S Andrews
- Department of Lead Discovery, Amgen, Cambridge, Massachusetts 02142
| | | | - Tomas Mustelin
- Department of Inflammation, Amgen, Seattle, Washington 98119
| | - Jeffrey C Silva
- Cell Signaling Technology Inc., Danvers, Massachusetts 01923
| | - Roy A Black
- Department of Inflammation, Amgen, Seattle, Washington 98119
| | - John R Doedens
- Department of Inflammation, Amgen, Seattle, Washington 98119.
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Wright GP, Stauss HJ, Ehrenstein MR. Therapeutic potential of Tregs to treat rheumatoid arthritis. Semin Immunol 2011; 23:195-201. [PMID: 21880506 DOI: 10.1016/j.smim.2011.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 07/10/2011] [Indexed: 01/12/2023]
Abstract
There is accumulating evidence for regulatory T cell defects in rheumatoid arthritis and that some biologic interventions, in particular anti-TNF, can target this population. Despite the challenges in defining regulatory T cells in patients, there are a number of approaches currently being developed to utilise their potent immunosuppressive properties. Through genetic manipulation Tregs can be generated ex vivo or in vivo that target antigens present in the inflamed joint. Here we discuss these approaches, their refinement to restore tolerance in patients with rheumatoid arthritis, and strategies to prevent their conversion towards a Th17 phenotype.
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Affiliation(s)
- Graham P Wright
- Centre for Rheumatology Research, University College London, Rayne Building, 5 University Street, London WC1E 6JF, United Kingdom.
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Chavele KM, Ehrenstein MR. Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. FEBS Lett 2011; 585:3603-10. [PMID: 21827750 DOI: 10.1016/j.febslet.2011.07.043] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Accepted: 07/28/2011] [Indexed: 12/18/2022]
Abstract
Regulatory T-cells (Tregs) are the guardians of peripheral tolerance acting to prevent autoimmune diseases such as systemic lupus erythomatosus (SLE) and rheumatoid arthritis (RA). Defects in Tregs have been reported in these two diseases despite significant differences in their clinical phenotype and pathogenesis. In both diseases the potency of Treg fails to keep pace with the activation of effector cells and are unable to resist the ensuing inflammation. This review will discuss the phenotypic, numeric, and functional abnormalities in Tregs and their role in patients and murine models of SLE and RA.
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Fleissner D, Frede A, Knott M, Knuschke T, Geffers R, Hansen W, Dobos G, Langhorst J, Buer J, Westendorf AM. Generation and function of immunosuppressive human and murine CD8+ T cells by transforming growth factor-β and retinoic acid. Immunology 2011; 134:82-92. [PMID: 21711349 DOI: 10.1111/j.1365-2567.2011.03469.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The intestinal immune system is constantly challenged by foreign antigens and commensal bacteria. Therefore, proper control of the intestinal microenvironment is required. One important arm of this regulatory network consists of regulatory T cells. In contrast to CD4(+) Foxp3(+) regulatory T cells, which have been well characterized, immunomodulatory CD8(+) T cells that express Foxp3 are less well defined in terms of their generation and function. Failures of these regulatory mechanisms contribute to the development of inflammatory bowel disease. In this study we demonstrate that the frequency of CD8(+) Foxp3(+) T cells is reduced in the peripheral blood of patients with ulcerative colitis. As these cells might play a currently underestimated role in the maintenance of intestinal homeostasis, we have investigated human and murine CD8(+) Foxp3(+) T cells generated by stimulating naive CD8(+) T cells in the presence of transforming growth factor-β and retinoic acid, mediators that are abundantly produced in the intestinal mucosa. These CD8(+) Foxp3(+) fully competent regulatory T cells show strong expression of regulatory molecules CD25, Gpr83 and CTLA-4 and exhibit cell-cell contact-dependent immunosuppressive activity in vitro. Our study illustrates a previously unappreciated critical role of CD8(+) Foxp3(+) T cells in controlling potentially dangerous T cells and in the maintenance of intestinal homeostasis.
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Affiliation(s)
- Diana Fleissner
- Institute of Medical Microbiology, University Hospital, University Duisburg-Essen, Essen
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CTLA-4-Ig therapy diminishes the frequency but enhances the function of Treg cells in patients with rheumatoid arthritis. J Clin Immunol 2011; 31:588-95. [PMID: 21487894 DOI: 10.1007/s10875-011-9527-5] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 03/28/2011] [Indexed: 12/18/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease. Natural T regulatory (nTreg) cells, which constitutively express the CTLA-4 molecule, have an important role in the pathogenesis of autoimmune conditions. Although it has been reported that biological agents are able to modulate the levels or function of Treg lymphocytes, the possible effect of Abatacept (CTLA-4-Ig) therapy on these cells has not been studied in autoimmune conditions. We explored the effect of Abatacept therapy on Treg cells in patients with RA. The number of different subsets of Treg cells was analyzed by flow cytometry in the peripheral blood from 45 patients with RA that were (n = 30) or not (n = 15) under Abatacept therapy as well as in 20 healthy controls. The function of Treg cells was assessed by an assay of inhibition of lymphocyte proliferation. We found that Abatacept therapy was associated with a significant diminution in the levels of CD4+CD25(bright)Foxp3+, and CD4+CTLA-4+ nTreg cells. In contrast, the regulatory function of CD4+CD25+ lymphocytes was significantly enhanced after the administration of Abatacept. Our data suggest that CTLA-4-Ig exerts a complex and interesting effect on Treg cells in patients with RA.
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Mayer CT, Floess S, Baru AM, Lahl K, Huehn J, Sparwasser T. CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity. Eur J Immunol 2011; 41:716-25. [DOI: 10.1002/eji.201040913] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 11/25/2010] [Accepted: 12/21/2010] [Indexed: 12/19/2022]
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Gompels LL, Paleolog EM. A window on disease pathogenesis and potential therapeutic strategies: molecular imaging for arthritis. Arthritis Res Ther 2011; 13:201. [PMID: 21345267 PMCID: PMC3157632 DOI: 10.1186/ar3197] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Novel molecular imaging techniques are at the forefront of both preclinical and clinical imaging strategies. They have significant potential to offer visualisation and quantification of molecular and cellular changes in health and disease. This will help to shed light on pathobiology and underlying disease processes and provide further information about the mechanisms of action of novel therapeutic strategies. This review explores currently available molecular imaging techniques that are available for preclinical studies with a focus on optical imaging techniques and discusses how current and future advances will enable translation into the clinic for patients with arthritis.
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Affiliation(s)
- Luke L Gompels
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College, Charing Cross Hospital Campus, 65 Aspenlea Road, London W68LH, UK.
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Bhatt R, Nelson CC, Douglas RS. Thyroid-associated orbitopathy: Current insights into the pathophysiology, immunology and management. Saudi J Ophthalmol 2011; 25:15-20. [PMID: 23960898 DOI: 10.1016/j.sjopt.2010.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Accepted: 11/01/2010] [Indexed: 01/12/2023] Open
Abstract
Half the patients suffering from Graves' disease develop thyroid-associated orbitopathy (TAO). The severity of TAO varies considerably with a mild form characterized by dry eyes and discomfort to the severe form with sight-threatening exposure keratopathy and optic neuropathy. The pathogenesis and immunologic mechanisms underlying Graves' disease and TAO is unknown, however, advances toward this understanding have indicated a prominent role of orbital fibroblasts, T cells and B cells. These advances have led to novel strategies for clinical treatment using immunomodulatory modalities. Initial results included use of infliximab and etanercept (anti-TNF agents), but currently there is an increasing interest in anti-B cell (Rituximab) therapy. Rituximab has shown promising results in progressive, sight-threatening TAO. It has also shown encouraging results in halting or slowing the disease process in patients unresponsive to corticosteroids. The primary advantage of these immunomodulatory agents is based upon targeting the molecular mediators of the disease and avoiding the potential side effects of non-specific therapies.
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Affiliation(s)
- Rina Bhatt
- Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
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Notley CA, Ehrenstein MR. The yin and yang of regulatory T cells and inflammation in RA. Nat Rev Rheumatol 2010; 6:572-7. [PMID: 20808295 DOI: 10.1038/nrrheum.2010.143] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by chronic inflammation leading to joint destruction. Regulatory T (T(REG)) cells are potent suppressors of autoimmunity, but are not capable of controlling every aspect of the inflammatory reaction. We have found that T(REG)-cell function is abnormal in patients with RA, and that a distinct population of T(REG) cells with potent suppressive properties is induced after therapy with inhibitors of tumor necrosis factor. In this Review, we discuss the mutual interactions between the opposing forces of T(REG) cells and inflammation in the context of RA. Therapeutic approaches that enhance T(REG)-cell function whilst controlling inflammation are likely to be the most effective strategies for restoring immune tolerance in patients with this disease.
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Affiliation(s)
- Clare A Notley
- Centre for Rheumatology Research, Windeyer Institute of Medical Science, University College London, London W1P 4JF, UK
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Wu HY, Maron R, Tukpah AM, Weiner HL. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. THE JOURNAL OF IMMUNOLOGY 2010; 185:3401-7. [PMID: 20720210 DOI: 10.4049/jimmunol.1000836] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Mucosal (nasal or oral) administration of anti-CD3 mAb is effective in ameliorating animal models of autoimmunity (experimental autoimmune encephalomyelitis, diabetes, and lupus) by inducing LAP(+) regulatory T cells. We tested this approach in an arthritis model using type II collagen. We found that nasal anti-CD3 was more effective than oral anti-CD3 in attenuating the development of arthritis. Nasal anti-CD3 induced a LAP(+) regulatory T cell that secreted high levels of IL-10 and suppressed collagen-specific T cell proliferation and anti-collagen Ab production. However, neither nasal nor oral anti-CD3 attenuated disease when given to animals with ongoing arthritis, and this was associated with a lack of induction of LAP(+) regulatory T cells. We found, however, that coadministration of a novel emulsome adjuvant, which enhances Th2 responses, resulted in the induction of LAP(+) regulatory T cells and suppression of ongoing arthritis by both nasal and oral anti-CD3. Suppression of arthritis by mucosal anti-CD3 was associated with less joint damage, a decrease of TNF-alpha and IFN-gamma mRNA expression in joints, and a reduction in anti-collagen Abs. These results demonstrate that mucosal anti-CD3 therapy may serve as a therapeutic approach in arthritis and that the biologic effect is enhanced by an emulsome-based adjuvant.
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Affiliation(s)
- Henry Yim Wu
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
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Matsumura M, Takasu N, Nagata M, Nakamura K, Kawai M, Yoshino S. Effect of ultrafine zinc oxide (ZnO) nanoparticles on induction of oral tolerance in mice. J Immunotoxicol 2010; 7:232-7. [DOI: 10.3109/1547691x.2010.487879] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Kosloski LM, Ha DM, Hutter JAL, Stone DK, Pichler MR, Reynolds AD, Gendelman HE, Mosley RL. Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem 2010; 114:1261-76. [PMID: 20524958 DOI: 10.1111/j.1471-4159.2010.06834.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Neurodegenerative diseases, notably Alzheimer's and Parkinson's diseases, are amongst the most devastating disorders afflicting the elderly. Currently, no curative treatments or treatments that interdict disease progression exist. Over the past decade, immunization strategies have been proposed to combat disease progression. Such strategies induce humoral immune responses against misfolded protein aggregates to facilitate their clearance. Robust adaptive immunity against misfolded proteins, however, accelerates disease progression, precipitated by induced effector T cell responses that lead to encephalitis and neuronal death. Since then, mechanisms that attenuate such adaptive neurotoxic immune responses have been sought. We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This review summarizes advances in immune regulation to achieve a homeostatic glial response for therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are also discussed.
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Affiliation(s)
- Lisa M Kosloski
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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