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rheumatoid arthritis, regulatory t cell

Joachim R Kalden
Diverse strategies to develop novel treatments for rheumatoid arthritis which specifically target those patients who do not respond to available medications, including biologics, are currently being explored. New potential therapeutic approaches which may become available as part of standard therapeutic regimens include the propagation of regulatory T cells and-in the future-of regulatory B cells. New biologic disease-modifying antirheumatic drugs (b-DMARDs) against interleukin-17 and -6, granulocyte-macrophage colony-stimulating factor, and complement component 5 are now standard components of clinical treatment programs...
June 2016: Rheumatol Ther
Endy Adnan, Takuya Matsumoto, Jun Ishizaki, Sachiko Onishi, Koichiro Suemori, Masaki Yasukawa, Hitoshi Hasegawa
Tolerogenic dendritic cells (tDCs) are a promising therapeutic tool for specific induction of immunological tolerance. Human tDCs can be generated ex vivo using various compounds. However, the compound(s) most suitable for clinical application remain undefined. We compared the tolerogenic properties of tDCs treated with protein kinase C inhibitor (PKCI), dexamethasone, vitamin D3 (Vit D3), rapamycin (Rapa), interleukin (IL)-10, transforming growth factor (TGF)-β, and a combination of peroxisome proliferator-activated receptor γ agonist and retinoic acid...
September 19, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Tamara H Ramwadhdoebe, Janine Hähnlein, Karen I Maijer, Leonard J van Boven, Danielle M Gerlag, Paul P Tak, Lisa G M van Baarsen
The balance between proinflammatory and regulatory CD4(+) T cells is tightly controlled in lymphoid organs. In autoimmune diseases this balance is altered in the periphery and target tissue of patients. However, not much is known about the balance initiated in lymphoid organs during the development of disease. Since systemic autoimmunity is present years before the clinical manifestations of rheumatoid arthritis (RA), it is possible to study the immunoregulatory balance during the earliest (preclinical) phases of disease...
September 20, 2016: European Journal of Immunology
Yu-Ling Wang, Ju-Mei Gao, Li-Zhi Xing
Excessive inflammation contributes greatly to the pathogenesis and development of rheumatoid arthritis (RA). Oroxylin A (OA) is a natural anti-inflammatory flavonoid compound. In this study, we investigated the effects of OA on collagen-induced arthritis (CIA) and human RA fibroblast-like synoviocytes (FLS). CIA was induced in DBA/1 mice and mice were intraperitoneally treated with OA (10mg/kg) for 10days. Arthritis severity was evaluated every day and the histopathologic examination of joints was done. Serum levels of anti-collagen II antibodies (anti-CII Abs) and cytokines were determined by ELISA...
September 16, 2016: International Immunopharmacology
Takayoshi Morita, Yoshihito Shima, James Badger Wing, Shimon Sakaguchi, Atsushi Ogata, Atsushi Kumanogoh
BACKGROUND: Regulatory T cells (Tregs) have important functions in peripheral immune tolerance. Dysfunction of Tregs is considered to be a pivotal cause of autoimmune diseases, including rheumatoid arthritis (RA). However, previous reports describing the proportion of Tregs among CD4+ T cells in RA patients were controversial because a range of markers are used to identify Tregs with little consensus. To clarify the status of Tregs in RA, we investigated the proportion of Tregs with focusing on the definitions of them...
2016: PloS One
Sheikh Fayaz Ahmad, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M A Zoheir, Saleh A Bakheet, Othman A Al-Shabanah, Ammar Cherkess Al Rikabi, Sabry M Attia
Protein tyrosine kinases are key mediators of the signal transduction cascades that control expression of many genes involved in the induction of inflammation caused by arthritis. Here we investigate the effect of the tyrosine kinase inhibitor tyrphostin AG126 on a mouse model of adjuvant-induced arthritis (AIA). We report that when given at 5mg/kg i.p. every 48h from days 0-21, AG126 exerts potent anti-arthritic effects. Further, we investigated the role of AG126 on the key mediators of arthritic inflammation, namely, edema, arthritic score, presence of immunophenotypes including Foxp3(+), CD4(+)Foxp3(+), and CD25(+)Foxp3(+) T regulatory (Treg) cells, as well as pro- and anti-inflammatory mediators...
October 2016: Molecular Immunology
Mitali Bidkar, Robert Vassallo, David Luckey, Michele Smart, Kelly Mouapi, Veena Taneja
Rheumatoid arthritis (RA) is an autoimmune disease marked by chronic synovial inflammation and both, genetic and environmental factors are involved in its pathogenesis. Human leukocyte antigen (HLA) DRB1*0401 is associated with susceptibility to develop RA, while cigarette smoke (CS) exposure promotes seropositive disease with increased severity in DRB1*0401+ individuals. Smokers have higher levels of antibodies against citrullinated peptides. In this study, we determined whether the response to a known autoantigen, Vimentin (Vim) is shared epitope specific and how CS influences this response using transgenic-mice carrying RA-susceptible,*0401, and -resistant, *0402, genes...
2016: PloS One
Dmitry Tyrsin, Sergey Chuvpilo, Alexey Matskevich, Daniil Nemenov, Paula S Römer, Paula Tabares, Thomas Hünig
CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study...
July 2016: Clinical and Experimental Rheumatology
Koen M J Janssen, Johanna Westra, Paulina Chalan, Annemieke M H Boots, Menke J de Smit, Arie Jan van Winkelhoff, Arjan Vissink, Elisabeth Brouwer
OBJECTIVE: Seropositive arthralgia patients (SAP) are at high risk of developing rheumatoid arthritis (RA). This prospective study aimed to determine whether altered peripheral regulatory T-cells (Tregs) and defined subsets, besides a broadened anti-citrullinated protein antibody (ACPA) response, may qualify as biomarkers for RA development in SAP. METHODS: Thirty-four consecutive SAP were prospectively assessed every 6 months for minimally 2 years. At inclusion, peripheral Treg (CD4+CD25+FoxP3+) numbers and subsets, defined as CD45RA+FoxP3low naive Tregs (Fr I), CD45RA-FoxP3high activated Tregs (Fr II) and CD45RA-FoxP3low non-Tregs (Fr III), were compared to age- and sex-matched healthy controls (HC, n = 16) and treatment-naive RA patients (n = 12)...
2016: PloS One
Xiaoyin Niu, Shaohua Deng, Shan Li, Yebin Xi, Chengzhen Li, Li Wang, Dongyi He, Zhaojun Wang, Guangjie Chen
Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th)1, Th17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it's necessary to find a truly effective and convenient treatment. Several studies intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find the potential ergotope peptides and investigate its effect in treating the animal model of RA and their underlying regulatory mechanisms...
August 30, 2016: Molecular Medicine
Margherita Sisto, Loredana Lorusso, Sabrina Lisi
IL-15 is a key regulatory cytokine that shares many biological properties with IL-2. Recently, it has been shown that IL-15 could be up-regulated in T cell-mediated inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases. However, the role and expression of IL-15 in the inflammatory autoimmune disease Sjögren's syndrome (SS) has not been investigated. In the present study we evaluated the expression of IL-15 mRNA and protein in minor salivary gland (MSG) biopsy specimens and in human salivary gland epithelial cell (SGEC) cultures obtained from patients with primary SS (pSS) and compared their expression with that seen in normal healthy control subjects...
October 2016: Pathology
P N Kravchenko, G A Zhulai, A V Churov, E K Oleinik, V M Oleinik, O Yu Barysheva, N N Vezikova, I M Marusenko
BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory rheumatic disease associated with a dysfunction of the T cell-mediated tolerance and leading to the disability of working population. The regulatory CD4' T cells play an important role in the regulation of autoimmunity and can suppress immune responses. With that, there is no consensus on the content of these lymphocytes and their role in the pathogenesis of RA. Objective: The aim of the study was to assess the content ofperipheral blood regulatory Tcells (Treg) according to the expression of membrane markers CD4, CD25, CD127 and intracellular FOXP3 marker, as well as the expression of two functional molecules (CTLA-4 and CCR4) in Treg cells of patients with RA...
2016: Vestnik Rossiĭskoĭ Akademii Meditsinskikh Nauk
Francis Bonnefoy, Anna Daoui, Séverine Valmary-Degano, Eric Toussirot, Philippe Saas, Sylvain Perruche
BACKGROUND: Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy. METHODS: The effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen...
2016: Arthritis Research & Therapy
Ting Wang, Shufeng Li, Yun Yang, Kaining Zhang, Shixiao Dong, Xiuhua Wang, Xinguang Liu, Yanjun Ren, Ming Zhang, Xinfeng Yan, Jianmin Li, Lei Zhang
OBJECTIVES: The present study is to investigate the profiles of Th17, Th1 and Treg cells in bone marrow of patients with rheumatoid arthritis (RA). METHODS: Flow cytometry was used to analyze the frequencies of Th17, Th1 and Treg cells in paired peripheral blood and bone marrow of 26 RA patients and 11 osteoarthritis (OA) patients, as well as 10 healthy controls. In addition, the disease activity was analyzed by the 28-joint disease activity score (DAS28). RESULTS: The frequencies of Th17 and Th1 cells were significantly elevated in bone marrow of RA patients...
2016: American Journal of Translational Research
Bruce Kirkham, Khaldoun Chaabo, Christopher Hall, Toby Garrood, Timothy Mant, Elizabeth Allen, Alexandra Vincent, Joana C Vasconcelos, Andrew T Prevost, Gabriel S Panayi, Valerie M Corrigall
OBJECTIVES: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. METHODS: Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg...
August 7, 2016: Rheumatology
Jérôme Biton, Sara Khaleghparast Athari, Allan Thiolat, François Santinon, Delphine Lemeiter, Roxane Hervé, Laure Delavallée, Anais Levescot, Stéphane Roga, Patrice Decker, Jean-Philippe Girard, André Herbelin, Marie-Christophe Boissier, Natacha Bessis
IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Xiao-Qin Wang, Yan Liu, Huan-Huan Cai, Yu-Ping Peng, Yi-Hua Qiu
Tyrosine hydroxylase (TH), a rate-limiting enzyme for the synthesis of catecholamines, is expressed in T lymphocytes. However, the role of T cell-expressed TH in rheumatoid arthritis (RA) is less clear. Herein, we aimed to show the contribution of TH expression by CD4(+) T cells to alleviation of helper T (Th)17/regulatory T (Treg) imbalance in collagen-induced arthritis (CIA), a mouse model of RA. CIA was prepared by intradermal injection of collagen type II (CII) at tail base of DBA1/J mice. Expression of TH in the spleen and the ankle joints was measured by real-time polymerase chain reaction and Western blot analysis...
July 20, 2016: Experimental Biology and Medicine
I Nagaev, M Andersen, M K Olesen, O Nagaeva, J Wikberg, L Mincheva-Nilsson, G N Andersen
Rheumatoid arthritis (RA) is caused by complex interactions between immune cells and sustained by Th1 response cytokines. Resistin [resistance to insulin; (RETN)] is an inflammatory cytokine, first discovered in murine adipocytes. In man, RETN is mainly secreted by monocytes. The distinct role of RETN in the immune reaction is uncertain; however, RETN has pro-inflammatory, pro-fibrotic and possibly tolerogenic properties. The aim was to assess the reaction of RETN gene expression to TNF-α inhibition (I) in pathogenetic immune cell subsets in RA, in the context of Th1, inflammatory and regulatory cytokine gene expressions...
October 2016: Scandinavian Journal of Immunology
Yoshifumi Tada, Nobuyuki Ono, Rie Suematsu, Satoko Tashiro, Yuri Sadanaga, Yukiko Tokuda, Yukihide Ono, Yoshinobu Nakao, Akihito Maruyama, Akihide Ohta, Syuichi Koarada
BACKGROUND: The balance between Th17 cells and regulatory T (Treg) cells has been shown to play an important role in the development of rheumatoid arthritis (RA). Recent studies have shown that treatment with abatacept (ABT) or tocilizumab (TCZ) affects Th17 and Treg cell populations. Although not unanimously accepted, several reports have shown that Treg cells are decreased by ABT and increased by TCZ, and that Th17 cells are decreased by TCZ. To further investigate the effects of ABT and TCZ on the skewing of T cell populations, we analyzed the expression of master regulators genes of helper T cell lineages following ABT/TCZ treatment of RA patients...
July 16, 2016: BMC Musculoskeletal Disorders
Huihui Xu, Hongyan Zhao, Cheng Lu, Qi Qiu, Gui Wang, Jing Huang, Minghui Guo, Baosheng Guo, Yong Tan, Cheng Xiao
Triptolide, a purified component of Tripterygiumwilfordii Hook F, has been shown to have immunosuppressive and anti-inflammatory properties in rheumatoid arthritis (RA). Although triptolide has demonstrated that it could suppress bone destruction in collagen-induced mice, its therapeutic mechanism remains unclear. Many studies have investigated the effect of triptolide on Tregs and Tregs-related cytokine involved in RA. Additionally, previous studies have implied that Tregs inhibit osteoclast differentiation and bone resorption...
2016: Mediators of Inflammation
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