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arthritis and CTLA-4

Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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
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
Noriko Komatsu
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by inflammation and bone destruction in the joints. Abnormal activation of the immune system leads to RANKL-dependent osteoclast differentiation, which ultimately results in bone destruction in RA. A newly identified Th17 subset induces osteoclastogenesis potently by upregulating RANKL on synovial fibroblasts, indicating a synergy between T-synovial fibroblast plays a primary role in the bone destruction. Immune-regulating factors, such as CTLA-4 highly expressed on regulatory T cells, are identified as new bone-regulating factors and can be attractive therapeutic targets for bone destruction in RA...
June 2016: Nihon Rinsho. Japanese Journal of Clinical Medicine
Laura C Cappelli, Anna Kristina Gutierrez, Alan N Baer, Jemima Albayda, Rebecca L Manno, Uzma Haque, Evan J Lipson, Karen B Bleich, Ami A Shah, Jarushka Naidoo, Julie R Brahmer, Dung Le, Clifton O Bingham
OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours...
June 15, 2016: Annals of the Rheumatic Diseases
Rossella Talotta, Fabiola Atzeni, Piercarlo Sarzi Puttini
BACKGROUND: Abatacept (ABA) is a fusion receptor protein containing the CTLA-4 domain that prevents the activation of naïve T cells by binding the CD80 and CD86 molecules expressed on the surface of dendritic cells, indicated for the treatment of moderate to severe rheumatoid arthritis (RA). There is still little evidence concerning the safety of ABA in RA patients with positive serology for hepatitis virus B (HBV) infection. CASE PRESENTATION: We report the case of a HBV infection reactivation in an ABA-treated male RA patient...
2016: BMC Pharmacology & Toxicology
Katrin Klocke, Shimon Sakaguchi, Rikard Holmdahl, Kajsa Wing
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies...
April 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Maurizio Cutolo, Alberto Sulli, Sabrina Paolino, Carmen Pizzorni
Rheumatoid arthritis (RA) is characterized by chronic joint inflammation as well as by extra-articular involvement. The immunopathology of RA is polygenic and involves different cell populations. Patients with an inadequate response to non-biologic disease- modifying antirheumatic drugs (DMARDs) should integrate their therapy with biologic DMARDs. Biologic DMARDs can target several inflammatory cytokines, or CD20+ B cells, or can modulate T-cell co-stimulation and activation. The cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig: abatacept) that selectively modulates the CD28:CD80/86 co-stimulation signal appears a biologic DMARD interacting with T cells but also with other cell populations involved in RA pathophysiology...
2016: Expert Review of Clinical Immunology
Noriko Komatsu, Hiroshi Takayanagi
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by inflammation and subsequent bone destruction in multiple joints. In mice, depletion of regulatory T (Treg) cells results in the onset of a variety of autoimmune diseases including arthritis, while replenishment of Treg cells alleviates arthritic symptoms. The importance of Treg cells in RA is supported by the effectiveness of CTLA4-Ig therapy, an increased Treg cell/effector T cell ratio after anti-IL-6R or anti-TNF-α treatment and the identification of CTLA-4 as an RA-associated gene...
2015: Progress in Molecular Biology and Translational Science
Anna Laura Fedele, Stefano Alivernini, Elisa Gremese, Gianfranco Ferraccioli
We describe a patient suffering from seropositive rheumatoid arthritis (RA) and type I diabetes mellitus (T1DM), who achieved a good EULAR response together with an improvement of the glycemic profile under treatment with CTLA-4 Ig. A close association is known to exist between T1DM and RA, and CTLA-4 exon 1 polymorphism has been associated to RA with coexisting autoimmune endocrinopathies. The possible common genetic background and the potential role of CTLA-4 Ig in the early phases of T1DM, could be considered in the therapeutic interventions in RA patients with type 1 diabetes...
March 2016: Clinical and Experimental Rheumatology
M P M Vierboom, E Breedveld, Y S Kap, C Mary, N Poirier, B A 't Hart, B Vanhove
T cells have a central pathogenic role in the aetiopathogenesis of rheumatoid arthritis (RA), and are therefore a favoured target of immunotherapy aiming at physical or functional elimination. Here we report an efficacy test of FR104, a new co-stimulation inhibitor directly targeting CD28 on T cells, in a translationally relevant model, the rhesus monkey model of collagen-induced arthritis (CIA). As a relevant comparator we used abatacept [cytotoxic T lymphocyte antigen immunoglobulin (CTLA Ig)], an antagonist of CTLA-4 binding to CD80/86 clinically approved for treatment of RA...
March 2016: Clinical and Experimental Immunology
Diahann T S L Jansen, Hanane el Bannoudi, Ramon Arens, Kim L L Habets, Marjolijn Hameetman, Tom W J Huizinga, Jeroen N Stoop, René E M Toes
INTRODUCTION: Abatacept is a fusion protein of human cytotoxic T-lymphocyte-associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28-B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 molecules is crucial for activation of naive cells, whereas it is unclear whether the action of already activated CD4(+) T cells, which are readily present in established disease, also depends on this interaction...
2015: Arthritis Research & Therapy
David H Gardner, Louisa E Jeffery, Blagoje Soskic, Zoe Briggs, Tie Zheng Hou, Karim Raza, David M Sansom
Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell-mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity...
September 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Lei Zhang, Hui Liang, Hui Guan, Hualin Liu
The aim of the present study was to investigate the immune function of children with juvenile idiopathic arthritis (JIA). Flow cytometry and three-color direct immunofluorescence were used to examine cluster of differentiation (CD)3(+) T-lymphocyte subsets and CD28/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in whole blood (using the no-wash method) from 36 children with JIA and 39 healthy children. During the active phase of JIA, CD28 expression on CD4(+) T cells in children with JIA was significantly reduced; thus, CD4(+)CD28(-) T-cell frequency increased, suggesting that CD4(+) T-cell and CD4(+)CD28(-) T-cell apoptosis was inhibited in patients with JIA...
May 2015: Experimental and Therapeutic Medicine
Sharee A Basdeo, Barry Moran, Deborah Cluxton, Mary Canavan, Jennifer McCormick, Mary Connolly, Carl Orr, Kingston H G Mills, Douglas J Veale, Ursula Fearon, Jean M Fletcher
In autoimmune diseases such as rheumatoid arthritis (RA), regulatory T cells (Tregs) fail to constrain autoimmune inflammation; however, the reasons for this are unclear. We investigated T cell regulation in the RA joint. Tregs from RA synovial fluid suppressed autologous responder T cells; however, when compared with Tregs from healthy control peripheral blood, they were significantly less suppressive. Despite their reduced suppressive activity, Tregs in the RA joint were highly proliferative and expressed FOXP3, CD39, and CTLA-4, which are markers of functional Tregs...
July 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Karin M E Andersson, Nicola Filluelo Cavallini, Dan Hu, Mikael Brisslert, Ron Cialic, Hadi Valadi, Malin C Erlandsson, Sofia Silfverswärd, Rille Pullerits, Vijay K Kuchroo, Howard L Weiner, Maria I Bokarewa
T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing...
2015: Molecular Medicine
Young Ho Lee, Sang-Cheol Bae, Gwan Gyu Song
OBJECTIVE: We explored whether cytotoxic T lymphocyte antigen-4 (CTLA-4) rs5742909, CD226 rs763361, FAS rs1800682, and FASL rs763110 polymorphisms are associated with rheumatoid arthritis (RA). METHODS: We performed a meta-analysis on the association between the four gene polymorphisms and RA. RESULTS: Nineteen studies were included in the meta-analysis. Meta-analysis of all study subjects showed no association between RA and the CTLA-4 rs5742909 T allele (OR=1...
March 2015: Human Immunology
Stefanie Meister, Robby Engelmann, Christian Kneitz, Brigitte Müller-Hilke
The inhibitory FcγRIIB plays an important role for the peripheral B cell tolerance and plasma cell homeostasis, and any malfunctioning is predicted to result in humoral autoimmunity. An association between rheumatoid arthritis (RA) and FCGR2B promoter and TM region variant alleles, both of which result in a reduced functionality, is only insufficiently elucidated. We here set out to investigate the impact of these variants on disease progression in European RA patients. One hundred and five ACPA-positive RA patients were genotyped for the FCGR2B -386G>C promoter and the 695T>C transmembrane region variants...
August 2015: Rheumatology International
Lingling Zhang, Jingjing Fu, Kangliang Sheng, Ying Li, Shanshan Song, Peipei Li, Shasha Song, Qingtong Wang, Jingyu Chen, Jianhua Yu, Wei Wei
Tolerogenic dendritic cells (DCs) are well-known to show an immunosuppressive function. In this study we determine the therapeutic effects and potential mechanisms of transferred bone marrow (BM) CD11b(+)F4/80(+) DCs on collagen-induced arthritis (CIA) in mice. Murine BM CD11b(+)F4/80(+) DCs were generated under the stimulation of GM-CSF and IL-4, and the function of BM CD11b(+) F4/80(+) DCs was identified by measuring the levels of IL-10, TGF-beta and indoleamine 2,3-dioxygenase (IDO). BM CD11b(+)F4/80(+) DCs were transferred to CIA mice by intravenous injections...
March 2015: International Immunopharmacology
Adam P Cribbs, Alan Kennedy, Henry Penn, Parisa Amjadi, Patricia Green, Jordan E Read, Fionula Brennan, Bernard Gregory, Richard O Williams
OBJECTIVE: We have previously shown, in a cohort of untreated rheumatoid arthritis (RA) patients, that the suppressive function of Treg cells is defective. However, other studies in cohorts of patients with established RA have shown that Treg cell function is normal. We hypothesized that treatment may restore Treg cell function and lead to reduced disease activity. The aim of this study was to investigate whether treatment with methotrexate (MTX) can result in epigenetic changes that lead to restoration of the Treg cell suppressive function in RA...
May 2015: Arthritis & Rheumatology
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