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arthritis and CTLA-4

Ke Wang, Qin Zhu, Yunjie Lu, Hao Lu, Feng Zhang, Xuehao Wang, Ye Fan
BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a pivotal role in immune homeostasis. Dysregulated expression of CTLA-4 leads to many autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes (T1D). There has been a controversial association between the CTLA-4 +49 G/A SNP (rs231775) and autoimmune diseases. Therefore, this meta-analysis was performed to assess the link between rs231775 and autoimmune disease risk. MATERIALS AND METHODS: We retrieved the available studies from PUBMED and EMBASE through February, 2016 and then performed meta-analyses that included all populations, as well as by ethnicity...
April 2017: Genetic Testing and Molecular Biomarkers
Johannes Fessler, Andrea Raicht, Rusmir Husic, Anja Ficjan, Christine Schwarz, Christina Duftner, Wolfgang Schwinger, Winfried B Graninger, Martin H Stradner, Christian Dejaco
OBJECTIVE: Premature senescence of lymphocytes is a hallmark of inflammatory rheumatic diseases such as rheumatoid arthritis (RA). Early T-cell aging affects conventional T-cells but is presumably not limited to this cell population; rather it might also occur in the regulatory T-cells (Tregs) compartment. In RA, Tregs fail to halt aberrant immune reactions and disease progression. Whether this is associated with early Treg senescence leading to phenotypic and functional changes of this subset is elusive so far...
2017: Frontiers in Immunology
Heather L MacGregor, Pamela S Ohashi
With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment anti-tumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies...
March 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Katarzyna Luterek-Puszyńska, Damian Malinowski, Agnieszka Paradowska-Gorycka, Krzysztof Safranow, Andrzej Pawlik
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction caused by infiltrating leukocytes including T cells. An important role in T cell co-stimulation is played by the CD28, as a stimulatory signal transducer and the inhibitory CTLA-4. CCL5 is produced by circulating T cells and plays an active role in the chemotactic activity of T cells in RA. The aim of this study was to examine the associations between polymorphisms within CD28, CTLA-4, and CCL5 genes and RA. We examined 422 patients (340 female, 82 male, mean age 57...
December 17, 2016: Clinical Rheumatology
R E Schiotis, A D Buzoianu, D F Mureșanu, S Suciu
Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania...
July 2016: Journal of Medicine and Life
Chun-Feng Ren, Ya-Xin Zhao, Chun-Feng Hou, Luan Luan, Guo-Qing Duan, Shu-Jie Li, Jian-Hong Zhao
The present study aimed to investigate the role of the soluble programmed death‑1 (sPD-1) protein, which is released by peripheral blood regulatory T cells (Treg) during the progression of rheumatoid arthritis (RA). From October 2012 to May 2014, 82 RA patients (RA group) and 90 healthy volunteers (healthy controls; HC) were recruited. Cluster of differentiation (CD)4, CD25 and forkhead/winged helix transcription factor p3 (Foxp3) and expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and Foxp3 were detected by flow cytometry...
January 2017: Molecular Medicine Reports
Vanessa Carregaro, Marcelo H Napimoga, Raphael S Peres, Luciana Benevides, Laís Amorim Sacramento, Larissa G Pinto, Renata Grespan, Thiago M Cunha, João Santana da Silva, Fernando Q Cunha
The prostaglandin, 15-deoxy Δ(12,14)-prostaglandin J2 (15d-PGJ2), is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA) is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines...
2016: Mediators of Inflammation
Shaimaa A Fattah, Maivel H Ghattas, Samy M Saleh, Dina M Abo-Elmatty
CONTEXT: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a CD28-family receptor expressed on T-cells which suppresses T cell proliferation. CTLA-4 -318C/T polymorphism is involved in regulation of CTLA-4 expression. OBJECTIVE: The study aimed to investigate the genetic association of CTLA-4 -318C/T polymorphism with rheumatoid arthritis (RA) and the activity and severity of the disease in the Egyptian population. METHODS: A single nucleotide polymorphism (rs5742909) in CTLA-4 was genotyped in 100 RA patients and 100 healthy controls using polymerase chain reaction-restriction fragment length polymorphism...
February 2017: Archives of Physiology and Biochemistry
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...
January 2017: 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...
April 21, 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
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