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      Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis

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          Abstract

          Objectives

          Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages.

          Methods

          First, we undertook to examine whether the folate receptor beta (FR-β) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-β monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis.

          Results

          Human tissue samples of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-β, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-β accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-β-positive macrophages upon treatment with an anti-FR-β monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions.

          Conclusions

          These data suggest that specific elimination of FR-β-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-β monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages.

          Electronic supplementary material

          The online version of this article (10.1186/s13075-019-1912-0) contains supplementary material, which is available to authorized users.

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          Most cited references33

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          Macrophages in inflammation.

          The inflammatory process is usually tightly regulated, involving both signals that initiate and maintain inflammation and signals that shut the process down. An imbalance between the two signals leaves inflammation unchecked, resulting in cellular and tissue damage. Macrophages are a major component of the mononuclear phagocyte system that consists of closely related cells of bone marrow origin, including blood monocytes, and tissue macrophages. From the blood, monocytes migrate into various tissues and transform macrophages. In inflammation, macrophages have three major function; antigen presentation, phagocytosis, and immunomodulation through production of various cytokines and growth factors. Macrophages play a critical role in the initiation, maintenance, and resolution of inflammation. They are activated and deactivated in the inflammatory process. Activation signals include cytokines (interferon gamma, granulocyte-monocyte colony stimulating factor, and tumor necrosis factor alpha), bacterial lipopolysaccharide, extracellular matrix proteins, and other chemical mediators. Inhibition of inflammation by removal or deactivation of mediators and inflammatory effector cells permits the host to repair damages tissues. Activated macrophages are deactivated by anti-inflammatory cytokines (interleukin 10 and transforming growth factor beta) and cytokine antagonists that are mainly produced by macrophages. Macrophages participate in the autoregulatory loop in the inflammatory process. Because macrophages produce a wide range of biologically active molecules participated in both beneficial and detrimental outcomes in inflammation, therapeutic interventions targeted macrophages and their products may open new avenues for controlling inflammatory diseases.
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            Updated Projected Prevalence of Self-Reported Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation Among US Adults, 2015-2040.

            To update the projected prevalence of arthritis and arthritis-attributable activity limitations among US adults, using a newer baseline for estimates.
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              Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity

              Macrophages and neutrophils are key components involved in the regulation of numerous chronic inflammatory diseases, infectious disorders, and especially certain autoimmune disease. However, little is known regarding the contribution of these cells to the pathogenesis of autoimmune disorders. Recent studies have aimed to clarify certain important factors affecting the immunogenicity of these cells, including the type and dose of antigen, the microenvironment of the cell-antigen encounter, and the number, subset, and phenotype of these cells, which can prevent or induce autoimmune responses. This review highlights the role of macrophage subsets and neutrophils in injured tissues, supporting their cooperation during the pathogenesis of certain autoimmune diseases.
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                Author and article information

                Contributors
                765-494-5272 , plow@purdue.edu
                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                7 June 2019
                7 June 2019
                2019
                : 21
                : 143
                Affiliations
                [1 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Department of Chemistry, , Purdue University, ; 560 Oval Drive, West Lafayette, IN 47907 USA
                [2 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Institute for Drug Discovery, , Purdue University, ; West Lafayette, IN 47907 USA
                [3 ]Department of Pathology and Cardiac Surgery, ACS, Amsterdam UMC, location VUMC, Amsterdam, The Netherlands
                [4 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Division of Rheumatology, and Department of Health Sciences Research, , Mayo Clinic, ; Rochester, MN USA
                [5 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Biochemistry and Molecular Biology, , Mayo Clinic College of Medicine, ; Rochester, MN USA
                [6 ]Justus-Liebig University Giessen, Department of Internal Medicine, Biomedizinisches Forschungszentrum Seltersberg, Giessen, Germany
                [7 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, , VU University Medical Center, ; Amsterdam, The Netherlands
                [8 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Department of Medicine, , New York University School of Medicine, ; New York, NY USA
                [9 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer, National Cancer Institute-Frederick, , National Institutes of Health, ; Frederick, MD 21702 USA
                [10 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Center for Antibody Therapeutics, , University of Pittsburgh, ; Pittsburgh, PA 15216 USA
                [11 ]HuLow Medical, Northbrook, IL USA
                Article
                1912
                10.1186/s13075-019-1912-0
                6555977
                31174578
                ba1044ac-e3e5-4724-a980-544fea85d6f2
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 December 2018
                : 9 May 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Orthopedics
                folate receptor beta,activated macrophages,inflammatory disease,autoimmune disease,rheumatoid arthritis

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