PMID- 32194539 OWN - NLM STAT- MEDLINE DCOM- 20201204 LR - 20211204 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation in vitro and in vivo. PG - 2344 LID - 10.3389/fimmu.2019.02344 [doi] LID - 2344 AB - Introduction: Spondyloarthritis (SpA) is characterized by inflammation, articular bone erosions and pathologic new bone formation. Targeting TNFalpha or IL-17A with current available therapies reduces inflammation in SpA, however, treatment of the bone pathology in SpA remains an unmet clinical need. Activation of the mammalian target Of rapamycin (mTOR) promotes IL-17A expression and osteogenesis. Therefore, the inhibition of mTOR (with rapamycin) could be a promising therapeutic avenue in SpA. Objectives: To investigate the effect of blocking mTOR on inflammation, bone erosions and new bone formation in SpA. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with SpA were stimulated with anti-CD3/CD28 in the presence or absence of rapamycin and the resulting cytokine expression was assessed. Fibroblast-like synoviocytes (FLS) from SpA patients were assessed for osteogenic differentiation potential in conditions with TNFalpha, IL-17A, or TNFalpha plus IL-17A, in the presence or absence of rapamycin. HLA-B27/Hubeta2m transgenic rats were immunized with low dose heat-inactivated Mycobacterium tuberculosis (M. tub), treated with 1.5 mg/kg rapamycin prophylactically or therapeutically and monitored for arthritis and spondylitis. Histology and mRNA analysis were performed after 5 weeks of treatment to assess inflammation and bone pathology. Results:In vitro TNFalpha and IL-17A protein production by SpA PBMCs was inhibited in the presence of rapamycin. Rapamycin also inhibited osteogenic differentiation of human SpA FLS. Ex vivo analysis of SpA synovial biopsies indicated activation of the mTOR pathway in the synovial tissue of SpA patients. In vivo, prophylactic treatment of HLA-B27/Hubeta2m transgenic rats with rapamycin significantly inhibited the development and severity of inflammation in peripheral joints and spine (arthritis and spondylitis), with histological evidence of reduced bone erosions and new bone formation around peripheral joints. In addition, therapeutic treatment with rapamycin significantly decreased severity of arthritis and spondylitis, with peripheral joint histology showing reduced inflammation, bone erosions and new bone formation. IL-17A mRNA expression was decreased in the metacarpophalangeal joints after rapamycin treatment. Conclusion: mTOR blockade inhibits IL-17A and TNFalpha production by PBMCs, and osteogenic differentiation of FLS from patients with SpA in vitro. In the HLA-B27 transgenic rat model of SpA, rapamycin inhibits arthritis and spondylitis development and severity, reduces articular bone erosions, decreases pathologic new bone formation and suppresses IL-17A expression. These results may support efforts to evaluate the efficacy of targeting the mTOR pathway in SpA patients. CI - Copyright (c) 2020 Chen, van Tok, Knaup, Kraal, Pots, Bartels, Gravallese, Taurog, van de Sande, van Duivenvoorde and Baeten. FAU - Chen, Sijia AU - Chen S AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States. FAU - van Tok, Melissa N AU - van Tok MN AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Knaup, Veronique L AU - Knaup VL AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Kraal, Lianne AU - Kraal L AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Pots, Desiree AU - Pots D AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Bartels, Lina AU - Bartels L AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Gravallese, Ellen M AU - Gravallese EM AD - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States. FAU - Taurog, Joel D AU - Taurog JD AD - Internal Medicine, Rheumatic Diseases Division, UT Southwestern Medical Center, Dallas, TX, United States. FAU - van de Sande, Marleen AU - van de Sande M AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - van Duivenvoorde, Leonie M AU - van Duivenvoorde LM AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. FAU - Baeten, Dominique L AU - Baeten DL AD - Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. AD - UCB Pharma, Slough, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200227 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Interleukin-17) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Female MH - Humans MH - Interleukin-17/genetics/immunology MH - Leukocytes, Mononuclear/drug effects/immunology MH - Male MH - Osteogenesis/*drug effects MH - Rats MH - Rats, Transgenic MH - Sirolimus/*administration & dosage MH - Spondylarthritis/*drug therapy/genetics/immunology/physiopathology MH - Synoviocytes/drug effects/immunology MH - TOR Serine-Threonine Kinases/genetics/*immunology MH - Tumor Necrosis Factor-alpha/genetics/immunology PMC - PMC7065603 OTO - NOTNLM OT - HLA-B27 tg rats OT - IL-17A OT - animal models OT - fibroblast-like synoviocytes OT - mTOR OT - rapamycin OT - small molecule treatment OT - spondyloarthtritis EDAT- 2020/03/21 06:00 MHDA- 2020/12/15 06:00 PMCR- 2019/01/01 CRDT- 2020/03/21 06:00 PHST- 2019/07/11 00:00 [received] PHST- 2019/09/17 00:00 [accepted] PHST- 2020/03/21 06:00 [entrez] PHST- 2020/03/21 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.02344 [doi] PST - epublish SO - Front Immunol. 2020 Feb 27;10:2344. doi: 10.3389/fimmu.2019.02344. eCollection 2019.