The role of innate immunology in the patients with early rheumatoid arthritis and resistant-anti rheumatic drugs

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K10995
• Research Institution: Yamagata University
• Principal Investigator: 高窪 祐弥 山形大学, 医学部, 准教授 (80431641)
• Co-Investigator(Kenkyū-buntansha): 高木 理彰 山形大学, 医学部, 教授 (40241707) ; 佐々木 幹 山形大学, 医学部, 非常勤講師 (00444034) ; 長沼 靖 山形大学, 医学部, 客員研究員 (10463811) ; 大木 弘治 山形大学, 医学部, 非常勤講師 (20463812)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 関節リウマチ / 薬剤耐性 / 自然免疫 / 獲得免疫 / Toll様受容体

Outline of Annual Research Achievements

昨年までに，詳細に行った免疫組織化学，免疫蛍光二重染色法による解析，FACS解析とRT-PCR法により，薬剤未投与の早期RAと，晩期RA，特に薬剤抵抗性RA患者における末梢血と関節液，滑膜組織におけるToll様受容体陽性細胞の局在とその働きが明らかになりました。本年は，早期群，晩期群において，FACS ariaによりToll様受容体陽性単球系血球細胞を分離し，抗Toll様受容体抗体を添加した系とRA患者から分離した微小粒子と健常人単球系血球細胞を共培養し，そのサイトカイン産生やToll様受容体の発現を比較，検討しました。
また晩期群では，TNF阻害薬，IL-6受容体抗体製剤，CTLA-4Ig製剤投与群に分け，それぞれの自然免疫系，獲得免疫系の役割を明らかにしました。
早期群では，自然免疫，獲得免疫が炎症度に応じて残存している症例が多くみられ，晩期群では，T細胞、B細胞と比較し，多くのTLR陽性細胞が残存していました。
一方，抗原提示細胞とT細胞の第二シグナルを抑制するCTLA-4Ig群では，リンパ球集簇において制御性T細胞や制御性樹状細胞が増加していました。適切な治療介入により，自然免疫，獲得免疫とも抑制され，制御性免疫細胞が増加する傾向がみられましたが，Toll様受容体陽性細胞を中心に，自然免疫系反応が残存していることが示唆されました。
今後，従来型の疾患修飾性抗リウマチ薬や生物学的製剤，分子標的型合成抗リウマチ薬を用いても症状の寛解が得られない患者では，自然免疫系反応をターゲットとした治療が重要になると考えられました。

Research Products

• [Int'l Joint Research] スタンフォード大学/Stuart Goodman教授(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: スタンフォード大学/Stuart Goodman教授
• [Int'l Joint Research] ヘルシンキ大学/Kari Eklund教授(フィンランド)
  • Country Name: FINLAND
  • Counterpart Institution: ヘルシンキ大学/Kari Eklund教授
• [Journal Article] Comparative Study of HO-1 Expressing Synovial Lining Cells Between RA and OA. (2019)
  • Author(s): Yang S, Ohe R, Aung NY, Kato T, Kabasawa T, Utsunomiya A, Takakubo Y, Takagi M, Yamakawa M
  • Journal Title: Mod Rheumatol. Volume: 12 Pages: 1-18
  • DOI: 10.1080/14397595.2019.1704976.
  • Peer Reviewed
• [Journal Article] Analysis of intestinal immunity and flora in a collagen-induced mouse parthritis model: differences during arthritis progression. (2019)
  • Author(s): Nemoto N, Takeda Y, Nara H, Araki A, Gazi Y, Takakubo Y, Naganuma Y, Takagi M, Asao H
  • Journal Title: Int Immunol. Volume: 32 Pages: 49-56
  • DOI: 10.1093/intimm/dxz058.
  • Peer Reviewed
• [Journal Article] Rapid disappearing of gouty tophi of foot due to reducing urate pool by resection of huge gouty tophi of opposite foot in the patient with hyperuricemia; a case of report. (2019)
  • Author(s): Takakubo Y, Imamura Y, Tezuka H, Okada S, Naganuma Y, Ito J, Sugawara M, Yang S, Oki H, Sasaki A, Sasaki K, Takagi M
  • Journal Title: Modern Rheumatology Case Reports Volume: 4 Pages: 1-6
  • DOI: 10.1080/24725625.2019.1680135
  • Peer Reviewed / Open Access
• [Journal Article] Assessing an alpha-defensin lateral flow device for diagnosing septic arthritis: reporting on a false-negative case and a false-positive case. (2019)
  • Author(s): 2.Narita A, Suzuki A, Nakajima T, Takakubo Y, Ito J, Sasaki A, Takagi M
  • Journal Title: Modern Rheumatology Case Reports. Volume: 4 Pages: 156-160
  • DOI: org/10.1080/24725625.2019.1683134
  • Peer Reviewed / Open Access
• [Journal Article] Disassembly of bilateral bipolar heads within 10 years after hip hemiarthroplasties for avascular necrosis of femoral heads: a case report. (2019)
  • Author(s): Ito J, Takakubo Y, Monma R, Oki H, Sasaki K, Takagi M
  • Journal Title: Modern Rheumatology Case Reports. Volume: 4 Pages: 148-151
  • DOI: 10.1080/24725625.2019.1662596
  • Peer Reviewed / Open Access
• [Presentation] Distrbution of Toll-like receptors expressing immune-cells in rheumatoid synovial tissues of the patients who received CTLA4-Ig agent. (2019)
  • Author(s): 1.Takakubo Y, Oki H, Yang S, Sasaki A, Sasaki K, Naganuma Y, KatoY, Takagi M
  • Organizer: ORS 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] Anti-tumor necrosis factor agents influence the apoptosis of inflammatory synovial cells in the patients with rheumatoid arthritis. (2019)
  • Author(s): Takakubo Y, Suzuki Y, Yang S, Oki H, Takagi M
  • Organizer: The 2nd International Combined Meeting of Orthopaedic Reserch Societies
  • Int'l Joint Research
• [Presentation] Rehabilitation of the salvege arthrodesis with bone auto- and allografts for failed total ankle arthroplasties in the patient with rheumatoid arthritis. (2019)
  • Author(s): Takakubo Y, Narita A, Takano M, Suzuki Y, Sasaki K, Ito J, Sagae H, Kanauchi Y, Kobayashi S, Takagi M
  • Organizer: 56th Annual Meeting of Japanese Association of Rehabilitation Medicine
  • Int'l Joint Research
• [Presentation] Induction of podoplanin in synovial lining cell of lipopolysaccharide-induced rabbit arthritis model. (2019)
  • Author(s): Honma R, Maruyama M, Liu X, Oki H, Takakubo Y, Takagi M
  • Organizer: The 2nd International Combined Meeting of Orthopaedic Reserch Societies
  • Int'l Joint Research
• [Presentation] Podoplanin is a potential biomarker in lipopolysaccharide-induced inflamed human fibroblast-like synoviocytes. (2019)
  • Author(s): Suzuki T, Liu X, Takakubo Y, Oki H**, Honma R, Takagi M
  • Organizer: The 2nd International Combined Meeting of Orthopaedic Reserch Societies
  • Int'l Joint Research
• [Presentation] Radiographic joint destruction in the patients with rheumatoid arthritis who have withdrawn, spaced or continued biologics after reaching remission from local biologics registry. (2019)
  • Author(s): Nagai J, Takakubo Y, Yang S, Suzuki Y, Sasaki A**, Oki H**, Naganuma Y**, Sasaki K**, Takagi M
  • Organizer: The 92nd Annual Meeting of the Japanese Orthopaedic Association
• [Presentation] Utility of alpha-defesin lateral flow device for periprosthetic joint onfection and septic arthritis. (2019)
  • Author(s): Narita A, Suzuki A, Nakajima, Takakubo Y, Ito J, Yuki I, Oki H, Naganuma Y, Takagi M
  • Organizer: ORS 2019 Annual Meeting
  • Int'l Joint Research