免疫チェックポイント分子阻害を利用した細胞内寄生菌感染に対する新規ワクチンの開発

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18H02818
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 須田 隆文 浜松医科大学, 医学部, 教授 (30291397)
• Co-Investigator(Kenkyū-buntansha): 藤澤 朋幸 浜松医科大学, 医学部, 助教 (20402357) ; 榎本 紀之 浜松医科大学, 医学部附属病院, 講師 (50436961) ; 中村 祐太郎 浜松医科大学, 医学部附属病院, 講師 (60436962) ; 永田 年 浜松医科大学, 医学部, 教授 (90275024)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 樹状細胞 / 免疫チェックポイント分子 / ワクチン / PD-1/PD-L1 / 細胞内寄生菌

Outline of Annual Research Achievements

研究期間中に，以下の実験を行った．
①マウスの骨髄細胞を培養し，CD11cビーズを用いて骨髄由来のBM-DCを単離した．次にBMDCの表面抗原の検討し，約70%のBMDCにPD-L1，PD-L2が発現していることを確認した．
②C57BL/6マウス由来のBMDCに卵白アルブミン (OVA) 由来のCTL epitopeであるSINFEKLペプチドをパルスし，OT-１マウスの脾臓由来のCD8陽性T細胞と共培養して，CFSEを用いてCD8陽性T細胞の増殖を検討した．その結果，有意差はないものの，抗PD-1抗体を添加した方がCD8陽性T細胞の増殖が抑制されていた．
③リステリア菌のdominant CTL epitope (LLO91-99) リステリア菌のdominant CTL epitope (LLO91-99)をパルスしたBMDCをBALB/cマウスに接種し，まずLLO91-99特異的CTLの誘導をLLO91-99特異的MHCクラスIテトラマーを用いて評価したところ，抗PD-1抗体を投与したマウスの方が，有意に多くLLO91-99特異的CTLが誘導された．また，免疫したマウスの脾細胞にLLO91-99ペプチドをパルスし，LLO91-99特異的T細胞増殖とIFN-γ産生能を検討したところ，抗PD-1抗体を投与されたマウスでは，T細胞増殖に違いはなかったが，IFNγは抗PD-1抗体投与で有意に産生量が増加した．
④BALBマウスにLLO91-99ペプチドをパルスしたBMDCワクチンを接種し，その49日後にリステリア菌を接種し，3日後に脾臓を回収し，リステリア菌量を測定することによって，BMDCによって獲得される感染防御能を評価した．抗PD-1抗体を投与したマウスと投与しなかったマウスで，脾臓内のリステリア菌の菌量に有意な差はなかった．

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung (2021)
  • Author(s): Sakurai S, Furuhashi K, Horiguchi R, Nihashi F, Yasui H, Karayama M, Suzuki Y, Hozumi H, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T,
  • Journal Title: Allergology International Volume: - Pages: -
  • DOI: 10.1016/j.alit.2021.01.008
  • Peer Reviewed
• [Journal Article] Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis (2021)
  • Author(s): Sakaue S, Yamaguchi E, Inoue Y, Handa T, Tanizawa K, Ishii H, Ishida M, Kato T, Takeda N, Yokomura K, Matsui T, Watanabe M, Inoue H, Imaizumi K, Goto Y, Kida H, Fujisawa T, Suda T, Yamada T, Satake Y, Ibata H, Hizawa N, Mochizuki H, Kumanogoh A, Matsuda F, Nakata K, Hirota T, Tamari M, Okada Y
  • Journal Title: Nature Communications Volume: 12 Pages: -
  • DOI: 10.1038/s41467-021-21011-y
  • Peer Reviewed / Open Access
• [Journal Article] Ursodeoxycholic acid impairs liver‐infiltrating T‐cell chemotaxis through IFN‐γ and CX3CL1 production in primary biliary cholangitis (2021)
  • Author(s): Shimoyama S, Kawata K, Ohta K, Chida T, Suzuki T, Tsuneyama K, Shimoda S, Kurono N, Leung PSC, Gershwin ME, Suda T, Kobayashi Y
  • Journal Title: European Journal of Immunology Volume: - Pages: -
  • DOI: 10.1002/eji.202048589
  • Peer Reviewed
• [Journal Article] Development of a novel T cell‐oriented vaccine using CTL/Th‐hybrid epitope long peptide and biodegradable microparticles, against an intracellular bacterium (2020)
  • Author(s): Tanaka K, Enomoto N, Uehara M, Furuhashi K, Sakurai S, Yasui H, Karayama M, Hozumi H, Suzuki Y, Fujisawa T, Inui N, Nakamura Y, Nagata T, Suda T
  • Journal Title: Microbiology and Immunology Volume: 64 Pages: 666～678
  • DOI: 10.1111/1348-0421.12836
  • Peer Reviewed
• [Journal Article] Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium (2020)
  • Author(s): Kamiya Y, Fujisawa T, Katsumata M, Yasui H, Suzuki Y, Karayama M, Hozumi H, Furuhashi K, Enomoto N, Nakamura Y, Inui N, Setou M, Ito M, Suzuki T, Ikegami K, Suda T
  • Journal Title: Respiratory Research Volume: 21 Pages: -
  • DOI: 10.1186/s12931-020-01555-1
  • Peer Reviewed / Open Access
• [Journal Article] CD248 and integrin alpha-8 are candidate markers for differentiating lung fibroblast subtypes (2020)
  • Author(s): Matsushima S, Aoshima Y, Akamatsu T, Enomoto Y, Meguro S, Kosugi I, Kawasaki H, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Funai K, Suda T, Iwashita T
  • Journal Title: BMC Pulmonary Medicine Volume: 20 Pages: -
  • DOI: 10.1186/s12890-020-1054-9
  • Peer Reviewed / Open Access
• [Journal Article] CD200 and CD200R1 are differentially expressed and have differential prognostic roles in non-small cell lung cancer (2020)
  • Author(s): Yoshimura K, Suzuki Y, Inoue Y, Tsuchiya K, Karayama M, Iwashita Y, Kahyo T, Kawase A, Tanahashi M, Ogawa H, Inui N, Funai K, Shinmura K, Niwa H, Sugimura H, Suda T
  • Journal Title: OncoImmunology Volume: 9 Pages: 1746554～1746554
  • DOI: 10.1080/2162402X.2020.1746554
  • Peer Reviewed
• [Journal Article] Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non?small Cell Lung Cancer (2020)
  • Author(s): Inoue Y、Yoshimura K、Nishimoto K、Inui Ni、Karayama M、Yasui H、Hozumi H、Suzuki Y、Furuhashi K、Fujisawa T、Enomoto Ni、Nakamura Y、Asada Ko、Uto T、Fujii M、Matsui T、Matsuura S、Hashimoto D、Sugimura H、Suda T
  • Journal Title: JAMA Network Open Volume: 3 Pages: e2011818
  • DOI: 10.1001/jamanetworkopen.2020.11818
  • Peer Reviewed / Open Access
• [Journal Article] HDAC3 Is Required for XPC Recruitment and Nucleotide Excision Repair of DNA Damage Induced by UV Irradiation (2020)
  • Author(s): Nishimoto K、Niida H、Uchida C、Ohhata T、Kitagawa K、Motegi A、Suda Ti、Kitagawa M
  • Journal Title: Molecular Cancer Research Volume: 18 Pages: 1367～1378
  • DOI: 10.1158/1541-7786.MCR-20-0214
  • Peer Reviewed
• [Presentation] Development of a Novel T-Cell-Oriented Vaccine, Which Is Composed of Biodegradable Microparticles and T-Cell-Hybrid Epitope Long Peptide, Against Intracellular Bacteria (2020)
  • Author(s): Tanaka K, Enomoto N, Yasui H, Karayama M, Suzuki Y, Hozumi H, Furuhashi K, Fujisawa T, Nakamura Y, Inui N, Nagata T, Suda T
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] Conventional Type 2 Lung Dendritic Cells in Asthma Mouse Model Significantly Induce Follicular Helper T Cells Than Conventional Type 1 (2020)
  • Author(s): Sakurai S, Furuhashi K, Horiguchi R, Hozumi H, Suzuki Y, Karayama M, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T:
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research