Transplantation tolerance by regulatory immune response through innate immunity stimulation

• Project/Area Number: 15K10043
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Fujino Masayuki 国立感染症研究所, エイズ研究センター, 研究員 (50392329)
• Co-Investigator(Kenkyū-buntansha): 森 一泰 国立感染症研究所, エイズ研究センター, 主任研究官 (20270655) ; 村上 努 国立感染症研究所, エイズ研究センター, 室長 (50336385) ; 梨井 康 国立研究開発法人国立成育医療研究センター, 移植免疫研究室, 室長 (60321890)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 移植免疫 / 免疫制御 / 自然免疫

Outline of Final Research Achievements

Gene expression analysis was performed by microarray analysis using peripheral blood mononuclear cells isolated from three groups of rhesus macaques, which are a sugar chain mutant virus (d5G), a wild strain, and uninfected control. As a result, in the d5G, detailed gene expression profile was obtained about the gene group in which the difference in expression is specifically seen. In particular, significant differences were observed in the expression of CXCL10 in myeloid lineage cells. In addition, gene expression analysis by NGS was performed using RNA extracted for each cell type fractionated from the peripheral blood mononuclear cells to obtain a gene expression profile for each cell type.
In the field of transplantation, zymosan was used to examine the survival prolongation effect in mouse cardiac allografting. As a result, significant cardiac allograft survival was confirmed in the zymosan administration group compared to the control group.

Academic Significance and Societal Importance of the Research Achievements

現在臓器移植は、免疫抑制剤の開発により臓器不全に対する究極的な治療法として確立されるに至っている。しかし、移植患者は終生の免疫抑制剤投与が必要とされ、感染症ならびに、癌の発生頻度が上昇するため、免疫抑制剤の投与量軽減方法、あるいは離脱方法等の移植免疫寛容誘導方法の確立が検討されている。しかし、移植免疫寛容の誘導方法は確立されておらず、詳細な免疫学的な機序ならびに分子機構は不明のままである。移植後免疫寛容の誘導方法の確立は、未だ明らかにされていない免疫制御機序の解明に寄与すると共に、移植患者のQOLの向上、医療費削減等に寄与し、移植医療のさらなる前進のために非常に重要である。

Research Products

• [Journal Article] 5-aminolaevulinic acid (ALA), enhances heme oxygenase (HO)-1 expression and attenuates tubulointerstitial fibrosis and renal apoptosis in chronic cyclosporine nephropathy. (2019)
  • Author(s): Liu C, Zhu P, Fujino M, Isaka Y, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhuang J, Li XK
  • Journal Title: Biochem Biophys Res Commun Volume: 508 Issue: 2 Pages: 583-589
  • DOI: 10.1016/j.bbrc.2018.11.175
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Liver transplantation: New treatment for mucopolysaccharidosis type VI in rats. (2019)
  • Author(s): Toyama S, Migita O, Fujino M, Kunieda T, Kosuga M, Fukuhara Y, Nagahara Y, Li XK, Okuyama T.
  • Journal Title: Pediatr Int Volume: 261 Issue: 2 Pages: 180-189
  • DOI: 10.1111/ped.13751
  • Peer Reviewed / Open Access
• [Journal Article] Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands (2019)
  • Author(s): 3.Sakyiamah MM., Kobayakawa T., Fujino M., KonnoM., Narumi T., Tanaka T., Nomura W., Yamamoto N., Murakami T., and Tamamura H.
  • Journal Title: Bioorg. Med. Chem Volume: 2 Issue: 6 Pages: 1130-1138
  • DOI: 10.1016/j.bmc.2019.02.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Myeloid heme oxygenase-1 a new therapeutic target in anti-inflammation (2018)
  • Author(s): Zhao M, Yang M, Que W, Zhong L, Fujino M, Li XK.
  • Journal Title: Frontiers in Bioscience Volume: 23 Issue: 11 Pages: 2001-2015
  • DOI: 10.2741/4685
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Combination of 5-aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft-versus-host disease. (2018)
  • Author(s): Liu C, Yang X, Zhu P, Fujino M, Ito H, Takahashi K, Nakajima M, Tanaka T, Wang J, Zhuang J, Zou H, Li XK.
  • Journal Title: Exp Dermatol. Volume: 10 Issue: 10 Pages: 1104-1111
  • DOI: 10.1111/exd.13730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression. (2018)
  • Author(s): Li S, Fujino M, Ichimaru N, Kurokawa R, Hirano S, Mou L, Takahara S, Takahara T, Li XK.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 14019-14019
  • DOI: 10.1038/s41598-018-32411-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of human immunodeficiency virus type-1 Gag-TSG101 interaction inhibitors by high-throughput screening (2018)
  • Author(s): Lowela Siarot, Nopporn Chutiwitoonchai, Hirotaka Sato, Hao Chang, Hironori Sato, Masayuki,Fujino,Tsutomu Murakami,Toshihiro Aono, Eiichi Kodama, Kazumichi Kuroda, Masami Takei, Yoko Aida
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 503 Issue: 4 Pages: 2970-2976
  • DOI: 10.1016/j.bbrc.2018.08.079
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induced pluripotent stem cells-derived myeloid-derived suppressor cells regulate the CD8 + T cell response (2018)
  • Author(s): Joyce Daniel、Fujino Masayuki、Morita Miwa、Araki Ryoko、Fung John、Qian Shiguang、Lu Lina、Li Xiao-Kang
  • Journal Title: Stem Cell Research Volume: 29 Pages: 32-41
  • DOI: 10.1016/j.scr.2018.03.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A standardized fold change method for microarray differential expression analysis used to reveal genes involved in acute rejection in murine allograft models (2018)
  • Author(s): Zhou Weichen、Wang Yi、Fujino Masayuki、Shi Leming、Jin Li、Li Xiao-Kang、Wang Jiucun
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 3 Pages: 481-490
  • DOI: 10.1002/2211-5463.12343
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SIV targeting of CXCR3+CD4+ T cells in secondary lymphoid organs associates with robust CXCL10 expression in monocyte/macrophage subsets. (2017)
  • Author(s): Fujino, M., H. Sato, T. Okamura, A. Uda, S. Takeda, N. Ahmed, S. Shichino, T. Shiino, Y. Saito, S. Watanabe, C. Sugimoto, M. Kuroda, M. Ato, Y. Nagai, S. Izumo, K. Matsushima, M. Miyazawa, A. Ansari, F. Villinger, and K. Mori
  • Journal Title: Journal of Virology Volume: 印刷中 Issue: 13
  • DOI: 10.1128/jvi.00439-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid identification of pathogenic streptococci isolated from moribund red tilapia (Oreochromis spp.) (2017)
  • Author(s): Abdelsalam Mohamed、Elgendy Mamdouh Y.、Shaalan Mohamed、Moustafa Mohamed、Fujino Masayuki
  • Journal Title: Acta Veterinaria Hungarica Volume: 65 Issue: 1 Pages: 50-59
  • DOI: 10.1556/004.2017.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Astaxanthin prevents ischemia-reperfusion injury of the steatotic liver in mice (2017)
  • Author(s): Li Shaowei、Takahara Terumi、Fujino Masayuki、Fukuhara Yasuyuki、Sugiyama Toshiro、Li Xiao-Kang、Takahara Shiro
  • Journal Title: PLOS ONE Volume: 12 Issue: 11 Pages: 1-16
  • DOI: 10.1371/journal.pone.0187810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A modified graft-versus-host-induced model for systemic sclerosis, with pulmonary fibrosis in Rag2-deficient mice (2017)
  • Author(s): Yang Xue、Liu Chi、Fujino Masayuki、Yang Ji、Li Xiao-Kang、Zou Hejian
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1316-1327
  • DOI: 10.1002/2211-5463.12268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by?Generating Alloantigen-Specific Regulatory T Cells (2017)
  • Author(s): Cai Songjie、Hou Jiangang、Fujino Masayuki、Zhang Qi、Ichimaru Naotsugu、Takahara Shiro、Araki Ryoko、Lu Lina、Chen Ji-Mei、Zhuang Jian、Zhu Ping、Li Xiao-Kang
  • Journal Title: Stem Cell Reports Volume: 8 Issue: 5 Pages: 1174-1189
  • DOI: 10.1016/j.stemcr.2017.03.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation (2017)
  • Author(s): Abe Toyofumi、Yazawa Koji、Fujino Masayuki、Imamura Ryoichi、Hatayama Naoyuki、Kakuta Yoichi、Tsutahara Koichi、Okumi Masayoshi、Ichimaru Naotsugu、Kaimori Jun-ya、Isaka Yoshitaka、Seki Kunihiro、Takahara Shiro、Li Xiao-Kang、Nonomura Norio
  • Journal Title: Laboratory Investigation Volume: 97 Issue: 4 Pages: 468-477
  • DOI: 10.1038/labinvest.2016.157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic Polymorphisms of Cytotoxic T-Lymphocyte Antigen 4 in Primary Biliary Cholangitis: A Meta-Analysis (2017)
  • Author(s): Yang Xing-Chen、Fujino Masayuki、Cai Song-Jie、Li Shao-Wei、Liu Chi、Li Xiao-Kang
  • Journal Title: Journal of Immunology Research Volume: 2017 Pages: 1-12
  • DOI: 10.1155/2017/5295164
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia-reperfusion injury in the mouse fatty liver model. (2016)
  • Author(s): Li S, Takahara T, Li XK, Fujino M, Sugiyama T, Tsukada K, Liu C, Kakuta Y, Nonomura N, Ito H, Takahashi K, Nakajima M, Tanaka T, Takahara S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 470(4) Pages: 900-6
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells. (2016)
  • Author(s): Nishio Y, Fujino M, Cai S, Kitajima Y, Saito T, Tsumura H, Ito M, Ito Y, Nagahara Y, Li XK.
  • Journal Title: Transpl Immunol. Volume: 35 Pages: 34-9
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prolonged Mouse Cardiac Graft Cold Storage via Attenuating Ischemia-Reperfusion Injury Using a New Antioxidant-Based Preservation Solution. (2016)
  • Author(s): Cai S, Ichimaru N, Zhao M, Fujino M, Ito H, Ota U, Nakajima M, Tanaka T, Nonomura N, Li XK, Takahara S.
  • Journal Title: Transplantation Volume: 100(5) Pages: 1032-40
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction. (2016)
  • Author(s): Fujino M, Nishio Y, Ito H, Tanaka T, Li XK.
  • Journal Title: Int Immunopharmacol Volume: 37 Pages: 71-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNAs Involved in Acute Rejection and Tolerance in Murine Cardiac Allografts. (2016)
  • Author(s): Fujino M, Zhu P, Cai S, Nishio Y, Zhuang J, Li XK.
  • Journal Title: Exp Clin Transplant. Volume: 14(4) Pages: 424-30
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 5-Aminolevulinic acid with sodium ferrous citrate induces autophagy and protects cardiomyocytes from hypoxia-induced cellular injury through MAPK-Nrf-2-HO-1 signaling cascade. (2016)
  • Author(s): Zhao M, Zhu P, Fujino M, Nishio Y, Chen J, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhao L, Zhuang J, Li XK.
  • Journal Title: Biochem Biophys Res Commun. Volume: 479(4) Pages: 663-669
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. (2016)
  • Author(s): Zhao M, Zhu P, Fujino M, Zhuang J, Guo H, Sheikh I, Zhao L, Li XK.
  • Journal Title: Int J Mol Sci. Volume: 17(12)
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 5-aminolaevulinic acid with ferrous iron induces permanent cardiac allograft acceptance in mice via the induction of regulatory cells (2015)
  • Author(s): Hou JG, Zhang Q, Fujino M, Cai SJ, Ito H, Takahashi K, Abe F, Nakajima M, Tanaka T, Xu JH, Zou HJ, Ding Q, Li Xiao K*
  • Journal Title: J Heart Lung Transplant Volume: 34(2) Issue: 2 Pages: 254-63
  • DOI: 10.1016/j.healun.2014.09.037
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system (2015)
  • Author(s): Zhang Q, Ichimaru N, Higuchi S, Cai SJ, Hou JG, Fujino M, Nonomura N, Kobayashi M, Ando H, Uno A, Sakurai K, Mochizuki S, Adachi Y, Ohno N, Zou HJ, Xu JH, Li Xiao K*. Takahara S
  • Journal Title: Gene Ther Volume: 22(3) Issue: 3 Pages: 1-10
  • DOI: 10.1038/gt.2014.119
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells. (2015)
  • Author(s): Zhao M, Guo H, Chen J, Fujino M, Ito H, Takahashi K, Abe F, Nakajima M, Tanaka T, Wang J, Huang H, Zheng S, Hei M, Li J, Huang S, Li J, Ma X, Chen Y, Zhao L, Zhuang J, Zhu P, Li XK
  • Journal Title: Int Immunopharmacol. Volume: Oct;28(2) Issue: 2 Pages: 938-44
  • DOI: 10.1016/j.intimp.2015.04.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role and Potential Therapeutic Application of Myeloid-Derived Suppressor Cells in Allo- and Autoimmunity. (2015)
  • Author(s): Zhang Q, Fujino M, Xu J, Li XK.
  • Journal Title: Mediators Inflamm. Volume: 2015 Issue: 1 Pages: 421927-421927
  • DOI: 10.1155/2015/421927
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Development of new membrane fusion inhibitors against HIV-1 by “dimerization” strategy (2018)
  • Author(s): Murakami T, X Ebihara K, Fujino M, Honda Y, Kobayakawa T, Nomura W, Tamamura H
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 二量体化に基づいた新規抗HIV-1膜融合阻害薬の創出 (2018)
  • Author(s): 村上 努、海老原健人、藤野真之、本田柚奈、小早川拓也、野村 渉、玉村啓和
  • Organizer: 第32回日本エイズ学会学術集会
• [Presentation] ウイルスポリメラーゼの不可逆阻害を目指した新規2'-&βセレノ核酸アナログの創製 (2018)
  • Author(s): 村上 努、木村康明、新美結士、藤野真之、片倉秀雄、鈴木哲朗、児玉栄一、阿部 洋
  • Organizer: 第32回日本エイズ学会学術集会
• [Presentation] Characterization of novel HIV-1 inhibitors targeting Gag-TSG101 interaction (2018)
  • Author(s): Siarot Lowela、Chutiwitoonchai Nopporn、佐藤洋隆、Chang Hao、小谷 治、横山 勝、佐藤裕徳、藤野真之、村上 勉、近藤恭光、本田香り、長田裕之、上田一樹、伊藤嘉浩、青野俊裕、児玉栄一、黒田和道、武井正美、間 陽子
  • Organizer: 第32回日本エイズ学会学術集会
• [Presentation] エイズウイルス病原性における糖鎖の役割 (2018)
  • Author(s): 森 一泰、藤野真之
  • Organizer: 第5回糖鎖免疫研究会 Glyco-immunology 2019
• [Presentation] Biological and molecular characterization of a novel anti-HIV-1 compound created by in silico design and de novo organic synthesis (2018)
  • Author(s): Murakami T, Fujino M, Yokoyama M, Kobayakawa T, Takeuchi H, Masuda T, Kotani O, Tamamura H, Sato H.
  • Organizer: The 2018 Meeting on Retroviruses
  • Int'l Joint Research
• [Presentation] Astaxanthin Prevents Ischemia-Reperfusion Injury of the Steatotic Liver in Mice (2018)
  • Author(s): Li S, Takahara T, Fujino M Li XK, Takahara S
  • Organizer: 27th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] Protective immune responses elicited by a live-attenuated SIV vaccine required for containment of heterologous SIV infection (2018)
  • Author(s): Mori K, Watanabe S, Fujino M, Okamura T, Sugimoto C
  • Organizer: The 30th The International Workshop on Retroviral Pathogenesis
  • Int'l Joint Research
• [Presentation] HIV外皮タンパク質gp41由来ペプチドC34を基にした二価型膜融合阻害剤の創製 (2017)
  • Author(s): 海老原健人, 本田柚子奈, 水口貴章, 野村 渉, 藤野真之, 村上 努, 玉村啓和
  • Organizer: 第27回抗ウイルス療法学会学術集会
• [Presentation] Design and virological evaluation of partial peptides of HIV-1 capsid (2017)
  • Author(s): Tsutomu Murakami, Moemi Kaneko, Masayuki Fujino, Wataru Nomura, Hirokazu Tamamura
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Combination of 5-aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous grafts-versus-host disease (2017)
  • Author(s): Chi Liu, Xue Yang, Masayuki Fujino, Hejian Zou, Xiao-Kang Li
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] iPSCs Derived Regulatory Dendritic Cells Induce Murine Cardiac Allografts Acceptance via Generating Donor-specific Regulatory T Cells (2017)
  • Author(s): Cai S, Hou J, Fujino M, Ichimaru N, Nishio Y, Lu L, Takahara S, Li XK
  • Organizer: Cutting Edge of Transplantation 2017
  • Int'l Joint Research
• [Presentation] マウス肝移植免疫寛容の誘導におけるエフェクターT細胞とMDSCの役割 (2016)
  • Author(s): 李 小康、森田美和、藤野真之
  • Organizer: 第30回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 富山
  • Year and Date: 2016-11-25
  • Invited
• [Presentation] Macrophage specific delivery of TNF-α siRNA complexed with schizophyllan inhibits fatty-induced inflammation and fibrosis in a murine NASH model (2016)
  • Author(s): Li S, Takahara T, Fujino M, Higuchi S, Ando H, Li XK
  • Organizer: 第30回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 富山
  • Year and Date: 2016-11-25
• [Presentation] Systemic Therapy of Regulatory Dendritic Cells Derived form Induced Pluripotent Stem Cells Allows Allogeneic Cardiac Grafts Acceptance (2016)
  • Author(s): Cai S, Hou J, Fujino M, Ichimaru N, Lu L, Takahara S, Li XK
  • Organizer: The 26th International Congress of The Transplantation Society
  • Place of Presentation: Honkong, China
  • Year and Date: 2016-08-18
  • Int'l Joint Research
• [Presentation] Effects of hydrogen saline pretreatment on mouse fatty liver ischemia-reperfusion injury (2016)
  • Author(s): Li S, Takahara T, Fujino M, Liu C, Kurokawa R, Hirano S, Sato B, Li XK
  • Organizer: 日本分子状水素医学生物学会設立記念大会
  • Place of Presentation: 神奈川
  • Year and Date: 2016-05-27
• [Presentation] Effects of Astaxanthin Pretreatment on Ischemia-Reperfusion Injury in Fatty Liver Model of Mice (2016)
  • Author(s): Li S, Takahara T, Fujino M, Liu C, Li XK
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] Systemic administration of donor-type regulatory dendritic cells derived from induced pluripotent stem cells leads to murine allogeneic cardiac grafts permanent acceptance (2015)
  • Author(s): Cai S, Fujino M, Nishio Y, Li X-K.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2015-11-18
• [Book] 医学のあゆみ マクロファージのすべて (2016)
  • Author(s): 藤野真之、森一泰
  • Total Pages: 573
  • Publisher: 医歯薬出版株式会社