Cellular and molecular bases for chronic GVHD

• Project/Area Number: 25293113
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: Matsushima Kouji 東京大学, 医学(系)研究科(研究院), 教授 (50222427)
• Co-Investigator(Kenkyū-buntansha): HASHIMOTO Shinichi 金沢大学, 医学系, 特任教授 (00313099) ; UEHA Satoshi 東京大学, 大学院医学系研究科, 講師 (00447385) ; SHIMAOKA Takeshi 東京大学, 大学院医学系研究科, 助教 (90422279)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 移植免疫 / 造血幹細胞移植 / GVHD / T細胞 / 免疫制御 / 免疫不全 / 自己免疫 / 造血幹細胞 / 免疫制御・移植免疫

Outline of Final Research Achievements

Both graft-derived T cells (gT) and HSC-derived reconstituted T cells have been implicated in chronic GVHD after hematopoietic stem cell transplantation. In a newly developed mouse model of chronic GVHD, gT with the potential to proliferate and produce cytokines were predominant in the target tissues during the observation period. Depletion of gT after transplantation increased the number of rT and did not ameliorate cGVHD, whereas depletion of rT activated gT and resulted in lethal exacerbation of cGVHD. Identification of the molecular mechanisms underlying the interaction between TG and THSC is likely to lead to novel therapeutic strategies for the prevention and treatment of cGVHD.

Research Products

• [Journal Article] Cigarette Smoke Delays Regeneration of the Olfactory Epithelium in Mice. (2016)
  • Author(s): Ueha R, Ueha S, Sakamoto T, Kanaya K, Suzukawa K, Nishijima H, Kikuta S, Kondo K, Matsushima K, Yamasoba T.
  • Journal Title: Neurotox Res. Volume: -
  • Peer Reviewed
• [Journal Article] Damage to Olfactory Progenitor Cells Is Involved in Cigarette Smoke-Induced Olfactory Dysfunction in Mice. (2016)
  • Author(s): Ueha R, Ueha S, Kondo K, Sakamoto T, Kikuta S, Kanaya K, Nishijima H, Matsushima K, Yamasoba T.
  • Journal Title: Am J Pathol. Volume: 186 Issue: 3 Pages: 579-586
  • DOI: 10.1016/j.ajpath.2015.11.009
  • Peer Reviewed / Open Access
• [Journal Article] Local fibroblast proliferation but not influx is responsible for synovial hyperplasia in a murine model of rheumatoid arthritis. (2016)
  • Author(s): Yusuke Matsuo, Fumitaka Mizoguchi, Tetsuya Saito, Kimito Kawahata, Satoshi Ueha, Kouji Matsushima, Yutaka Inagaki, Nobuyuki Miyasaka, and Hitoshi Kohsaka
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 3 Pages: 504-509
  • DOI: 10.1016/j.bbrc.2016.01.121
  • Peer Reviewed / Open Access
• [Journal Article] Heat Shock Protein 27 Plays a Pivotal Role in Myofibroblast Differentiation and in the Development of Bleomycin-Induced Pulmonary Fibrosis (2016)
  • Author(s): Park AM, Kanai K, Itoh T, Sato T, Tsukui T, Inagaki Y, Selman M, Matsushima K, Yoshie O.
  • Journal Title: Plos One Volume: 11 Issue: 2 Pages: e0148998-e0148998
  • DOI: 10.1371/journal.pone.0148998
  • Peer Reviewed / Open Access
• [Journal Article] A combination of mitochondrial oxidative stress and excess fat/calorie intake accelerates steatohepatitis by enhancing hepatic CC chemokine production in mice. (2016)
  • Author(s): Moro T, Nakao S, Sumiyoshi H, Ishii T, Miyazawa M, Ishii N, Sato T, Iida Y, Okada Y, Tanaka M, Hayashi H, Ueha S, Matsushima K, Inagaki Y
  • Journal Title: PLoS ONE Volume: 11 Issue: 1 Pages: e0146592-e0146592
  • DOI: 10.1371/journal.pone.0146592
  • Peer Reviewed / Open Access
• [Journal Article] Reduced supply of monocyte-derived macrophages leads to a transition from nodular to diffuse lesions and tissue cell activation in silica-induced pulmonary fibrosis in mice. (2015)
  • Author(s): Shigeyuki Shichino, Jun Abe, Satoshi Ueha, Mikiya Otsuji, Tatsuya Tsukui, Mizuha Kosugi-Kanaya, Francis HW Shand, Shin-ichi Hashimoto, Hiroshi I. Suzuki, Teppei Morikawa, Yutaka Inagaki, and Kouji Matsushima:
  • Journal Title: Am J Pathol Volume: 185 Issue: 11 Pages: 2923-2938
  • DOI: 10.1016/j.ajpath.2015.07.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis. (2015)
  • Author(s): TatsuyaTsukui, Satoshi Ueha, Shigeyuki Shichino, Yutaka Inagaki, and Kouji Matsushima:
  • Journal Title: Am J Pathol Volume: 185 Issue: 11 Pages: 2939-2948
  • DOI: 10.1016/j.ajpath.2015.07.022
  • Peer Reviewed
• [Journal Article] Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-1/PD-L1 immune checkpoint antibody treatment in mice. (2015)
  • Author(s): Ueha S, Yokochi S, Ishiwata Y, Ogiwara H, Chand K, Nakajima T, Hachiga K, Shichino S, Terashima Y, Toda E, Shand FH, Kakimi K, Ito S, Matshushima K.
  • Journal Title: Cancer Immunol Res Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. (2015)
  • Author(s): Anzai A, Shimoda M, Endo J, Kohno T, Katsumata Y, Matsuhashi T, Yamamoto T, Ito K, Yan X, Shirakawa K, Shimizu-Hirota R, Yamada Y, Ueha S, Shinmura K, Okada Y, Fukuda K, Sano M.
  • Journal Title: Circ Res Volume: 116 Issue: 4 Pages: 612-623
  • DOI: 10.1161/circresaha.116.304918
  • Peer Reviewed / Open Access
• [Journal Article] Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease. (2015)
  • Author(s): Suenaga, F., Ueha, S., Abe, J., Kosugi-Kanaya, M., Wang, Y., Yokoyama, A., Shono, Y., Shand, F. H., Morishita, Y., Kunisawa, J., Sato, S., Kiyono, H. and Matsushima, K.
  • Journal Title: J. Immunol. Volume: 194(1) Issue: 1 Pages: 398-406
  • DOI: 10.4049/jimmunol.1401022
  • Peer Reviewed / Open Access
• [Journal Article] Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes. (2014)
  • Author(s): Tomura M, Hata A, Matsuoka S, Shand FH, Nakanishi Y, Ikebuchi R, Ueha S, Tsutsui H, Inaba K, Matsushima K, Miyawaki A, Kabashima K, Watanabe T, Kanagawa O.
  • Journal Title: Sci Rep. Volume: 4 Issue: 1 Pages: 6030-6030
  • DOI: 10.1038/srep06030
  • NAID: 120005749847
  • Peer Reviewed / Open Access
• [Journal Article] Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4+ T Cell Responses. (2014)
  • Author(s): Abe J, Shichino S, Ueha S, Hashimoto S, Tomura M, Inagaki Y, Stein JV, Matsushima K.
  • Journal Title: J Immunol. Volume: 193 Issue: 4 Pages: 1636-1644
  • DOI: 10.4049/jimmunol.1302946
  • Peer Reviewed
• [Journal Article] Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. (2014)
  • Author(s): Shand FH, Ueha S, Otsuji M, Koid SS, Shichino S, Tsukui T, Kosugi-Kanaya M, Abe J, Tomura M, Ziogas J, Matsushima K.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 111 Issue: 21 Pages: 7771-7776
  • DOI: 10.1073/pnas.1402914111
  • Peer Reviewed / Open Access
• [Journal Article] Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation (2014)
  • Author(s): Souichi Shiratori, Mizuha Kosugi-Kanaya, Satoshi Ueha, Junichi Sugita1, Akio Shigematsu, Takeshi Kondo, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Satoshi Hashino, Yoshihiro Matsuno, Kouji Matsushima, Junji Tanaka, Masahiro Imamura, Takanori Teshima
  • Journal Title: Biol Blood Marrow Transplant Volume: 20 Issue: 4 Pages: 495-500
  • DOI: 10.1016/j.bbmt.2013.12.568
  • NAID: 120005427744
  • Peer Reviewed / Open Access
• [Journal Article] Coordinated Changes in DNA Methylation in Antigen-Specific Memory CD4 T Cells (2013)
  • Author(s): Hashimoto S, Ogoshi K, Sasaki A, Abe J, Qu W, Nakatani Y, Ahsan B, Oshima K, Shand FH, Ametani A, Suzuki Y, Kaneko S, Wada T, Hattori M, Sugano S,Morishita S, Matsushima K
  • Journal Title: J Immunol Volume: 190 Issue: 8 Pages: 4076-4091
  • DOI: 10.4049/jimmunol.1202267
  • Peer Reviewed
• [Presentation] Reduced Supply of Monocyte-derived Macrophages Leads to a Transition from Nodular to Diffuse Lesions and Tissue Cell Activation in Silica-induced Pulmonary Fibrosis in Mice (2016)
  • Author(s): Shigeyuki Shichino, Jun Abe, Tatsuya Tsukui, Satoshi Ueha, Shin-ichi Hashimoto, Teppei Morikawa, Yutaka Inagaki, and Kouji Matsushima
  • Organizer: Keystone symposia, Fibrosis: From Basic Mechanisms to Targeted Therapies (Q3)
  • Place of Presentation: Keystone Resort. Colorado, USA
  • Year and Date: 2016-02-10
  • Int'l Joint Research
• [Presentation] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis. (2016)
  • Author(s): Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K.
  • Organizer: Keystone symposia, Fibrosis: From Basic Mechanisms to Targeted Therapies (Q3)
  • Place of Presentation: Keystone Resort. Colorado,
  • Year and Date: 2016-02-09
  • Int'l Joint Research
• [Presentation] Anti-CD4 depleting mAb improves costimulatory signals and cytokine microenvironments in the tumor draining lymph node (2015)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌、北海道）
  • Year and Date: 2015-11-18
• [Presentation] Global transcriptome analysis reveals the expression signatures of cell surface receptors in the lung tissue cell subsets (2015)
  • Author(s): Shigeyuki Shichino, Tatsuya Tsukui, Satoshi Ueha, Yutaka Inagaki, Shin-ichi Hashimoto, and Kouji Matsushima
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis (2015)
  • Author(s): Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-L1 antibody treatment in mice (2015)
  • Author(s): Satoshi Ueha, Shoji Yokochi, Yoshiro Ishiwata, Satoru Ito, Yuya Terashima, Kazuhiro Kakimi, Kouji Matsushima
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋、愛知）
  • Year and Date: 2015-10-05
• [Presentation] Lineage tracing of resident fibroblasts by the intratracheal cell transfer elucidates the cellular origin of activated fibroblasts in pulmonary fibrosis (2015)
  • Author(s): Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K
  • Organizer: 12th World Congress on Inflammation
  • Place of Presentation: Boston, MA, USA.
  • Year and Date: 2015-08-10
  • Int'l Joint Research
• [Presentation] Global transcriptome analysis reveals the expression signatures of cell surface receptors in the lung tissue cell subsets in mice (2015)
  • Author(s): Shigeyuki Shichino, Tatsuya Tsukui, Satoshi Ueha, Yutaka Inagaki, Shin-ichi Hashimoto, and Kouji Matsushima
  • Organizer: International Conference of Cancer Immunotherapy and Macrophages
  • Place of Presentation: Ion International Research center, Tokyo, Japan
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] Robust anti-tumor CD8+ T cell responses elicited by the anti-CD4 depleting antibody therapy (2015)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Krishant Chand, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: International Conference of Cancer Immunotherapy and Macrophages
  • Place of Presentation: Ion International Research center, Tokyo, Japan
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] 慢性移植片対宿主病が骨髄造血微小環境に及ぼす影響 (2015)
  • Author(s): 上羽 悟史、小杉 瑞葉、須藤 直人、王泳、松島 綱治
  • Organizer: 第1回日本骨免疫学会
  • Place of Presentation: ホテルブリーズベイマリーナ（宮古島、沖縄）
  • Year and Date: 2015-06-30
• [Presentation] Loss of lymph node fibroblastic reticular cells and high endothelial cells underlies humoral immunodeficiency in mouse GVHD. (2014)
  • Author(s): Satoshi Ueha, Fumiko Suenaga, Jun Abe, Mizuha Kosugi, Yusuke Shono, Jun Kunisawa, Shintaro Sato, Hiroshi Kiyono, Kouji Matsushima.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 担癌マウスにおける腫瘍浸潤マクロファージの起源：脾臓および骨髄由来単球の動態. (2014)
  • Author(s): 上羽悟史、Francis Shand、津久井達也、七野成之、戸村道夫、松島綱治.
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄県、名護市）
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] Tracking of inter-tissue migration reveals the origins of tumor-infiltrating monocytes. (2014)
  • Author(s): Satoshi Ueha, Francis Shand, Mikiya Otsuji, Shigeyuki Shichino, Tatsuya Tsukui, Mizuha Kosugi, Jun Abe, Michio Tomura, Kouji Matsushima.
  • Organizer: The 22th International Symposium on Molecular Cell Biology of Macrophages.
  • Place of Presentation: 神戸商工会議所（兵庫県、神戸市）
  • Year and Date: 2014-06-02 – 2014-06-03
• [Presentation] Delayed and aberrant immunological reconstitution in allogeninc hematopoietic stem cell transplantation (2013)
  • Author(s): Kouji Matsushima
  • Organizer: 11th World Congress on Inflammation
  • Place of Presentation: Natal, Brazil
  • Invited
• [Presentation] Kouji Matsushima. Molecular and cellular bases for chronic inflammation-associated organ fibrosis (2013)
  • Author(s): Kouji Matsushima
  • Organizer: 11th World Congress on Inflammation
  • Place of Presentation: Natal, Brazil
  • Invited
• [Presentation] 骨髄GVHDにおける間葉系細胞障害の細胞・分子機序 (2013)
  • Author(s): 上羽悟史、小杉瑞葉、王泳、横山顕大、朝比奈晏那、松島綱治
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 京都
• [Remarks] 東京大学大学院医学系分子予防医学教室ホームページ
  • URL: http://www.prevent.m.u-tokyo.ac.jp/
• [Remarks] 東京大学医学部・大学院医学研究科・分子予防医学教室ホームページ
  • URL: http://www.prevent.m.u-tokyo.ac.jp/
• [Remarks] 東京大学 分子予防医学教室ホームページ
  • URL: http://www.prevent.m.u-tokyo.ac.jp/