Investigation of the mechanisms underlying humoral immunodeficiency following GVHD

• Project/Area Number: 25460491
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Satoshi Ueha 東京大学, 医学(系)研究科(研究院), 講師 (00447385)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 移植免疫 / 造血幹細胞移植 / GVHD / 液性免疫 / リンパ節 / 免疫 / 免疫不全 / 移植 / 造血幹細胞

Outline of Final Research Achievements

This study focused on the pathogenesis of prolonged humoral immunodeficiency following allogeneic hematopoietic stem cell transplantation (allo-HSCT). In a mouse allo-HCST model, mice with a history of CD8+ T cell-mediated GVHD developed severe atrophy of the lymph nodes and failed to mount T-cell dependent humoral immune responses to subcutaneous or oral immunization. Lymph node fibroblastic reticular cells were impaired in the early phase of GVHD through Fas-FasL dependent cytotoxicity, and inhibition of FasL partially ameliorated lymph node impairment. Depletion of CD8+ T cells in the graft or inhibition of FasL signaling would be expected to prevent lymph node GVHD and humoral immunodeficiency.

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] 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] Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFN-γ-dependent cell cycle arrest. (2015)
  • Author(s): Matsushita H, Hosoi A, Ueha S, Abe J, Fujieda N, Tomura M, Maekawa R, Matsushima K, Ohara O, Kakimi K.
  • Journal Title: Cancer Immunol Res. Volume: 3 Issue: 1 Pages: 26-36
  • DOI: 10.1158/2326-6066.cir-14-0098
  • Peer Reviewed
• [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] Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells. (2014)
  • Author(s): Hosoi A, Matsushita H, Shimizu K, Fujii SI, Ueha S, Abe J, Kurachi M, Maekawa R, Matsushima K, Kakimi K.
  • Journal Title: Int J Cancer. Volume: 134 Issue: 8 Pages: 1810-22
  • DOI: 10.1002/ijc.28506
  • Peer Reviewed
• [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] Specific Antibody in IV Immunoglobulin for Postsplenectomy Sepsis (2013)
  • Author(s): Kensuke Nakamura, Kent Doi, Koji Okamoto, Syunnya Arai, Satoshi Ueha, Kouji Matsushima, Susumu Nakajima, Naoki Yahagi, Eisei Noiri
  • Journal Title: Crit Care Med Volume: 41 Issue: 8 Pages: e163-e170
  • DOI: 10.1097/ccm.0b013e318287f1de
  • Peer Reviewed
• [Journal Article] Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota (2013)
  • Author(s): Koji Atarashi, Takeshi Tanoue, et al.
  • Journal Title: Nature Volume: 500 Issue: 7461 Pages: 232-236
  • DOI: 10.1038/nature12331
  • Peer Reviewed
• [Journal Article] Qualitative Rather than Quantitative Changes Are Hallmarks of Fibroblasts in Bleomycin-Induced Pulmonary Fibrosis (2013)
  • Author(s): Tatsuya Tsukui, Satoshi Ueha, Jun Abe, Shin-ichi Hashimoto, Shigeyuki Shichino, Takeshi Shimaoka, Francis H. W. Shand, Yasuka Arakawa, Kenshiro Oshima, Masahira Hattori, Yutaka
  • Journal Title: The American Journal of Pathology Volume: 3 Issue: 3 Pages: 758-773
  • DOI: 10.1016/j.ajpath.2013.06.005
  • Peer Reviewed
• [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] 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] Robust anti-tumor CD8+ T cell responses elicited by the anti-CD4 depleting antibody therapy (2015)
  • Author(s): atoshi 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] 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
  • Place of Presentation: 国立京都国際会館、京都
  • Invited
• [Presentation] Population dynamics of spleen- and bone marrow-pool monocytes in tumor-bearing mice (2013)
  • Author(s): Satoshi Ueha
  • Organizer: The 21th International Symposium on Molecular Cell Biology of Macrophages
  • Place of Presentation: 都市センターホテル、東京
  • Invited
• [Presentation] Population dynamics of spleen- and bone marrow-pool monocytes in tumor-bearing mice (2013)
  • Author(s): Satoshi Ueha, Francis HW Shand, Mizuha Kosugi, Shigeyuki Shichino, Takeshi Shimaoka, Tatsuya Tsukui, Jun Abe, Michio Tomura, Kouji Matsushima
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ、千葉
• [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/