Novel therapy for sepsis targeting to IgM receptor

• Project/Area Number: 26293383
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: University of Tsukuba
• Principal Investigator: HONDA Shinichiro 筑波大学, 医学医療系, 研究員 (60360640)
• Co-Investigator(Kenkyū-buntansha): 小田 ちぐさ 筑波大学, 医学医療系, 助教 (50510054)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 敗血症 / Fc受容体 / 自然抗体 / IgM自然抗体 / 境界領域B細胞

Outline of Final Research Achievements

We found that mice lacking Fcα/μR, an Fc receptor for IgA/M showed attenuated inflammatory cytokine and chomokine productions and survived during lipopolysaccharide (LPS)-induced septic shock. Analyses using mixed bone marrow chimeric mice showed that Fcα/μR on marginal zone (MZ) B cells enhances systemic inflammatory responses by producing IL-6. IL-6 production from MZ B cells starts at 4-hr after LPS injection, following to that from macrophages. Thus, we tried to neutralize IL-6 by antibody injection for the treatment of septic shock. Although IL-6 is shown to be pro- and/or anti-inflammatory, we found that neutralization of delayed IL-6 leads to the attenuation of systemic inflammatory responses and the improvement of survival of mice.

Research Products

• [Journal Article] Improved protocol for the isolation of naive follicular dendritic cells (2016)
  • Author(s): Sato K, Honda SI, Shibuya A, Shibuya K
  • Journal Title: Mol Immunol Volume: 78 Pages: 140-145
  • DOI: 10.1016/j.molimm.2016.09.011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling (2016)
  • Author(s): Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K, Nakahashi-Oda C, Tahara-Hanaoka S, Shibuya K, Shibuya A
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 1-10
  • DOI: 10.1038/ncomms11498
  • NAID: 120007135503
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces (2016)
  • Author(s): Nakahashi-Oda C, Udayanga KGS, Nakamura Y, Nakazawa Y, Miki H, Iino S, Tahara-Hanaoka S, Shibuya K, Shibuya A.
  • Journal Title: Nature Immunol, 17(4):441-453, 2016 Volume: 17 Issue: 4 Pages: 441-453
  • DOI: 10.1038/ni.3345
  • Peer Reviewed / Open Access
• [Journal Article] IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor (2015)
  • Author(s): Weinstein JR, Quan Y, Hanson JF, Colonna L, Iorga M, Honda S, Shibuya K, Shibuya A, Elkon KB, Möller T.
  • Journal Title: J Immunol Volume: 195(11) Issue: 11 Pages: 5309-5317
  • DOI: 10.4049/jimmunol.1401195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune regulation by Fcα/μ receptor (CD351) on marginal zone B cells and follicular dendritic cells (2015)
  • Author(s): Shibuya A, Honda S.
  • Journal Title: Immunol Rev Volume: 268(1) Issue: 1 Pages: 288-295
  • DOI: 10.1111/imr.12345
  • Peer Reviewed
• [Journal Article] CD155 (PVR/Necl5) Mediates a Costimulatory Signal in CD4+ T Cells and Regulates Allergic Inflammation (2015)
  • Author(s): 4.Yamashita--Kanemaru Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda S, Bernhardt G, Shibuya A, Shibuya K.
  • Journal Title: J Immunol, 194(12):5644-5653, 2015 Volume: 194 Issue: 12 Pages: 5644-5653
  • DOI: 10.4049/jimmunol.1401942
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant–Induced Th2 Responses (2015)
  • Author(s): Miki H, Nakahashi-Oda C, Sumida T, Shibuya A.
  • Journal Title: J Immunol Volume: 194(11) Issue: 11 Pages: 5069-5076
  • DOI: 10.4049/jimmunol.1402915
  • Peer Reviewed / Open Access
• [Journal Article] CD155 (PVR/Necl5) mediates a costimulatory signal in CD4+ T cells and regulates allergic inflammations. (2015)
  • Author(s): Yamashita Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda S, Bernhardt G, Shibuya A, Shibuya K.
  • Journal Title: J Immunol, in press
• [Journal Article] Increased serum IgA in Fcα/μR-deficient mice on the (129 x C57BL/6) F1 genetic background (2015)
  • Author(s): Kurita N, Honda S, Shibuya A.
  • Journal Title: Mol Immunol Volume: 63 Issue: 2 Pages: 367-372
  • DOI: 10.1016/j.molimm.2014.09.008
  • NAID: 120007136500
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated infammatory monocyte migration (2014)
  • Author(s): Naoya T otsuka, Yun-Gi Kim, Kazumasa Kanemaru, Kouta Niizuma, Eiji Umemoto, Kei Nagai, Satoko T ahara-Hanaoka, Chigusa Nakahasi-Oda, Shin-ichiro Honda, Masayuki Miyasaka, Kazuko Shibuya & Akira Shibuya
  • Journal Title: Nature Communications Volume: 5:4710 Issue: 1 Pages: 4710-4710
  • DOI: 10.1038/ncomms5710
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serum under-O-glycosylated IgA1 level is not correlated with glomerular IgA deposition based upon heterogeneity in the composition of immune complexes in IgA nephropathy. (2014)
  • Author(s): Satake K, Shimizu Y, Sasaki Y, Yanagawa H, Suzuki H, Suzuki Y, Horikoshi S, Honda S, Shibuya K, Shibuya A, Tomino Y.
  • Journal Title: BMC Nephrology Volume: 15:89 Issue: 1 Pages: 89-89
  • DOI: 10.1186/1471-2369-15-89
  • Peer Reviewed / Open Access
• [Presentation] 上皮アポトーシス細胞による制御性T細胞の調節 (2016)
  • Author(s): 小田 ちぐさ
  • Organizer: 第25回東京免疫フォーラム
  • Place of Presentation: 東京医科学研究所付属病院（東京）
  • Year and Date: 2016-03-01
• [Presentation] Apoptotic epithelial cells control the abundance of regulatory T cells at barrier surfaces (2016)
  • Author(s): Nakahashi-Oda C, Udayanga K. G. S, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, Iino S, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: Melbourne Convention and Ehibition Centre, Australia
  • Int'l Joint Research
• [Presentation] CD300a on mast cells and dendritic cells control the pathogenesis of experimental sepsis (2015)
  • Author(s): Udayanga K G S, Nakahashi-Oda C, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-20
• [Presentation] Functional analysis of CD300a in atopi c dermatitis and colitis (2015)
  • Author(s): Nakamura Y, Nakahashi-Oda C, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] MAIR-II exacerbates bleomycin-induced pulmonary fibrosis through neutrophilic inflammation (2015)
  • Author(s): Ohtsuka S, Totsuka N, Nakahashi-Oda C, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] Development of a novel method for isolation of follicular dendritic cells (2015)
  • Author(s): Sato K, Honda S, Shibuya K, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] Eolvl6 attenuates OVA-induced atopic dermatitis by reducing the response to mechanical stress (2015)
  • Author(s): Nakamura Y, Nakahashi-Oda C, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-18
• [Presentation] Eolvl6 attenuates OVA-induced atopic dermatitis by reducing the response to mechanical stress (2015)
  • Author(s): Nakamura Y, Oda C, Matsuzaka T, Shimano H, Shibuya A
  • Organizer: 14th International Workshop on Langerhans Cells
  • Place of Presentation: Kyoto International Community House, Kyoto
  • Year and Date: 2015-11-06
• [Presentation] Apoptotic epithelial cells control regulatory T cell expansion (2015)
  • Author(s): Nakahashi-Oda C, Udayanga K G S, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, Iino S, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/µR-coupled TLR4 signaling (2015)
  • Author(s): Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K, Nakahashi-Oda C, Tahara-Hanaoka S, Shibuya K, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Marginal zone B cells exacerbate endotoxin shock by secretion of interleukin-6 (2014)
  • Author(s): Honda S, Sato K, Fujiyama S, Fujimoto M, Miyake K, Shibuya A.
  • Organizer: 第43 回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10
• [Presentation] Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration. (2014)
  • Author(s): Totsuka N, Kim YG, Kanemaru K, Niizuma K, Umemoto E, Nagai K, Tahara-Hanaoka S, Nakahashi-Oda C, Honda S, Miyasaka M, Shibuya K, Shibuya A.
  • Organizer: 第43 回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10
• [Remarks] 免疫学研究室ホームページ
  • URL: http://immuno-tsukuba.com/index.html
• [Remarks] つくばリポジトリ
  • URL: https://tsukuba.repo.nii.ac.jp/index.php?action=pages_view_main&active_action=repository_view_main_item_snippet&index_id=984&pn=1&count=20&order=7&lang=japanese&page_id=13&block_id=83
• [Remarks] 筑波大学 免疫学研究室 業績
  • URL: http://immuno-tsukuba.com/publication/english.html
• [Remarks] つくばリポジトリ
  • URL: http://www.tulips.tsukuba.ac.jp/dspace/simple-search?query=%E6%9C%AC%E5%A4%9A+%E4%BC%B8%E4%B8%80%E9%83%8E