Analysis of therapeutic effect of anti-TIM-4 mAb on inflammatory disease.

• Project/Area Number: 25461503
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Akiba Hisaya 順天堂大学, 医学(系)研究科(研究院), 准教授 (60338316)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 自己免疫疾患 / 抗炎症作用 / アレルギー疾患 / 細胞表面分子機能 / 細胞表面分子

Outline of Final Research Achievements

In this study, mice were treated with anti-TIM-4 mAb during the effector phase of collagen-induced arthritis (CIA). Treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing pro-inflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen antibody-induced arthritis (CAIA) were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of pro-inflammatory cytokines in the joints. In vitro, macrophages secreted pro-inflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone resorbing activity of osteoclasts. The therapeutic effect of anti-TIM-4 mAb is mediated by the inhibition of pro-inflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption.

Research Products

• [Journal Article] Characteristics of alveolar macrophages from murine models of OVA-induced allergic airway inflammation and LPS-induced acute airway inflammation. (2015)
  • Author(s): 1)Katsura Y, Harada N, Harada S, Ishimori A, Makino F, Ito J, Kamachi F, Okumura K, Akiba H, Atsuta R, Takahashi K
  • Journal Title: Exp Lung Res Volume: 41 Pages: 370-382
  • DOI: 10.3109/01902148.2015.1044137
  • Peer Reviewed
• [Journal Article] ICOS promotes group 2 innate lymphoid cell activation in lungs. (2015)
  • Author(s): Kamachi F, Isshiki T, Harada N, Akiba H, Miyake S
  • Journal Title: Biochem Biophys Res Commun Volume: 463 Pages: 739-745
  • DOI: 10.1016/j.bbrc.2015.06.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells. (2015)
  • Author(s): Tripathi S, Chabtini L, Dakle PJ, Smith B, Akiba H, Yagita H, Guleria I.
  • Journal Title: PLoS One. Volume: 10
  • DOI: 10.1371/journal.pone.0123439
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] OX40 ligand regulates splenic CD8(-) dendritic cell-induced Th2 responses in vivo. (2014)
  • Author(s): Kamachi F, Harada N, Usui Y, Sakanishi T, Ishii N, Okumura K, Miyake S, Akiba H
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 444 Pages: 235-240
  • DOI: 10.1016/j.bbrc.2014.01.060
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The TIM-3 pathway ameliorates Theiler's murine encephalomyelitis virus-induced demyelinating disease. (2014)
  • Author(s): Kaneyama T, Tomiki H, Tsugane S, Inaba Y, Ichikawa M, Akiba H, Yagita H, Kim BS, Koh CS.
  • Journal Title: Int Immunol Volume: 26 Pages: 369-81
  • DOI: 10.1093/intimm/dxt056
  • Peer Reviewed
• [Journal Article] Endogenous Tim-1 promotes severe systemic autoimmunity and renal disease MRL-Fas(lpr) mice. (2014)
  • Author(s): Nozaki Y, Kitching AR, Akiba H, Yagita H, Kinoshita K, Funauchi M, Matsumura I.
  • Journal Title: Am J Physiol Renal Physiol Volume: 306
  • DOI: 10.1152/ajprenal.00570.2013
  • Peer Reviewed
• [Journal Article] TIM-4 has dual function in the induction and effector phases of murine arthritis. (2013)
  • Author(s): Abe Y, Kamachi F, Kawamoto T, Makino F, Ito J, Kojima Y, Moustapha Ael D, Usui Y, Yagita H, Takasaki Y, Okumura K, Akiba H
  • Journal Title: J Immunol Volume: 191巻 Pages: 4562-4572
  • DOI: 10.4049/jimmunol.1203035
  • Peer Reviewed
• [Journal Article] Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival. (2013)
  • Author(s): Yeung M, McGrath M, Nakayama M, Shimizu T, Boenisch O, Magee CN, Abdoli R, Akiba H, Ueno T, Turka L, and Najafian N
  • Journal Title: J Immunol Volume: 191 Pages: 4447-4455
  • DOI: 10.4049/jimmunol.1300992
  • Peer Reviewed
• [Journal Article] TIM-4 glycoprotein - mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance (2013)
  • Author(s): Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y, Nagai S, Akiba H, Foretz M, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Takeya M, Viollet B, Yagita H, Jinushi M
  • Journal Title: Immunity Volume: 39 Pages: 1070-1081
  • DOI: 10.1016/j.immuni.2013.09.014
  • Peer Reviewed
• [Journal Article] Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. (2013)
  • Author(s): Takahashi N, Imanishi K, Uchiyama T
  • Journal Title: Immunity Volume: 57 Pages: 584-598
  • DOI: 10.1016/j.immuni.2013.06.019
  • NAID: 40020181881
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TIM-3 regulates innate immune cells to induce fetomaternal tolerance. (2013)
  • Author(s): Chabtini L, Mfarrej B, Mounayar M, Zhu B, Batal I, Dakle PJ, Smith BD, Boenisch O, Najafian N, Akiba H, Yagita H, Guleria I.
  • Journal Title: J Immunol Volume: 190 Pages: 88-96
  • DOI: 10.4049/jimmunol.1202176
  • Peer Reviewed
• [Journal Article] T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis. (2013)
  • Author(s): Foks AC, Ran IA, Wasserman L, Frodermann V, Ter Borg MN, de Jager SC, van Santbrink PJ, Yagita H, Akiba H, Bot I, Kuiper J, van Puijvelde GH.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 33 Pages: 2558-65
  • DOI: 10.1161/atvbaha.113.301879
  • Peer Reviewed
• [Journal Article] Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts. (2013)
  • Author(s): Shimmura-Tomita M, Wang M, Taniguchi H, Akiba H, Yagita H, Hori J
  • Journal Title: PLoS One Volume: 8(5)
  • DOI: 10.1371/journal.pone.0063620
  • Peer Reviewed
• [Journal Article] Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. (2013)
  • Author(s): Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 62 Pages: 629-37
  • DOI: 10.1007/s00262-012-1371-9
  • Peer Reviewed
• [Presentation] Breast milk conditions intestinal immune system and gut barrier of the infant. (2015)
  • Author(s): SAKAGUCHI Keita, KAWASAKI Akemi, KAMACHI Fumitaka, CHIBA Asako, AKIBA Hisaya, SHIMIZU Toshiaki, MIYAKE Sachiko
  • 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] ICOS promotes group 2 innate lymphoid cell activation in lungs. (2015)
  • Author(s): KAMACHI Fumitaka, ISSHIKI Takuma, HARADA Norihiro, AKIBA Hisaya, MIYAKE Sachiko
  • 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] Anti-TIM-4 mAb ameliorates allergic lung inflammation. (2014)
  • Author(s): F. Kamachi, N. Harada, J. Ito, K. Takahashi, K. Okumura, S. Miyake, H. Akiba
  • Organizer: The Multifaceted Roles of Type 2 Immunity
  • Place of Presentation: Bruges, Belgium
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Anti-TIM-4 mAb ameliorates allergic lung inflammation by inhibiting TIM-4-mediated mast cell stimulation (2013)
  • Author(s): F. Kamachi, M. Hara, N. Harada, Y. Katsura, Y. Kojima, K. Izawa, C. Nishiyama, K. Okumura, H. Akiba
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] Soluble form of TIM-4 regulates mast cell activation by binding to LMIR5 and TIM-3 (2013)
  • Author(s): KAMACHI Fumitaka, HARADA Norihiro, NISHIYAMA Chiharu, IZAWA Kumi, KITAURA Jiro, OKUMURA Ko, MIYAKE Sachiko, AKIBA Hisaya
  • Organizer: 第42回 日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ、千葉市
• [Remarks] 順天堂大学医学部免疫学講座
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html
• [Remarks] 順天堂大学医学部免疫学講座ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html
• [Remarks] 順天堂大学医学部免疫学講座ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html