Role of immune-regulatory macrophages in progressive kidney disorder; functional analysis and evaluation for therapeutic potency of cell transfusion

• Project/Area Number: 25461215
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Nagoya University
• Principal Investigator: Tsuboi Naotake 名古屋大学, 医学部附属病院, 講師 (50566958)
• Co-Investigator(Kenkyū-buntansha): MARUYAMA Shoichi 名古屋大学, 大学院医学系研究科, 准教授 (10362253) ; AKIYAMA Shinichi 名古屋大学, 大学院医学系研究科, 特任講師 (20500010)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: マクロファージ / 炎症 / 糸球体腎炎 / 免疫調整

Outline of Final Research Achievements

Alternatively activated M2 macrophages are involved in the resolution of inflammation in animal models of chronic kidney diseases. The aims of this study is to clarify renal distribution and roles of macrophage phenotypes in human and murine progressive kidney disorder, and to evaluate therapeutic potency of transfused M2 macrophages (M2Ms) for animal models with progressive kidney diseases.
Histological analysis of renal macrophages and their phenotypes on kidney samples from human progressive kidney disorders and assessment of urinary (u-)sCD163 level clearly demonstrated that glomerular CD163+ M2Ms are the predominant phenotype in the kidneys of lupus patients and that u-sCD163 level can serve as a biomarker for macrophage-dependent glomerular inflammation in human LN.
Adoptive transfer of CD206+ M2Ms derived from bone marrow and stimulated with IL-4/IL-13 in murine nephrotoxic glomerulonephritis demonstrated their protective effects for antibody-mediated renal dysfunction.

Research Products

• [Journal Article] Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis (2016)
  • Author(s): N Endo,N Tsuboi,K Funahashi,Y Shi,Q Du,T Abe,M Hori,T Imaizumi,H Kim,T Katsuno,T Ozaki,T Kosugi,S Matsuo,S Maruyama
  • Journal Title: Nephrology Dialysis Transplantation Volume: In press
  • NAID: 120006220242
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neutrophil/lymphocyte ratio as a predictor of cardiovascular events in incident dialysis patients: a Japanese prospective cohort study. (2014)
  • Author(s): Abe T, Kato S, Tsuruta Y, Sugiura S, Katsuno T, Kosugi T, Tsuboi N, Matsuo S, Maruyama S.
  • Journal Title: Clin Exp Nephrol Volume: Epub
  • Peer Reviewed
• [Journal Article] Patient age and the prognosis of idiopathic membranous nephropathy. (2014)
  • Author(s): Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
  • Journal Title: PLoS One Volume: 9(10) Issue: 10 Pages: 110376-110376
  • DOI: 10.1371/journal.pone.0110376
  • Peer Reviewed
• [Journal Article] Pristane-induced granulocyte recruitment promotes phenotypic conversion of macrophages and protects against diffuse pulmonary hemorrhage in Mac-1 deficiency. (2014)
  • Author(s): Shi Y, Tsuboi N, Furuhashi K, Du Q, Horinouchi A, Maeda K, Kosugi T, Matsuo S, Maruyama S.
  • Journal Title: J Immunol. Volume: 193 Issue: 10 Pages: 5129-39
  • DOI: 10.4049/jimmunol.1401051
  • Peer Reviewed
• [Journal Article] Smoking is a risk factor for the progression of idiopathic membranous nephropathy. (2014)
  • Author(s): Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
  • Journal Title: PLoS One. Volume: 9 Issue: 6 Pages: e100835-e100835
  • DOI: 10.1371/journal.pone.0100835
  • Peer Reviewed / Open Access
• [Journal Article] Rat adipose tissue-derived stem cells attenuate peritoneal injuries in rat zymosan-induced peritonitis accompanied by complement activation. (2013)
  • Author(s): Kim H, Mizuno M, Furuhashi K, Katsuno T, Ozaki T, Yasuda K, Tsuboi N, Sato W, Suzuki Y, Matsuo S, Ito Y ,Maruyama S1.
  • Journal Title: Cytotherapy. Volume: 16(3) Issue: 3 Pages: 357-68
  • DOI: 10.1016/j.jcyt.2013.10.011
  • Peer Reviewed
• [Journal Article] A ray of light in the dark: alternative approaches to the assessment and treatment of ischemic nephropathy. (2013)
  • Author(s): Tsuboi N, Maruyama S, Matsuo S, Imai E.
  • Journal Title: Nephrol Dial Transplant. Volume: 29(2) Issue: 2 Pages: 228-31
  • DOI: 10.1093/ndt/gft463
  • Peer Reviewed
• [Journal Article] Serum-Starved Adipose-Derived Stromal Cells Ameliorate Crescentic GN by Promoting Immunoregulatory Macrophages. (2013)
  • Author(s): Furuhashi K, Tsuboi N, Shimizu A, Katsuno T, Kim H, Saka Y, Ozaki T, Sado Y, Imai E, Matsuo S, Maruyama S.
  • Journal Title: J Am Soc Nephrol Volume: 24(4) Pages: 587-603
  • Peer Reviewed
• [Presentation] Transfused M2 Macrophages Ameliorate Renal Injury in Murine Nephrotoxic Serum Nephritis. (2015)
  • Author(s): Qiuna Du, Naotake Tsuboi, Yutaka Sugiyama, Seiichi Matsuo, Shoichi Maruyama
  • Organizer: 48th Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego,USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Transfused M2 macrophages ameliorate renal injury in murine nephrotoxic serum nephritis (2015)
  • Author(s): Du Q, Tsuboi N, Sugiyama Y, Shi Y, Matsuo S, Maruyama S
  • Organizer: 52nd Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association
  • Place of Presentation: London,UK
  • Year and Date: 2015-05-30
  • Int'l Joint Research
• [Presentation] A RISE IN ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY (ANCA) TITERS IS AN INDEPENDENT PREDICTOR OF RELAPSE IN ANCA-ASSOCIATED VASCULITIS (2015)
  • Author(s): M. Yamaguchi, S. Kato, T. Katsuno, N. Kato, T. Kosugi, N. Tsuboi, Y. Yasuda, Y. Ito, S. Matsuo, S. Maruyama
  • Organizer: World Congress of Nephrology 2015
  • Place of Presentation: Cape Town（South Africa）
  • Year and Date: 2015-03-13 – 2015-03-17
• [Presentation] Mac-1 Deficiency Exacerbates Glomerulonephritis In Experimental Model Of Systemic Lupus Erythematosus. (2015)
  • Author(s): Y. Shi, N. Tsuboi, S. Matsuo, S. Maruyama
  • Organizer: World Congress of Nephrology 2015
  • Place of Presentation: Cape Town（South Africa）
  • Year and Date: 2015-03-13 – 2015-03-17
• [Presentation] Association of Glomerular Macrophage Phenotypes and Urinary Soluble CD163 with Disease Activity in Human Lupus Nephritis (2014)
  • Author(s): Nobuhide Endo, DrMed, Naotake Tsuboi, MD, PhD, Kazuhiro Furuhashi, MD, PhD, Shoichi Maruyama, MD, Seiichi Matsuo, MD.
  • Organizer: Kidney Week 2014
  • Place of Presentation: フィラデルフィア (米国)
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] Smoking Is a Risk Factor for the Relapse of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. (2014)
  • Author(s): Makoto Yamaguchi, MD, Sawako Kato, MD, PhD, Takuji Ishimoto, MD, PhD, Tomoki Kosugi, MD, PhD, Waichi Sato, MD, PhD, Naotake Tsuboi, MD, PhD, Masashi Mizuno, MD, PhD, Yasuhiko Ito, MD, PhD, Seiichi Matsuo, MD, Shoichi Maruyama, MD.
  • Organizer: Kidney Week 2014
  • Place of Presentation: フィラデルフィア (米国)
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] PRESの画像所見を呈し、血漿交換と免疫抑制治療が奏効したNP-SLEの一例 (2014)
  • Author(s): 伊藤 一洸、田中 章仁、勝野 敬之、加藤 規利、鈴木 康弘、加藤 佐和子、石本 卓嗣、尾崎 武徳、小杉 智規、安田 宣成、佐藤 和一、坪井 直毅、水野 正司、伊藤 恭彦、丸山 彰一、松尾 清一
  • Organizer: 第44回日本腎臓学会西部学術大会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] 生体腎移植後に発症したPost-transplant lymphoproliferative disease (PTLD)の一例 (2014)
  • Author(s): 酒井 尊之、鈴木 康弘、坂田 史子、加藤 規利、勝野 敬之、石本 卓嗣、小杉 智規、佐藤 和一、坪井 直毅、水野 正司、丸山 彰一、伊藤 恭彦、松尾 清一
  • Organizer: 第44回日本腎臓学会西部学術大会
  • Place of Presentation: 神戸商工会議所(兵庫県神戸市)
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] 筋痛症状を呈し、CAPD継続が危惧されたPMRの2症例 (2014)
  • Author(s): 小崎 陽平、鈴木 康弘、坂田 史子、加藤 規利、勝野 敬之、石本 卓嗣、小杉 智規、佐藤 和一、坪井 直毅、水野 正司、丸山 彰一、伊藤 恭彦、松尾 清一
  • Organizer: 第44回日本腎臓学会西部学術大会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] 喫煙と特発性膜性腎症の腎予後との関連性について (2014)
  • Author(s): 山口 真、安藤 昌彦、秋山 真一、加藤 佐和子、勝野 敬之、小杉 智規、佐藤 和一、坪井 直毅、安田 宜成、水野 正司、伊藤 恭彦、松尾 清一、丸山 彰一
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] CD163陽性マクロファージ糸球体浸潤ならびに尿中可溶性CD163のループス腎炎活動性指標としての有用性 (2014)
  • Author(s): 遠藤 信英、坪井 直毅、松尾 清一、丸山 彰一
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市))
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] 腹膜透析患者におけるC.E.R.A.投与量に関連する因子の検討 (2014)
  • Author(s): 鈴木 康弘、坂田 史子、勝野 敬之、加藤 規利、尾崎 武徳、小杉 智規、佐藤 和一、坪井 直毅、丸山 彰一、水野 正司、松尾 清一、伊藤 恭彦
  • Organizer: 第59回日本透析医学会学術総会・集会
  • Place of Presentation: 神戸ポートピアホテル(兵庫県神戸市)
  • Year and Date: 2014-06-12 – 2014-06-15
• [Presentation] 長期腹膜透析（PD）患者に生じた左房内calcified amorphous tumor（CAT）の1例 (2014)
  • Author(s): 田中 章仁、水野 正司、大島 英揮、筑紫 さおり、石川 英昭、坂田 史子、加藤 規利、鈴木 康弘、勝野 敬之、尾崎 武徳、小杉 智規、坪井 直毅、佐藤 和一、丸山 彰一、松尾 清一、伊藤 恭彦
  • Organizer: 第59回日本透析医学会学術総会・集会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2014-06-12 – 2014-06-15
• [Presentation] Spironolactone improving intrarenal renin-angiotensin system activation in type ２diabetic nephropathy patients with overt albuminuria. (2014)
  • Author(s): Sawako Kato, Shoichi Maruyama, Hirofumi Makino, Jun Wada,Takashi Uzu, Hisazumi Araki, Daisuke Koya, Keizo Kanasaki, Akira Nishiyama, Hiroyuki Kobori, Enyu Imai, Masahiko Ando, Yutaka Oiso, Seiichi Matsuo
  • Organizer: The 14th Asian Pacific Congress of Nephrology
  • Place of Presentation: 品川プリンスホテル(東京都港区)
  • Year and Date: 2014-05-14 – 2014-05-17
• [Presentation] ASSOCIATION OF GLOMERULAR MACROPHAGE PHENOTYPES AND URINE SOLUBLE CD163 WITH DISEASE ACTIVITY IN HUMAN LUPUS NEPHRITIS. (2014)
  • Author(s): N. Endo, N. Tsuboi, K. Furuhashi, S. Matsuo, S. Maruyama.
  • Organizer: 9th International Congress on Autoimmunity
  • Place of Presentation: Nice（France)
• [Presentation] LOW SERUM CULTURED ADIPOSE-DERIVED MESENCHIMAL STROMAL CELLS AMERIORATE RAT MODEL WITH UNILATERAL URETERAL OBSTRUCTION. (2013)
  • Author(s): Tomoko Abe, Asuka Horinouchi, Hangsoo Kim, Kazuhiro Huruhashi, Shinichi Aiyama, Takayuki Katsuno, Kaoru Yasuda, Takinori Ozaki, Naotake Tsuboi, Seiichi Matsuo, Shouichi Maruyama.
  • Organizer: The World Congress of Nephrology 2013
  • Place of Presentation: Hong Kong（China）
• [Presentation] SERUM-STARVED ADIPOSE-DERIVED STROMAL CELLS AMELIORATE RENAL INJURY ASSOCIATED WITH RAT CRESCENTIC GLOMERULONEPHRITIS BY PROMOTING THE GENERATION OF IMMUNOREGULATORY MACROPHAGES. (2013)
  • Author(s): Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu,Hangsoo Kim, Takayuki Katsuno,Seiichi Matsuo, Shoichi Maruyama.
  • Organizer: The World Congress of Nephrology 2013
  • Place of Presentation: Hong Kong（China）
• [Presentation] RAT ADIPOSE TISSUE-DERIVED STROMAL CELLS ATTENUATE PERITONEAL INJURIES IN RAT ZYMOSAN-INDUCED PERITONITIS ACCOMPANIED BY COMPLEMENT ACTIVATION. (2013)
  • Author(s): Hangsoo Kim,Masashi Mizuno,Kazuhiro Furuhashi,Takayuki Katsuno,Takenori Ozaki,Kaoru Yasuda, Naotake Tsuboi, Yasuhiko Ito,Shoichi Maruyama, Matsuo Seiichi.
  • Organizer: The World Congress of Nephrology 2013
  • Place of Presentation: Hong Kong（China）
• [Presentation] Serum-starved adipose-derived stromal cells ameliorate rat crescentic glomerulonephritis by promoting immunoregulatory macrophages. (2013)
  • Author(s): Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu, Yiqin Shi, Hangsoo Kim, Takayuki Katsuno, Yosuke Saka, Takenori Ozaki, Waichi Sato, Enyu Imai, Seiichi Matsuo, Shoichi Maruyama
  • Organizer: ISSCR(International Society for Stem Cell Research) 11th Annual Meeting
  • Place of Presentation: Boston（USA)
• [Presentation] Mac-1 Deficiency Protects Mouse from Pulmonary Hemorrhage, whereas Exacerbates Glomerulonephritis in Experimental Model of Systemic Lupus Erythematosus. (2013)
  • Author(s): Yiqin Shi, Naotake Tsuboi, MD, PhD, Kazuhiro Furuhashi, MD, PhD, Shoichi Maruyama, MD, Seiichi Matsuo, MD
  • Organizer: Kidney Week 2013
  • Place of Presentation: Atlanta(USA)
• [Presentation] Serum-starved Adipose-derived Stromal Cells Ameliorate Rat Crescentic Glomerulonephritis By Promoting Immunoregulatory Macrophages. (2013)
  • Author(s): Naotake Tsuboi, Kazuhiro Furuhashi, Seiichi Matsuo, Shoichi Maruyama
  • Organizer: Forefronts in Nephrology Florence
  • Place of Presentation: フィレンツェ(イタリア)
• [Presentation] 片側尿管結紮モデルラットに対する低血清培養脂肪由来間葉系幹細胞の効果 (2013)
  • Author(s): 阿部 智子、堀之内 明日花、金 恒秀、古橋 和拡、秋山 真一、勝野 敬之、安田 香、尾崎 武徳、坪井 直毅、松尾 清一、丸山 彰一
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区）
• [Presentation] Zymosan投与により誘導される補体依存性腹膜炎モデルに対する脂肪由来間葉系幹細胞の有用性 (2013)
  • Author(s): 金 恒秀、水野 正司、古橋 和拡、勝野 敬之、安田 香、尾崎 武徳、坪井 直毅、伊藤 恭彦、松尾 清一、丸山 彰一
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区）
• [Presentation] ラットanti-GBM腎炎に対する脂肪由来間葉系幹細胞治療で誘導されるマクロファージフェノタイプの詳細検討 (2013)
  • Author(s): 古橋 和拡、坪井 直毅、清水 明日花、金 恒秀、勝野 敬之、安田 香、尾崎 武徳、佐藤 和一、松尾 清一、丸山 彰一
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区）
• [Presentation] Fabry病による慢性腎不全で長期に安定した腹膜透析(PD)施行中の一例 (2013)
  • Author(s): 武藤玲子、勝野敬之、鈴木康弘、安田香、尾崎武徳、小杉智規、安田宜成、佐藤和一、坪井直毅、水野正司、伊藤恭彦、丸山彰一、松尾清一
  • Organizer: 第58回日本透析医学会学術集会
  • Place of Presentation: 福岡国際センター(福岡市)
• [Presentation] 腹膜透析患者におけるC.E.R.A投与の検討 (2013)
  • Author(s): 鈴木康弘、勝野敬之、安田香、尾崎武徳、小杉智規、佐藤和一、坪井直毅、水野正司、丸山彰一、伊藤恭彦、松尾清一
  • Organizer: 第58回日本透析医学会学術集会
  • Place of Presentation: 福岡国際会議場(福岡市)
• [Presentation] 血友病A,慢性C型肝硬変、HIV三者合併の血液透析導入１症例 (2013)
  • Author(s): 坪井 直毅、武藤玲子、安田香、佐藤和一、丸山彰一、松尾清一
  • Organizer: 第58回日本透析医学会学術集会
  • Place of Presentation: マリンメッセ福岡(福岡市)
• [Presentation] 腹膜透析(PD)導入時に、高度の好酸球性腹膜炎にステロイド治療が有効であった一例 (2013)
  • Author(s): 水野正司、鈴木康弘、勝野敬之、尾崎武徳、佐藤和一、坪井直毅、丸山彰一
  • Organizer: 第58回日本透析医学会学術集会
  • Place of Presentation: マリンメッセ福岡(福岡市)
• [Presentation] 脂肪由来間葉系幹細胞を用いた急性呼吸窮迫症候群への治療戦略 (2013)
  • Author(s): 三村哲史，坪井直毅，橋本直純，清水明日花，金恒秀，古橋和拡，松尾清一，丸山彰一
  • Organizer: 第34回日本炎症再生医学会
  • Place of Presentation: 国立京都国際会館(京都市左京区)
• [Presentation] 低血清培養脂肪由来間葉系幹細胞の創傷治癒促進効果についての検討 (2013)
  • Author(s): 阿部 智子，尾崎 武徳，堀之内明日花，金 恒秀，古橋 和拡，秋山 真一，勝野 敬之，安田香，坪井直毅，松尾清一，丸山彰一
  • Organizer: 第34回日本炎症再生医学会
  • Place of Presentation: 国立京都国際会館(京都市左京区)
• [Presentation] Mac-1 deficiency protects mouse from pulmonary hemorrhage, whereas (2013)
  • Author(s): 石 一沁，坪井 直毅，古橋 和拡，Mayadas Tanya，丸山 彰一，松尾 清一
  • Organizer: 第34回日本炎症再生医学会
  • Place of Presentation: 国立京都国際会館(京都市左京区)
• [Presentation] SLEに伴うPodocyte infoldingの1例 (2013)
  • Author(s): 田中 章仁、神谷 文隆、永原 靖子、鈴木 康弘、加藤 規利、勝野 敬之、尾崎 武徳、小杉 智規、佐藤 和一、坪井 直毅、水野 正司、丸山 彰一、伊藤 恭彦、松尾 清一
  • Organizer: 第43回日本腎臓学会西部学術大会
  • Place of Presentation: 松山全日空ホテル(愛媛県松山市)
• [Presentation] 視力障害で発症し多発性硬化症と診断した腹膜透析患者の一例 (2013)
  • Author(s): 永原 靖子、鈴木 康弘、加藤 規利、勝野 敬之、尾崎 武徳、小杉 智規、佐藤 和一、坪井 直毅、水野 正司、丸山 彰一、伊藤 恭彦、松尾 清一
  • Organizer: 第43回日本腎臓学会西部学術大会
  • Place of Presentation: 松山全日空ホテル(愛媛県松山市)