Blocking of CCR5 and CXCR3 Suppresses Acute and Chronic Renal Allograft Rejection

• Project/Area Number: 23791753
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Osaka University
• Principal Investigator: OKUMI Masayoshi 大阪大学, 医学系研究科, 助教 (60512978)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腎移植 / 拒絶反応 / ケモカイン / 国際情報交流

Research Abstract

A combined therapy involving cyclosporin A (CsA) and CCR5/CXCR3 antagonistresulted in decreased macrophage infiltration, and graft survival was substantiallyprolonged in a rat kidney transplant model. The dual blocking of CCR5/CXCR3 can beuseful in decreasing rejection. This mechanism acts, not only to block T cell recruitment to a kidney graft but also to suppress the infiltration of macrophages to tubules, which leads to tubulitis. Thus, the dual blocking of both receptors has the potential to serve as a new therapeutic target in the future.

Research Products

• [Journal Article] A single daily dose enhances the adherence to immunosuppressive treatment in kidney transplant recipients: a cross-sectional study. (2013)
  • Author(s): Obi Y, Ichimaru N, Kato T, Kaimori JY, Okumi M, Yazawa K, Rakugi H, Nonomura N, Isaka Y, Takahara S
  • Journal Title: Clin Exp Nephrol. Volume: 17 Pages: 310-5
  • NAID: 10031169481
• [Journal Article] Blocking of CCR5 and CXCR3 Suppresses the Infiltration of Macrophages in Acute Renal Allograft Rejection (2012)
  • Author(s): Kakuta Y, Okumi M*, Miyagawa S, Tsutahara K, Abe T, Yazawa K, Matsunami K, Otsuka H, Takahara S, Nonomura N
  • Journal Title: Transplantation Volume: 93 Pages: 24-31
• [Journal Article] Hepatocyte growth factor sustains T regulatory cells and prolongs the survival of kidney allografts in major histocompatibility complex-inbred CLAWN-miniature swine (2012)
  • Author(s): Oku M, Okumi M, Shimizu A, Sahara H, Setoyama K, Nishimura H, Sada M, Scalea J, Ido A, Sachs DH, Tsubouchi H, Yamada K.
  • Journal Title: Transplantation Volume: 93 Pages: 148-55
• [Journal Article] Carbamylated erythropoietin ameliorates cyclosporine nephropathy without stimulating erythropoiesis (2012)
  • Author(s): Abe T, Isaka Y, Imamura R, Kakuta Y, Okumi M, Yazawa K, Ichimaru N, Tsuda H, Nonomura N, Takahara S, Okuyama A.
  • Journal Title: Cell Transplant Volume: 21 Pages: 571-80
• [Journal Article] A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney. (2012)
  • Author(s): Imamura R, Isaka Y, Sandoval RM, Ichimaru N, Abe T, Okumi M, Yazawa K, Kitamura H, Kaimori J, Nonomura N, Rakugi H, Molitoris BA, Takahara S.
  • Journal Title: Clin Exp Nephrol. Volume: 16 Pages: 852-62
  • NAID: 10031145917
• [Journal Article] Hydrogen-rich University of Wisconsin solution attenuates renal cold ischemia-reperfusion injury (2012)
  • Author(s): Abe T, Li XK, Yazawa K, Hatayama N, Xie L, Sato B, Kakuta Y, Tsutahara K, Okumi M, Tsuda H, Kaimori JY, Isaka Y, Natori M, Takahara S, Nonomura N
  • Journal Title: Transplantation Volume: 94 Pages: 14-21
• [Journal Article] The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes in rat renal ischemia reperfusion. (2012)
  • Author(s): Tsutahara K, Okumi M*, Yoichi Kakuta Y, Abe T, Yazawa K, Miyagawa S, Matsunami K, Otsuka H, Kaimori J, Takahara S, Nonomura N.
  • Journal Title: Nephrol Dial Transplant Volume: 27 Pages: 3799-806
• [Journal Article] Successful kidney transplantation for a dialysis patient with anthracycline-inducedcardiomyopathy: a case report (2012)
  • Author(s): Yoneda S, Okumi M*,, Yamaguchi S.
  • Journal Title: CEN case reports
• [Journal Article] Orally active vitamin d for potential chemoprevention of posttransplant malignancy (2012)
  • Author(s): Obi Y, Ichimaru N, Hamano T, Tomida K, Matsui I, Fujii N, Okumi M, Kaimori JY, Yazawa K, Kokado Y, Tsubakihara Y, Nonomura N, Rakugi H, Takahara S, Isaka Y
  • Journal Title: Cancer Prev Res (Phila) Volume: 5 Pages: 1229-35
• [Journal Article] Tolerogenicity of donor major histocompatibility complex-matched skin grafts in previously tolerant Massachusetts general hospital miniature swine (2012)
  • Author(s): Weiner J, Scalea J, Ishikawa Y, Okumi M, Griesemer A, Hirakata A, Etter J, Gillon B, Moran S, Shimizu A, Yamada K, Sachs DH
  • Journal Title: Transplantation Volume: 94 Pages: 1192-9
• [Journal Article] Blocking of CCR5 and CXCR3 Suppresses the Infiltration of Macrophages in Acute Renal Allograft Rejection. (2012)
  • Author(s): Yoichi Kakuta
  • Journal Title: Transplantation Volume: 93 Issue: 1 Pages: 24-31
  • DOI: 10.1097/tp.0b013e31823aa585
  • Peer Reviewed
• [Journal Article] The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes in rat renal ischemia reperfusion. (2012)
  • Author(s): Koichi Tsutahara
  • Journal Title: Nephrol Dial Transplant Volume: 27 Issue: 10 Pages: 3799-3806
  • DOI: 10.1093/ndt/gfs360
  • Peer Reviewed
• [Journal Article] Epigallocatechin-3-gallate protects kidneys from ischemia reperfusion injury by HO-1 upregulation and inhibition of macrophage infiltration. (2011)
  • Author(s): Kakuta Y, Okumi M*, Isaka Y, Tsutahara K, Abe T, Yazawa K, Ichimaru N, Matsumura K, Hyon SH, Takahara S, Nonomura N
  • Journal Title: Transplant Int. Volume: 24 Pages: 514-522
• [Journal Article] Prostatic inflammation detected in initial biopsy specimens and urinary pyuria are predictors of negative repeat prostate biopsy (2011)
  • Author(s): Fujita K, Hosomi M, Tanigawa G, Okumi M, Fushimi H, Yamaguchi S
  • Journal Title: J Urol Volume: 185 Pages: 1722-1727
• [Journal Article] Safety and efficacy of administering the maximal dose of candesartan in renal transplant recipients. (2011)
  • Author(s): Okumi M, Kawada N, Ichimaru N, Kitamura H, Abe T, Imamura R, Kojima Y, Kokado Y, Isaka Y , Rakugi H, Nonomura N, Moriyama T, Takahara S
  • Journal Title: Clin Exp Nephrol Volume: 15 Pages: 907-915
  • NAID: 10030341870
• [Presentation] CXCL10 による移植腎障害の予測. (2013)
  • Author(s): 蔦原宏一、奥見雅由、山中和明、加藤大悟、矢澤浩治、市丸直嗣、高原史郎、野々村祝夫
  • Organizer: 第46回日本臨床腎移植学会
  • Place of Presentation: 千葉県浦安市
  • Year and Date: 2013-02-01
• [Presentation] 心停止後ラット腎臓の functional MRI を用いた詳細な障害の検討 (2012)
  • Author(s): 貝森淳哉、岩井聡美、小林英司、畑中雅喜、津田秀年、小尾義嗣、奥見雅由、矢澤浩治、市丸直嗣、楽木宏美、野々村祝夫、猪阪善隆、高原史郎.
  • Organizer: 第39回日本臓器生物保存医学会学術集会
  • Place of Presentation: 福島県福島市
  • Year and Date: 2012-11-16
• [Presentation] CD8+NKT 細胞および CD4+T 細胞はラット腎阻血再灌流障害の形成に関与する (2012)
  • Author(s): 蔦原宏一、奥見雅由、角田洋一、山中和明、加藤大悟、宮川周士、矢澤浩治、高原史郎、 野々村祝夫
  • Organizer: 第39回日本臓器生物保存医学会学術集会
  • Place of Presentation: 福島県福島市
  • Year and Date: 2012-11-16
• [Presentation] CD8+NKT 細胞および CD4+T 細胞はラット腎阻血再灌流障害の形成に関与する (2012)
  • Author(s): 蔦原宏一、奥見雅由、角田洋一、矢澤浩治、宮川周士、高原史郎、野々村 祝夫
  • Organizer: 第48回日本移植学会総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2012-09-21
• [Presentation] 多光子顕微鏡による Intravital live imaging を用いたラット急性拒絶モデル腎臓の観察 (2012)
  • Author(s): 貝森淳哉、角田洋一、津田秀年、小尾義嗣、畑中雅喜、奥見雅由、矢澤浩治、猪阪善隆、楽木宏美、野々村祝夫、高原史郎
  • Organizer: 第48回日本移植学会総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2012-09-21
• [Presentation] 腎移植後の急性 T 細胞関連型拒絶反応における Membrane Cofactor Protein の発現 (2012)
  • Author(s): 宮川周士、角田洋一、奥見 雅由
  • Organizer: 第49回補体シンポジウム
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2012-08-24
• [Presentation] 腎虚血再灌流障害における卵膜由来間葉系幹細胞の抗炎症作用の機序検討 (2012)
  • Author(s): 津田秀年、山原研一、奥見雅由、矢澤浩治、貝森淳哉、猪阪善隆、池田智明、高原史郎
  • Organizer: 第55回日本腎臓学会学術集会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2012-06-01
• [Presentation] 腎移植後急性細胞性拒絶反応における補体制御因子 CD46 の発現がGraft Outcome に与える影響について (2012)
  • Author(s): 角田洋一、奥見雅由、加藤大悟、蔦原宏一、阿部豊文、矢澤浩治、高原史郎、野々村祝夫
  • Organizer: 第100回日本泌尿器科学会総会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2012-04-21
• [Presentation] 腎阻血再灌流障害におけるケモカインの発現と T 細胞浸潤抑制による腎保護効果 (2012)
  • Author(s): 蔦原宏一、奥見雅由、角田洋一、加藤大悟、阿部豊文、矢澤浩治、高原史郎、野々村祝夫
  • Organizer: 第100回日本泌尿器科学会総会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2012-04-21
• [Presentation] Multi-Photon Microscopy Based Kidney Live Imaging Identifies a Series of Micro-Circulation Changes in a Rat Acute Kidney Rejection Model (2012)
  • Author(s): J. Y. Kaimori, T. Abe, H. Tsuda, M. Ishii, M. Okumi, K. Yazawa, Y . Isaka, H. Rakugi, N. Nonomura, S. Takahara
  • Organizer: American Transplant Congress
  • Place of Presentation: Bosoton, USA
• [Presentation] Adipose Tissue ‐Derived Stem Cells Infusion Prevents Acute Cellular Rejection in Rat Kidney Transplantation (2012)
  • Author(s): T . Kato, K. Yazawa, M. Tanemura, Y . Kakuta, K. Tsutahara, M. Okumi, Y . Iwagami, Y . Ohmura, H. Nagano, S. Takahara, Y . Doki, M. Mori, and N. Nonomura.
  • Organizer: 24th International Congress of the Transplantation Congress
  • Place of Presentation: Berlin, German
• [Presentation] CD8+NKT cells and CD4+T cells mediate ischemia reperfusion injury at early phase in rat experimental model. (2012)
  • Author(s): K. Tsutahara, M. Okumi, Y . Kakuta, T . Kato, K. Yazawa, S. Miyagawa, J. Kaimori, S. Takahara, and N. Nonomura.
  • Organizer: 32nd Congress of the Societe Internationale d'Urologie
  • Place of Presentation: Fukuoka, Japan
• [Presentation] CD8+NKT細胞およびCD4+T細胞はラット腎阻血再灌流障害の形成に関与する (2012)
  • Author(s): 蔦原宏一
  • Organizer: 第48回日本移植学会総会
  • Place of Presentation: 愛知県名古屋市
• [Presentation] 水素含有 UW solution は移植腎における虚血再灌流傷害を軽減する (2011)
  • Author(s): 阿部豊文、李 小康、奥見雅由、矢澤浩治、貝森淳哉、高原史郎、野々村祝夫
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2011-10-06
• [Presentation] 急性拒絶反応におけるマクロファージのケモカイン受容体 CCR5 とCXCR3 の役割解明 (2011)
  • Author(s): 角田洋一、奥見雅由、蔦原宏一、阿部豊文、矢澤浩治、宮川周士、高原史郎、野々村祝夫
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2011-10-06
• [Presentation] CCR5/CXCR3 antagonist 投与によるラット腎阻血再灌流障害モデルにおける腎障害抑制効果 (2011)
  • Author(s): 蔦原宏一、奥見雅由、加藤大悟、角田洋一、阿部豊文、矢澤浩治、宮川周士、高原史郎、野々村祝夫
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2011-10-06
• [Presentation] 腎虚血再灌流障害における卵膜由来間葉系幹細胞を用いた治療効果の検討 (2011)
  • Author(s): 津田秀年、山原研一、奥見雅由、矢澤浩治、堀尾 勝、貝森淳哉、猪阪善隆、池田智明、高原史郎
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2011-06-17
• [Presentation] CCR5/CXCR3 antagonist のラット腎阻血再灌流障害モデルにおける腎障害抑制効果 (2011)
  • Author(s): 蔦原宏一、奥見雅由、角田洋一、阿部豊文、矢澤浩治、松浪勝義、宮川周士、貝森淳哉、高原史郎、野々村祝夫
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2011-04-23
• [Presentation] ラット腎移植急性拒絶反応モデルにおいてCCR5/CXCR3 antagonist は T 細胞およびマクロファージの recruitment を抑制する (2011)
  • Author(s): 角田洋一、奥見雅由、蔦原宏一、阿部豊文、矢澤浩治、松浪勝義、宮川周士、貝森淳哉、高原史郎、野々村祝夫
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2011-04-22
• [Presentation] ラット腎移植モデルにおける水素含有 UW solution の腎保護作用 (2011)
  • Author(s): 阿部豊文、李 小康、畑山直之、謝 琳、佐藤文平、角田洋一、蔦原宏一、奥見雅由、矢澤浩治、貝森淳哉、名取道也、高原史郎、野々村祝夫
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2011-04-21
• [Presentation] Successful Preservation of the Kidney Grafts under Desiccating Conditions with a Mixture of Carbon Monoxide and Oxygen Gases in Rat Kidney Transplantation Model (2011)
  • Author(s): T. Abe, XK .Li, M. Okumi, N. Hatayama, L. Xie, Y. Kakuta, K. Tsutahara, K. Yazawa, J. Kaimori, Y. Isaka, S. Takahara, and N. Nonomura
  • Organizer: American Transplant Congress
  • Place of Presentation: Philadelphia, USA
• [Presentation] Evidence for a Balance between Peripheral Alloreactive and Regulatory T -Cells in the Maintenance of Tolerance (2011)
  • Author(s): J.R. Scalea, H. Nishimura, M. Okumi, S.G. Moran, B. Gillon, T. Cormack, D.H. Sachs, and K. Yamada
  • Organizer: American Transplant Congress
  • Place of Presentation: Philadelphia, USA
• [Presentation] Allogeneic Fetal Membrane-Derived Mesenchymal Stem Cells Attenuate Renal Ischemia Reperfusion Injury inRats (2011)
  • Author(s): H. Tsuda, K. Yamahara, M. Okumi, K.Yazawa, N. Ichimaru, J. Kaimori, Y. Isaka, T. Ikeda, and S. Takahara.
  • Organizer: American Transplant Congress
  • Place of Presentation: Philadelphia, USA
• [Presentation] Hydrogen-Rich UW Solution Attenuates Renal Cold Ischemia Reperfusion Injury. (2011)
  • Author(s): T. Abe, XK .Li, N. Hatayama, L. Xie, B. Sato, Y. Kakuta, K. Tsutahara, M. Okumi, K. Yazawa, J. Kaimori, M. Natori, S. Takahara, and N. Nonomura.
  • Organizer: American Transplant Congress
  • Place of Presentation: Philadelphia, USA
• [Presentation] NonomuraEpigallocatechin-3-GallateProtects Kidneys from Ischemia Reperfusion Injury by Inhibition of Macrophage Infiltration. (2011)
  • Author(s): Y. Kakuta, M. Okumi, K. Tsutahara, K. Yazawa, K. Matsumura, S.H. Hyon, S. Takahara, and N.
  • Organizer: AUA Annual Meeting
  • Place of Presentation: Washington D.C., USA
• [Presentation] CCR5/CXCR3 Blockade Prolonged Kidney Allograft Survival with or without Cyclosporine via the Inhibition of T -Cell and Macrophage Recruitment. (2011)
  • Author(s): Y. Kakuta, M. Okumi, K. Tsutahara, T. Abe, K. Yazawa, K. Matsunami, S. Miyagawa, S. Takahara, and N. Nonomura
  • Organizer: AUA Annual Meeting
  • Place of Presentation: Washington D.C., USA