Immunomodulation of mesenchymal stem cells in composite tissue allotransplantation

• Project/Area Number: 20591753
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: 公益財団法人先端医療振興財団 (2010); Kyoto University (2008-2009)
• Principal Investigator: IKEGUCHI Ryosuke 公益財団法人先端医療振興財団, 先端医療センター, 研究員 (80437201)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 間葉系幹細胞 / 複合組織同種移植 / 免疫抑制 / 拒絶 / 手移植 / 移植再生医療 / 外科 / 免疫学 / 複合組織移植 / 移植・再生医療 / 間葉系幹組胞

Research Abstract

Hand transplantations have revolutionized the reconstruction field for patients with hand defects. However, immunosuppressants are essential for maintaining human hand transplant survival despite lethal side effects such as infections, drug toxicity and malignancies. Recent studies indicate that mesenchymal stem cells(MSCs) have some immunomodulatory properties to suppress T cell mediate responses that cause graft rejection. The purpose of this study is to evaluate the effect of intravenous donor MSC infusion for immunomodulation in the rat composite tissue allotransplantation model.
Orthotopic rat hind limb transplantation was performed using donor Wister rats and recipient Lewis rats. The recipient rats were randomly divided into two experimental groups : in group FK, 0.2 mg/kg/day intramuscular tacrolimus were administered to recipient rats for seven consecutive days(days 0.6); in group MSC, recipient rats were injected intravenously with 2×10^6 donor MSCs on day 6 with 0.2 mg/kg/day tacrolimus administered for 7 days.
Graft survival was assessed by daily inspection and histological study. Recipients' immunological reactions were evaluated by serum ELISA, RNA assays and mixed lymhocyte reactivity assays.
The graft survival of group MSC was significantly prolonged in comparison with that of group FK. Cytokine expression analysis of grafted limbs showed that MSC treatment significantly decreased pro-inflammatory cytokine expression. An in vitro mixed lymphocyte reaction showed MSCs inhibiting T cell proliferation.
MSCs induce T cell hyporesponsiveness and prolong graft survival in the rat composite allotransplantation model. MSCs demonstrate some immuno-modulatory properties that can be accomplished without the need for significant recipient immunosuppression.

Research Products

• [Journal Article] ラット四肢同種移植における骨髄間葉系幹細胞の拒絶反応抑制効果 (2011)
  • Author(s): 池口良輔,柿木良介,三井裕人,青山朋樹,布留守敏,太田壮一,藤田俊史,野口貴志,川那辺圭一,戸口田淳也,中村孝志
  • Journal Title: 日本マイクロ会誌 Volume: 24巻4号 Pages: 412-416
  • NAID: 130004843238
  • Peer Reviewed
• [Presentation] Immunomodulation of mesenchymal stem cells in composite tissue allotransplantation (2011)
  • Author(s): Ryosuke Ikeguchi, Ryosuke Kakinoki, Hiroto Mitsui, Moritoshi Furu, Tomoki Aoyama, Keiichi Kawanabe, Junya Toguchida, Takashi Nakamura
  • Organizer: American Academy of Orthopaedic Surgeons
  • Place of Presentation: San Diego
• [Presentation] Immunomodulation of mesenchymal stem cells in composite tissue allotransplantation (2011)
  • Author(s): Ryosuke Ikeguchi
  • Organizer: 2011年アメリカ整形外科学会
  • Place of Presentation: サンディエゴ(アメリカ合衆国)
• [Presentation] ラット四肢同種移植におけるレシピエント骨髄間葉系幹細胞による免疫応答制御 (2010)
  • Author(s): 池口良輔
  • Organizer: 第37回日本マイクロサージャリー学会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-18
• [Presentation] Immunomodulation of mesenchymal stem cells in composite tissue allotransplantation (2010)
  • Author(s): Ryosuke Ikeguchi, Ryosuke Kakinoki, Hiroto Mitsui, Tomoki Aoyama, Junya Toguchida, Takashi Nakamura
  • Organizer: America Society for Surgery of the Hand
  • Place of Presentation: Boston
• [Presentation] ラット四肢同種移植における骨髄間葉系幹細胞による免疫応答制御 (2010)
  • Author(s): 池口良輔,柿木良介,三井裕人,布留守敏,太田壮一,藤田俊史,野口貴志,青山朋樹,川那辺圭一,戸口田淳也,中村孝志
  • Organizer: 第37回日本マイクロサーシャリー学会
  • Place of Presentation: 名古屋
• [Presentation] Immunomodulation of mesenchymal stem cells in composite tissue allotransplantation (2010)
  • Author(s): Ryosuke Ikeguchi
  • Organizer: 第65回アメリカ手の外科学会
  • Place of Presentation: ボストン(アメリカ合衆国)
• [Presentation] 四肢同種移植における骨髄間葉幹細胞の拒絶反応抑制効果 (2009)
  • Author(s): 池口良輔, ほか
  • Organizer: 第36回日本マイクロサージャリー学会
  • Place of Presentation: 徳島
  • Year and Date: 2009-10-23