Study on prolonging survival of small intestine grafts by inhibiting macrophages

• Project/Area Number: 17K17001
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatric surgery
• Research Institution: Hyogo Medical University (2019); Osaka University (2017-2018)
• Principal Investigator: Kodama Tasuku 兵庫医科大学, 医学部, 病院助手 (60771045)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 小腸移植 / マクロファージ / 免疫抑制 / ラット / 臓器移植 / 拒絶抑制 / 移植免疫 / 移植・再生医療

Outline of Final Research Achievements

The effect of PQA-18, a novel immunosuppressive agent that inhibits PAK-2 and suppresses cytokine production and macrophage (Mφ) ifferentiation/proliferation, was evaluated using a rat small intestine transplant model.
Recipients were administered PQA-18 (4 mg/kg) intraperitoneal injection from post-operative day1 (POD1) to two weeks.The survival time of the graft was prolonged in the PQA administered group (PQA) than in the non-administration group (ITx). At POD6, suppression of recipient T cell proliferation, and suppression of Mφ infiltration into graft lymph nodes were observed in the PQA group.Further, when 20μM of PQA-18 was added to bone marrow stem cells and cultured, suppression of differentiation into Mφ was observed.
It was found that PQA-18 prolongs the survival of small intestine grafts and suppresses the infiltration of Mφ into the grafts and lymph nodes.

Academic Significance and Societal Importance of the Research Achievements

小腸移植後のグラフト生存期間は他の臓器と比較すると芳しくない。これは小腸自体が外界と接するためマクロファージといった自然免疫が発達していることと、既存の免疫抑制剤ではしばしば腎機能障害を認めることが原因として考えられる。
今回、ラット小腸移植後にマクロファージの増殖・分化を抑制する新規免疫抑制剤であるPQA-18を投与したところ、腎機能障害といった副作用なく、小腸移植グラフトの生存期間の延長を認め、グラフトリンパ節内のマクロファージ減少を認めた。今後、既存の免疫抑制剤と併用することで、副作用を軽減し小腸移植グラフトのさらなる生存期間延長が期待できる可能性が考慮された。

Research Products

• [Journal Article] The effect of a novel immunosuppressive drug, a PAK-2 inhibitor, on macrophage differentiation/polarization in a rat small intestinal transplantation model (2019)
  • Author(s): Kodama Tasuku、Maeda Akira、Lo Pei-chi、Noguchi Yuki、Toyama Chiyoshi、Takama Yuichi、Ueno Takehisa、Tazuke Yuko、Eguchi Hiroshi、Matsunami Katsuyoshi、Miyagawa Shuji、Okuyama Hiroomi
  • Journal Title: Transplant Immunology Volume: 57 Pages: 101246-101246
  • DOI: 10.1016/j.trim.2019.101246
  • Peer Reviewed / Open Access
• [Presentation] 小腸移植における新規免疫抑制薬PQA-18の効果 (2020)
  • Author(s): 児玉 匡、前田 晃、Lo Pei-chi、上野豪久、田附裕子、江口 寛、松波勝義、宮川周士、奥山宏臣
  • Organizer: 第57回日本小児外科学会総会 （9月）
• [Presentation] The effect of a novel immunosuppressive drug, PQA-18, in rat small intestinal transplantation (2019)
  • Author(s): Tasuku Kodama, Akira Maeda, Lo, Pei-chi, Yuki Noguchi, Rieko Sakai, Yuichi Takama, Takehisa Ueno, Yuko Tazuke, Katsuyoshi Matsunami, Syuji Miyagawa, Hiroomi Okuyama
  • Organizer: 16th International Congress of the Intestinal Rehabilitation and Transplant Association
  • Int'l Joint Research
• [Presentation] 小腸移植における新規免疫抑制薬PQA18の効果 (2019)
  • Author(s): 児玉 匡、前田晃、Lo Pei-chi、高倉千裕、野口侑記、上野豪久、田附裕子、江口 寛、松波勝義、宮川周士、奥山宏臣
  • Organizer: 第55回日本移植学会総会
• [Presentation] 小腸移植における新規免疫抑制薬PQA-18の効果 (2019)
  • Author(s): 児玉 匡
  • Organizer: 第31回日本小腸移植研究会
• [Presentation] 小腸移植における新規免疫抑制薬X-8の効果 (2018)
  • Author(s): 児玉 匡
  • Organizer: 第54回日本移植学会総会