The suppression of macrophage-mediated xenogeneic rejection by human TIGIT and PQA-18

• Project/Area Number: 19K09092
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Osaka University
• Principal Investigator: Maeda Akira 大阪大学, 医学系研究科, 招へい教員 (00319708)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 異種移植 / マクロファージ / PQA-18 / TIGIT / 自然免疫 / MDSC / PAK2阻害剤

Outline of Research at the Start

ヒトTIGIT(T-cell immunoreceptor with Ig and ITIM domains)分子等をブタ細胞に発現させることにより異種拒絶反応を抑制しうるかを検討する。一方、新規免疫抑制剤、PQA-18は末梢血単球より強力な免疫抑制作用を持つmyeloid derived suppressor cell (MDSC)を誘導する。PQA-18誘導MDSCとヒトTIGITとの相補的、相加的マクロファージ抑制効果をin vitroおよびin vivoの系を用いて検討する。

Outline of Final Research Achievements

In this study, the suppressive effect of a novel immunosuppression, PQA-18, and human TIGIT on porcine cells was investigated. Both PQA-18 and human TIGIT on porcine cells significantly suppressed macrophage-mediated cytotoxicity. Furthermore,to study the mechanism of the suppression by TIGIT, the phosphorylation of SHP-1 was assessed using a western blotting analysis.Our study revealed that human TIGIT induced a significant phosphorylation of SHP-1 in macrophages.These findings indicate that PQA-18 and human TIGIT are effective measures against xenogeneic rejection.

Academic Significance and Societal Importance of the Research Achievements

ブタの臓器や細胞を用いた異種移植は今後移植におけるドナー不足を解決するために非常に重要な課題である。今回の研究でPQA-18という新たな免疫抑制剤とヒトTIGITの遺伝子導入が異種移植拒絶反応の抑制に有効であることが分かった。つまりヒトTIGIT分子を発現するブタを作り出すことが異種臓器・細胞の生着率の改善につながることを意味している。また従来の免疫抑制剤に加えてPQA-18を使用することによってブタ細胞および臓器の生着のさらなる改善が見込める。

Research Products

• [Journal Article] The Innate Cellular Immune Response in Xenotransplantation (2022)
  • Author(s): Akira Maeda, et al.
  • Journal Title: Frontiers in Immunology Volume: in press
  • DOI: 10.3389/fimmu.2022.858604
  • Peer Reviewed
• [Journal Article] The strategy for suppression of macrophage-mediated rejection in xenotransplantation. (2020)
  • Author(s): Akira Maeda, Hiroshi Eguchi, Kengo Nakahata, Takuji Kawamura, Kazuaki Yamanaka, Rei Matsuura, Rieko Sakai, Peichi Lo, Mayumi Asada, Hiroomi Okuyama, Shuji Miyagawa
  • Journal Title: Transplantation Volume: 104 Issue: 4 Pages: 675-681
  • DOI: 10.1097/tp.0000000000003024
  • Peer Reviewed
• [Journal Article] The novel immunosuppressant prenylated quinolinecarboxylic acid-18 (PQA-18) suppresses macrophage differentiation and cytotoxicity in xenotransplantation (2019)
  • Author(s): Lo Pei-Chi、Maeda Akira、Kodama Tasuku、Takakura Chihiro、Yoneyama Tomohisa、Sakai Rieko、Noguchi Yuki、Matsuura Rei、Eguchi Hiroshi、Matsunami Katsuyoshi、Okuyama Hiroomi、Miyagawa Shuji
  • Journal Title: Immunobiology Volume: - Issue: 4 Pages: 575-584
  • DOI: 10.1016/j.imbio.2019.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Human TIGIT on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity (2019)
  • Author(s): Noguchi Yuki、Maeda Akira、Lo Pei-Chi、Takakura Chihiro、Haneda Tomoko、Kodama Tasuku、Yoneyama Tomohisa、Toyama Chiyoshi、Tazuke Yuko、Okuyama Hiroomi、Miyagawa Shuji
  • Journal Title: Immunobiology Volume: 224 Issue: 5 Pages: 605-613
  • DOI: 10.1016/j.imbio.2019.07.008
  • Peer Reviewed
• [Presentation] The novel immunosuppressant PQA- 18 suppresses macrophage differentiation cytotoxicity in xenotransplantation and (2019)
  • Author(s): Akira Maeda
  • Organizer: 15th congress of International Xenotransplantation Association
  • Int'l Joint Research
• [Presentation] Human tigit on swine endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity (2019)
  • Author(s): Akira Maeda
  • Organizer: 15th congress of International Xenotransplantation Association
  • Int'l Joint Research