The effect and mechanism of Vitamin-D analog on induction of transplant tolerance

• Project/Area Number: 13671418
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: Fukuoka University
• Principal Investigator: IWASAKI Akinori (2002) Fukuoka University, School of Medicine, Lecturer, 医学部, 講師 (50248506); 米田 敏 (2001) 福岡大学, 医学部, 助手 (90309922)
• Co-Investigator(Kenkyū-buntansha): SHIRAISHI Takeshi Fukuoka University, School of Medicine, Lecturer, 医学部, 講師 (10216179) ; KAWAHARA Katsunobu Fukuoka University, School of Medicine, Associate Professor, 医学部, 助教授 (80152990) ; SHIRAKUSA Takayuki Fukuoka University, School of Medicine, Professor, 医学部, 教授 (20038863) ; 岩崎 昭憲 福岡大学, 医学部, 講師 (50248506)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: Transplantation / Rejection / Lung / Janus Kinase 3 / Inter leukin 2 / Tyrphostin / Janus Kinase / Calcineurin / Tyrphostin-AG490 / 臓器移植 / 肺 / ラット / 拒絶反応 / Constimulatopry signal / Tryphostin A / Dihydroxyvitamin D3

Research Abstract

This project was primarily entitled as "The effect and mechanism of Vitamin-D analog on induction of transplant tolerance" expecting the Vitamin-D analog inhibit the costimulation signal (2nd signal) between antigen presenting cell and helper T cell during acute rejection. However, our preliminary investigation using rat lung transplant model revealed that the effect of Vitamin-D analog on suppression of acute rejection was insufficient. Thus we changed the project to investigate the effect of Tyrphostin AG490, a selective inhibitor of the JAK3/STAT pathway, on suppression of lung acute rejection.
Janus kinase 3 (Jak 3) is a cytoplasmic tyrosine kinase activated by cytokines that utilize the common interleukin-2 receptor gamma chain, such as IL-2, 4, 7, 9, 13, and 15. This pathway is named as 3rd signal on proliferation of effector T cell on allograft rejection. We examined the effects of the tyrosine kinase inhibition by Tyrosine AG490 using rat lung allograft model.
Our investigation demonstrated that AG 490, injected at a dose of 10-20mg/kg daily intraperitoneally, effectively suppressed rat lung allograft rejection pathologically and radiographically. Additionally, the effect of AG490 was shown to be dose dependent. Flow cytometric analysis of BALF (bronchio-alveolar lavage fluid) lymphocyte between no treatment recipient and AG490 recipient revealed that Th1/Th2 cytokine production was suppressed by AG490.