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

点击翻译按钮获取中文摘要

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.