Development of the new immunological tolerance induction which uses Notch ligands in islet transplantation

研究表明，Delta家族是Notch配体家族中的一员，它将免疫反应控制在积极的方向上。但是，对于另一个Notch配体家族--锯齿状家族在免疫应答中的作用，目前还不清楚的部分还有很多。这一次我们重点研究了Jagge1在免疫反应中的功能和特别是免疫反应的调控作用。体外实验的结果表明，在Delta1启示性树突状细胞中，它可以识别细胞增殖的加强，但与对照组相比，它在锯齿I启示性树突状细胞的增殖中有所减少(报道在日本外科学会第106届年会上)。本研究表明，Jagged1有可能在负向控制免疫反应，并通过T淋巴细胞将供体特有的低反应性引入移植免疫。体内实验结果表明，在A20细胞中，导入Jagged2的肿瘤面积较对照缩小。另外，引入Jagged2基因后，干扰素-α和颗粒酶B的分泌增加，可以识别NK细胞的激活。从这些结果可以看出，Notch配体不仅参与了移植免疫，也参与了肿瘤免疫，并提示了通过Notch配体控制移植排斥反应的可能性和肿瘤新药的开发。

It has been shown that the Delta family, which is one of Notch ligand family, control the immune response in positive direction. But, as for the function in immune response of the Jagged family, which is another Notch ligand family, the part which still does not become clear is a lot. This time we have focused on the function and the especially immune response control action in the immune response of Jagged 1. With the result of in vitro; in the Delta1 revelation dendritic cell, it could recognize the reinforcement of cell proliferation, but it had decreased by comparison with the contrast group in the Jagged I revelation dendritic cell proliferation (reported in the 106th annual congress of Japan Surgical Society). From this research, the possibility was shown that Jagged 1 has controlled immune response in negative direction, and through the T lymphocyte the donor unique low reactivity can be introduced in transplantation immunity.With the result of in vivo, in the A20 cell which introduces Jagged2, the tumor area reduced by comparison with control. In addition, the secretion of IFN- and Granzyme B increased by introducing the Jagged2 gene, could recognize the activation of NK cell. (Proc Natl Acad Sci USA (2008) in press)From these results, it was recognized that Notch ligands could participate not only transplantation immunity but also tumor immunity, and was suggested the possibility of the controlling the rejection in transplantation by Notch ligands and the development of the new remedy for the tumor.