Fujimura Junya, Takeda Kazuyoshi, Kaduka Yuki, Saito Masahoro, Akiba Hisaya, Yagita Hideo, Yamashiro Yuichiro, Shimizu Toshiaki, Okumura Ko
Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.
Pediatr Transplant. 2010 Jun;14(4):540-8. doi: 10.1111/j.1399-3046.2009.01279.x. Epub 2010 Feb 1.
Co-stimulatory molecules expressed on T cells critically regulate donor T-cell activation and are implicated in acute GVHD after allogeneic BMT. We here investigated the role of interaction between B7-related protein-1 (B7RP-1) and ICOS in murine acute GVHD model that received T cell-depleted BM cells and splenocytes. Administration of blocking anti-B7RP-1 mAb significantly reduced the lethality and symptoms in acute GVHD. A significant hypo-responsiveness of splenocytes to host alloantigen was observed in the recipient mice treated with anti-B7RP-1 mAb. Moreover, acute GVHD was significantly reduced in the recipients of T cells composed of ICOS-deficient CD8 T cells and WT CD4 T cells compared with that in the recipients of T cells composed of WT CD8 T cells and ICOS-deficient CD4 T cells. These results suggested that B7RP-1/ICOS co-stimulatory signal plays a role in the activation of alloantigen-reactive donor T cells, particularly in CD8 T cells, in murine acute GVHD model, and that the blockade of B7RP-1/ICOS interaction may be useful for selectively manipulating allo-reactive T cells in the recipients with acute GVHD.
T细胞上表达的共刺激分子对供体T细胞活化起着关键调节作用，并与异基因骨髓移植后的急性移植物抗宿主病有关。我们在此研究了B7相关蛋白-1（B7RP-1）与诱导性共刺激分子（ICOS）之间的相互作用在接受去除T细胞的骨髓细胞和脾细胞的小鼠急性移植物抗宿主病模型中的作用。给予抗B7RP-1单克隆抗体可显著降低急性移植物抗宿主病的致死率和症状。在用抗B7RP-1单克隆抗体治疗的受体小鼠中，观察到脾细胞对宿主同种异体抗原的显著低反应性。此外，与由野生型CD8 T细胞和ICOS缺陷型CD4 T细胞组成的T细胞受体小鼠相比，由ICOS缺陷型CD8 T细胞和野生型CD4 T细胞组成的T细胞受体小鼠的急性移植物抗宿主病明显减轻。这些结果表明，在小鼠急性移植物抗宿主病模型中，B7RP-1/ICOS共刺激信号在同种异体抗原反应性供体T细胞（特别是CD8 T细胞）的活化中起作用，并且阻断B7RP-1/ICOS相互作用可能有助于选择性地调控急性移植物抗宿主病受体中的同种异体反应性T细胞。
