Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18593-8. doi: 10.1073/pnas.1005582107. Epub 2010 Oct 11.
Acute graft-versus-host disease (GVHD) is a life-threatening complication following bone marrow transplantation; however, no effective molecular-targeting therapy has been determined. Here, we show that mice that received allogeneic splenocytes deficient in DNAX accessory molecule-1 (DNAM-1) had significantly milder GVHD and lower mortality than those that received allogeneic WT splenocytes. Donor CD8(+) T cells deficient in DNAM-1 showed significantly less proliferation and infiltration of the liver and intestines of recipient mice and produced less IFN-γ after coculture with allogeneic splenocytes than WT CD8(+) T cells. Mice prophylactically treated with an anti-DNAM-1 antibody showed milder GVHD and lower mortality than those treated with a control antibody. Moreover, treatment with a single administration of the antibody after the overt onset of GVHD ameliorated GVHD and prolonged survival. Finally, we show that the anti-DNAM-1 antibody therapy also ameliorated the overt GVHD in lethally irradiated mice after MHC-matched, minor antigen-mismatched bone marrow transplantation. These results indicate that DNAM-1 plays an important role in the development of GVHD and is an ideal molecular target for therapeutic approaches to GVHD.
移植物抗宿主病（GVHD）是骨髓移植后危及生命的并发症；然而，尚未确定有效的分子靶向治疗方法。在这里，我们表明，接受缺乏 DNAX 辅助分子-1（DNAM-1）的同种异体脾细胞的小鼠比接受同种异体 WT 脾细胞的小鼠具有明显较轻的 GVHD 和较低的死亡率。缺乏 DNAM-1 的供体 CD8(+) T 细胞在与同种异体脾细胞共培养后显示出明显较少的增殖和浸润受体小鼠的肝脏和肠道，并且产生的 IFN-γ 少于 WT CD8(+) T 细胞。用抗-DNAM-1 抗体预防性治疗的小鼠比用对照抗体治疗的小鼠具有较轻的 GVHD 和较低的死亡率。此外，在 GVHD 明显发作后单次给予抗体治疗可改善 GVHD 并延长存活时间。最后，我们表明，在用 MHC 匹配、次要抗原不匹配的骨髓移植后对致死性照射的小鼠进行抗-DNAM-1 抗体治疗也可改善明显的 GVHD。这些结果表明 DNAM-1 在 GVHD 的发展中起重要作用，是治疗 GVHD 的理想分子靶标。
