Critical role of DNAX accessory molecule-1 (DNAM-1) in the development of acute graft-versus-host disease in mice
Critical role of DNAX accessory molecule-1 (DNAM-1) in the development of acute graft-versus-host disease in mice
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DOI：
10.1073/pnas.1005582107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Shibuya, Akira
中科院分区：
文献类型：
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作者：
Nabekura, Tsukasa;Shibuya, Kazuko;Shibuya, Akira
急性移植物抗宿主病(GVHD)是骨髓移植后一种危及生命的并发症；然而，目前还没有确定有效的分子靶向治疗方法。在这里，我们发现接受缺乏DNAX辅助分子-1(dNaM-1)的同种异体脾细胞的小鼠与接受同种异基因WT脾细胞的小鼠相比，GVHD显著减轻，死亡率降低。DNaM-1基因缺失的供者CD8(+)T细胞与同种异体脾细胞共培养后，其肝脏和肠道的增殖和浸润明显低于WT CD8(+)T细胞，产生的干扰素-γ也明显低于WT CD8(+)细胞。与对照组相比，预防性使用抗dNaM-1抗体的小鼠表现出较轻的GVHD和较低的死亡率。此外，在GVHD明显发作后单次注射抗体可改善GVHD并延长生存期。最后，我们表明，抗dNaM-1抗体治疗也改善了MHC相合、微小抗原不相合的致死性照射小鼠骨髓移植后的明显移植物抗宿主病。这些结果表明，dNaM-1在GVHD的发生发展中起着重要作用，是治疗GVHD的理想分子靶点。
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-gamma after co-culture 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.