Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease
Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease
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DOI：
10.4049/jimmunol.1400954
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发表时间：
2014-09-01
影响因子：
4.4
通讯作者：
Tanimoto, Mitsune
中科院分区：
文献类型：
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作者：
Fujiwara, Hideaki;Maeda, Yoshinobu;Tanimoto, Mitsune
慢性移植物抗宿主病（GVHD）是异基因造血细胞移植后晚期死亡和发病的主要原因，但其发病机制尚不清楚。我们使用定义明确的BALB/c（H-2（d））受体的B10.D2（H-2（d））供体小鼠模型研究了程序性死亡-1（PD-1）通路在慢性GVHD中的作用。在慢性GVHD发展过程中，同种异体供体T细胞上的PD-1表达持续上调，而宿主组织中的PD-L1表达短暂上调，并在移植后期下降至基础水平。通过抗PD-1、抗PD-L1或抗PD-L2 mAb阻断PD-1通路加重了临床和病理慢性GVHD。嵌合小鼠显示，宿主组织中的PD-L1表达抑制IL-17（+）IFN-γ（+）T细胞的扩增，造血细胞上的PD-L1表达仅在移植早期在调节性T细胞的发育中起作用，但不影响慢性GVHD的严重程度。施用合成类维生素A Am 80克服了由PD-L1缺乏引起的IL-17（+）IFN-γ（+）T细胞扩增，导致PD-L1（-/-）受体中慢性GVHD损伤减少。PD-1通路的刺激也减轻了慢性GVHD。这些结果表明PD-1通路有助于抑制Th 17/Th 1介导的慢性GVHD，并可能代表预防或治疗慢性GVHD的新靶点。
Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2(d)) donor to BALB/c (H-2(d)) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti-PD-1, anti-PD-L1, or anti-PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17(+)IFN-gamma(+) T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17(+)IFN-gamma(+) T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1(-/-) recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.