Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets
Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets
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DOI：
10.1172/jci7894
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发表时间：
2000-05-01
影响因子：
15.9
通讯作者：
Sykes, M
中科院分区：
文献类型：
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作者：
Nikolic, B;Lee, S;Sykes, M
STAT4和STAT6是转录因子，分别在对IL-12和IL-4的反应中发挥关键作用。STAT4基因敲除(STAT(4/4))小鼠显著降低Th1应答，增强Th2应答。STAT6(-/-)小鼠表现出相反的表型。我们比较了骨髓移植(BMT)和来自STAT6(-/-)、STAT4(-/-)和野生型(WT)小鼠的脾细胞在致死性照射MHC不相合的受者中产生移植物抗宿主病(GVHD)的能力。STAT6(-/-)小鼠细胞诱导的急性移植物抗宿主病(GVHD)死亡率比STAT4(-/-)细胞诱导的更快。然而，与WT对照组相比，来自STAT4-/-和STAT6(-/-)供者的细胞都诱导了延迟的GVHD死亡，或者与联合使用的STAT4(-/-)和STAT6(-/-)细胞相比，这表明Th1细胞和Th2细胞在急性GVHD中都有贡献。接受STAT6(-/-)BMT的患者表现出急性移植物抗宿主病(GVHD)的证据，并伴有严重腹泻和明显的体重下降。接受STAT4(-/-)BMT的患者显示出GVHD的迹象，只有最初的一过性体重减轻，后来发展为严重的皮肤GVHD。组织病理学研究表明，Th2细胞参与了肝脏GVHD和重症皮肤GVHD的发生，而Th1和Th2细胞均可引起GVHD的肠道病理改变。我们的研究表明，Th1和Th2细胞在急性GVHD的发生中起着相加的作用，并建议采用细胞因子指导的方法来治疗GVHD的终末器官表现。
STAT4 and STAT6 are transcription factors that play crucial roles in responding to IL-12 and IL-4, respectively. STAT4 gene knockout (STAT(4/4)) mice have markedly reduced Th1 responses and enhanced Th2 responses. STAT6(-/-) mice show the inverse phenotype. We compared the ability of bone marrow transplantation (BMT) with the inclusion of spleen cells from STAT6(-/-), STAT4(-/-), and wildtype (WT) mice to produce graft-versus-host disease (GVHD) in lethally irradiated MHC-mismatched recipients. Acute GVHD mortality was more rapid when induced by cells from STAT6(-/-) mice than when induced by STAT4(-/-) cells. However, cells from STAT4-/- and STAT6(-/-) donors both induced delayed GVHD mortality compared with WT controls, or compared with combined STAT4(-/-) and STAT6(-/-) cells, indicating a contribution of both Th1 cells and Th2 cells to acute GVHD. Recipients of STAT6(-/-) BMT showed evidence of acute GVHD with severe diarrhea and marked weight loss. Recipients of STAT4(-/-) BMT showed signs of GVHD with only initial transient weight loss and later development of severe skin GVHD. Histopathology showed that Th2 responses were required for the induction of both hepatic and severe skin GVHD, In contrast, both Th1 cells and Th2 cells were capable of causing intestinal pathology of GVHD. Our studies demonstrate an additive role for Th1 and Th2 cells in producing acute GVHD, and suggest a cytokine-directed approach to treating end-organ manifestations of GVHD.