GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells
GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells
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DOI：
10.1002/eji.201847684
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发表时间：
2019-01-01
影响因子：
5.4
通讯作者：
Nomura, Shosaku
中科院分区：
文献类型：
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作者：
Hotta, Masaaki;Yoshimura, Hideaki;Nomura, Shosaku
调节性 T 细胞 (Treg) 会减弱过度的免疫反应，使其扩张有益于免疫介导的疾病，包括与移植物抗宿主病 (GVHD) 相关的同种异体骨髓移植。除了 IL-2 之外，Treg 还需要 T 细胞受体和来自抗原呈递细胞（例如 DC）的共刺激信号，以实现最佳增殖。粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 增加 DC 数量，并可能促进 DC 依赖性 Treg 增殖。在这里，我们证明 GM-CSF 治疗会增加 CD4(+)CD8(-) DC，这与 Treg 扩张相关。在慢性 GVHD (cGVHD) 小鼠模型中，GM-CSF 疗法扩大了 Tregs，防止皮肤 GVHD 的发展，并调节外周淋巴结中的 Th1 和 Th17 反应，从而减弱皮肤 cGVHD。值得注意的是，扩增的Tregs有助于GM-CSF介导的cGVHD抑制，这取决于Tregs与传统T细胞的比例增加，而不是抑制功能的增强。这些数据表明，GM-CSF 通过扩增 CD4(+)CD8(-) DC 诱导 Treg 增殖，进而调节 cGVHD 小鼠模型中的同种免疫反应。因此，GM-CSF 可用作治疗性 DC 调节剂，诱导 Treg 扩增并抑制免疫相关疾病中过度的同种免疫反应。
Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including allogeneic bone marrow transplantation associated with graft-versus-host disease (GVHD). In addition to interleukin-2, Tregs require T-cell receptor and costimulatory signals from antigen-presenting cells, such as DCs, for their optimal proliferation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. Here, we demonstrate that GM-CSF treatment increases CD4(+)CD8(-) DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM-CSF-mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM-CSF induces Treg proliferation by expanding CD4(+)CD8(-) DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM-CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune-related diseases.