Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.
Institute of Hematology, Jinan University, Guangzhou, China.
Cell Biol Toxicol. 2017 Apr;33(2):169-181. doi: 10.1007/s10565-016-9364-7. Epub 2016 Oct 21.
Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell-cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by γ-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival. Inhibition of Notch signaling pathway by DAPT ex vivo only reduced pathology aGVHD scores in the liver and intestine and had no impact on the onset time and clinical aGVHD scores. We investigated the possible mechanism by analyzing the phenotype of host APCs and donor-derived T cells. Notch signaling pathway had a broad effect on both host APCs and donor-derived T cells. The expressions of CD11c, CD40, and CD86 as the markers of activated dendritic cells (DCs) were decreased. The proliferative response of CD8+ T cell decreased, while CD4 Notch-deprived T cells had preserved expansion with increased expressions of CD25 and Foxp3 as markers of regulatory T cells (Tregs). In conclusion, Notch inhibition may minimize aGVHD by decreasing proliferation and activation of DCs and CD8 T cells while preserving Tregs expansion.
移植物抗宿主病（GVHD）由宿主抗原呈递细胞（APCs）和供体来源的 T 细胞引起，仍然是所有异体骨髓移植（allo-BMT）的主要限制因素。Notch 信号通路是一种高度保守的细胞间通讯，在 T 细胞发育中很重要。最近，有报道称 Notch 信号通路参与调节 GVHD。为了研究 Notch 抑制在调节 GVHD 中的作用，我们建立了 MHC 错配的小鼠 allo-BMT 模型。我们发现体内 Notch 信号通路的抑制通过γ-分泌酶抑制剂可以减少急性移植物抗宿主病（aGVHD），这表现为 aGVHD 的发病时间、体重、临床 aGVHD 评分、病理 aGVHD 评分和存活率。体外 DAPT 抑制 Notch 信号通路仅降低肝脏和肠道的病理 aGVHD 评分，对发病时间和临床 aGVHD 评分没有影响。我们通过分析宿主 APC 和供体来源的 T 细胞的表型来研究可能的机制。Notch 信号通路对宿主 APC 和供体来源的 T 细胞都有广泛的影响。作为激活树突状细胞（DC）标志物的 CD11c、CD40 和 CD86 的表达减少。CD8+T 细胞的增殖反应降低，而 CD4 Notch 剥夺的 T 细胞具有保留的扩增，同时作为调节性 T 细胞（Tregs）标志物的 CD25 和 Foxp3 的表达增加。总之，Notch 抑制可能通过减少 DC 和 CD8 T 细胞的增殖和激活，同时保留 Tregs 的扩增来最小化 aGVHD。
