Tang Bo, Ren Hanyun, Liu Huihui, Shi Yongjin, Liu Wei, Dong Yujun, Yin Yue, Miao Shengchao
Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
Inflamm Res. 2016 Nov;65(11):917-924. doi: 10.1007/s00011-016-0974-6. Epub 2016 Jul 16.
Our preview study found that CCR5 blockade combined with cyclosporine A could attenuate the severity of liver GVHD. But the potential immunological mechanisms have not yet been explored. So our present study was designed to clarify the potential immunological mechanisms in mouse models after allo-HSCT.
Firstly, we detected donor T cells homing to target organs, and analyzed the specific effector subsets in liver. Additionally, we assessed antigen-presenting cells (APCs), especially DCs and CD4 T cells differentiation in secondary lymphoid organs.
Data showed that MVC combined with CsA reduced donor T cells migration to target organs in vivo. MVC and CsA treatment reduced the amount of donor T cells in the absolute numbers, also in donor CD4 and CD8 T cells by targeting at CCR5. And MVC co-injected with CsA was capable of slightly suppressing DC maturation, and reduced the percentage of Th1 and Th17 mainly by noncompetitive combination of CCR5.
Combined use of MVC and CsA was effective in attenuating liver GVHD in murine model. It can suppress DC maturation, affect T cells differentiation, and reduce donor T cells homing to target organs. This may offer a novel therapeutic perspective approach for clinical liver GVHD after allo-HSCT.
我们的预实验研究发现，CCR5阻断联合环孢素A可减轻肝脏移植物抗宿主病（GVHD）的严重程度。但潜在的免疫机制尚未得到探索。因此，我们目前的研究旨在阐明异基因造血干细胞移植（allo-HSCT）后小鼠模型中的潜在免疫机制。
首先，我们检测归巢至靶器官的供体T细胞，并分析肝脏中的特异性效应子亚群。此外，我们评估了抗原呈递细胞（APC），特别是二级淋巴器官中的树突状细胞（DC）和CD4 T细胞分化。
数据显示，MVC联合CsA可减少体内供体T细胞向靶器官的迁移。MVC和CsA治疗通过靶向CCR5降低了供体T细胞的绝对数量，以及供体CD4和CD8 T细胞的数量。并且与CsA共同注射的MVC能够轻微抑制DC成熟，主要通过CCR5的非竞争性结合降低Th1和Th17的百分比。
MVC和CsA联合使用可有效减轻小鼠模型中的肝脏GVHD。它可以抑制DC成熟，影响T细胞分化，并减少供体T细胞归巢至靶器官。这可能为allo-HSCT后临床肝脏GVHD提供一种新的治疗视角方法。
