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TIRC7 通过上调 CTLA-4 和 STAT3 的表达抑制急性移植物抗宿主病小鼠中的 Th1 细胞。

TIRC7 inhibits Th1 cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease.

机构信息

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

Laboratory of Transplant Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

出版信息

Oncol Rep. 2020 Jul;44(1):43-54. doi: 10.3892/or.2020.7588. Epub 2020 Apr 21.

Abstract

In a previous study, it was demonstrated that T‑cell immune response cDNA 7 (TIRC7) levels reflect the efficacy of treatment of patients with acute graft‑versus‑host disease (GVHD). However, the pathogenesis of TIRC7 in acute GVHD remains poorly understood. Lymphocytes from patients with acute GVHD were selected as targeT cells, and the effects of TIRC7 on cytotoxic T lymphocyte antigen‑4 (CTLA‑4), T cell activation and cytokine secretion were observed by electroporation. A mouse model of acute GVHD was established; anti‑TIRC7 and anti‑CTLA‑4 monoclonal antibodies were intraperitoneally injected into recipient mice. Then, the effects of TIRC7 and CTLA‑4 on T cell activation and acute GVHD were monitored. After TIRC7 expression was downregulated, CTLA‑4 levels were decreased and STAT3 phosphorylation was reduced; conversely, the activation capacity of T lymphocytes was elevated, and the secretion of interferon‑γ and other cytokines was increased. The mice in the TIRC7 + CTLA‑4 co‑administration group exhibited the lowest acute GVHD scores, with the longest average survival time and shortest recovery time of hematopoietic reconstitution. In conclusion, the results indicated that TIRC7 may positively regulate the function of CTLA‑4 and inhibit T cell activation, thus suppressing the development and progression of acute GVHD.

摘要

在之前的一项研究中,已经证明 T 细胞免疫反应 cDNA 7(TIRC7)水平反映了急性移植物抗宿主病(GVHD)患者治疗效果。然而,TIRC7 在急性 GVHD 中的发病机制仍知之甚少。选择急性 GVHD 患者的淋巴细胞作为靶细胞,通过电穿孔观察 TIRC7 对细胞毒性 T 淋巴细胞抗原 4(CTLA-4)、T 细胞激活和细胞因子分泌的影响。建立急性 GVHD 小鼠模型;向受体小鼠腹腔内注射抗-TIRC7 和抗-CTLA-4 单克隆抗体。然后,监测 TIRC7 和 CTLA-4 对 T 细胞激活和急性 GVHD 的影响。下调 TIRC7 表达后,CTLA-4 水平降低,STAT3 磷酸化减少;相反,T 淋巴细胞的激活能力提高,干扰素-γ 等细胞因子的分泌增加。TIRC7+CTLA-4 联合给药组的小鼠表现出最低的急性 GVHD 评分,具有最长的平均存活时间和最短的造血重建恢复时间。总之,这些结果表明 TIRC7 可能正向调节 CTLA-4 的功能并抑制 T 细胞激活,从而抑制急性 GVHD 的发展和进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfe0/7254953/7147dbb7f941/OR-44-01-0043-g00.jpg

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