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沉默 CD70 的树突状细胞可诱导免疫性血小板减少症患者免疫耐受。

CD70-silenced dendritic cells induce immune tolerance in immune thrombocytopenia patients.

机构信息

The Hematology Department of Zhongnan Hospital of Wuhan University, Wuhan City, Hubei, China.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China.

出版信息

Br J Haematol. 2020 Nov;191(3):466-475. doi: 10.1111/bjh.16689. Epub 2020 May 18.

Abstract

The hyper-response of dendritic cell (DC) is believed to participate in the pathogenesis of immune thrombocytopenia (ITP). The CD70 expression on the surface of DCs that takes part in the CD27-CD70 costimulation pathway is an important element of DC 'licensing', which may initiate a series of autoreactive immune responses. To elucidate the roles CD70 molecules play in the DCs of ITP patients, we first stimulated the CD70 molecules on the DCs of ITP patients and normal controls, and found that the stimulated DCs from ITP patients exhibited higher ability to induce CD4 CD25 T lymphocytes proliferation, while lowering the ability of the induction of regulatory T cells (Tregs) from CD4 CD25 T lymphocytes. Meanwhile, higher IFN-γ and lower IL-10 levels were found in the co-culture system of stimulated DCs and CD4 CD25 T cells. We then silenced the CD70 genes on the induced DCs of ITP patients and normal controls by siRNA, and confirmed our suggestion that the silence of CD70 expression on the surface of DCs from ITP patients would decrease the CD4 CD25 T lymphocytes proliferation and Tregs differentiation, simultaneously inducing higher IL-10 and lower IFN-γ levels. Thus, the interference with the CD27-CD70 costimulatory pathway might lead to the alleviation of the consequent immune reactions, polarisation of Th2, induction of immune tolerance as well as shed new light on treatment of autoimmune diseases.

摘要

树突状细胞(DC)的高反应性被认为参与了免疫性血小板减少症(ITP)的发病机制。参与 CD27-CD70 共刺激途径的 DC 表面的 CD70 表达是 DC“许可”的重要组成部分,它可能引发一系列自身反应性免疫反应。为了阐明 CD70 分子在 ITP 患者的 DC 中的作用,我们首先刺激了 ITP 患者和正常对照者的 DC 上的 CD70 分子,发现来自 ITP 患者的刺激的 DC 具有更高的诱导 CD4 CD25 T 淋巴细胞增殖的能力,同时降低了诱导 CD4 CD25 T 淋巴细胞中的调节性 T 细胞(Tregs)的能力。同时,在刺激的 DC 和 CD4 CD25 T 细胞的共培养系统中发现更高水平的 IFN-γ和更低水平的 IL-10。然后,我们通过 siRNA 沉默了 ITP 患者和正常对照者诱导的 DC 上的 CD70 基因,并证实了我们的假设,即 ITP 患者 DC 表面 CD70 表达的沉默会降低 CD4 CD25 T 淋巴细胞的增殖和 Tregs 的分化,同时诱导更高水平的 IL-10 和更低水平的 IFN-γ。因此,干扰 CD27-CD70 共刺激途径可能导致随后的免疫反应减轻、Th2 极化、诱导免疫耐受,并为自身免疫性疾病的治疗提供新的思路。

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