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Inhibition of NF-KappaB during human dendritic cell differentiation generates anergy and regulatory T cell activity for one -but not two- HLA-DR mismatches

机译:人类树突状细胞分化过程中对NF-KappaB的抑制产生一种-但不是两种-HLA-DR错配的无能和调节性T细胞活性

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摘要

We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-κB blockade on T cell allo-stimulation, cytokine production, and regulatory T cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-α, IL-1β, and PGE2 as maturational stimuli with or without the NF-κB inhibitors, BAY11-7082 (BAY-DC) or Aspirin (ASA-DC). Stimulator and responder cells were one vs two HLA-DR mismatched in direct vs indirect presentation assays. Both BAY-DC and ASA-DC expressed high levels of HLA-DR and CD86 but always expressed less CD40 compared to controls. Some experiments showed slightly lower levels of CD80. Both BAY- and ASA- allogeneic DC and autologous alloantigen pulsed DC were weaker stimulators of T cells (by MLR) compared to controls, and there was reduced IL-2 and IFN-γ production by T cells stimulated with BAY-DC or ASA-DC (by ELISPOT) (more marked results were always observed with ASA-treated DC). In addition NF-κB blockade of DC maturation caused the generation of T cells with regulatory function (T regs) but only when T cells were stimulated by either allogeneic (direct presentation) or alloantigen pulsed autologous DC (indirect presentation) with one HLA-DR mismatch and not with two HLA-DR mismatched (either direct or indirect presentation). However, the T regs generated from these ASA-DC showed similar FoxP3 mRNA expression as those from non-treated DC. Extension of this study to human organ transplantation suggests potential therapies using one DR matched NF-κB blocked DC to help generate clinical tolerance.
机译:我们研究了通过对T细胞同种刺激,细胞因子产生和调节性T细胞生成的NF-κB阻断作用,对人单核细胞衍生的树突状细胞(DC)成熟的体外抑制作用。 DC是使用GM-CSF和IL-4分化并以TNF-α,IL-1β和PGE2作为成熟刺激(有或没有NF-κB抑制剂)从外周血中分离的CD14 + 单核细胞产生的,BAY11-7082(BAY-DC)或阿司匹林(ASA-DC)。在直接与间接呈递分析中,刺激细胞和应答细胞分别是一对错配的HLA-DR,两个错配。与对照相比,BAY-DC和ASA-DC均表达高水平的HLA-DR和CD86,但始终表达较少的CD40。一些实验表明CD80的含量略低。与对照组相比,BAY和ASA同种异体DC和自体异源抗原脉冲DC都是对T细胞的刺激性较弱(通过MLR),并且由BAY-DC或ASA-刺激的T细胞产生的IL-2和IFN-γ降低。 DC(通过ELISPOT)(使用ASA处理的DC总是观察到更明显的结果)。此外,NF-κB对DC成熟的阻断导致具有调节功能(T regs)的T细胞的产生,但仅当T细胞被同种异体(直接呈递)或同种异体抗原脉冲自体DC(间接呈递)与一种HLA-DR刺激时产生不匹配,而不是两个HLA-DR不匹配(直接或间接表示)。但是,从这些ASA-DC产生的T regs显示出与未处理的DC相似的FoxP3 mRNA表达。这项研究扩展到人体器官移植,表明一种潜在的疗法是使用一种DR匹配的NF-κB阻断DC来帮助产生临床耐受性。

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