Treatment of HIV-Infected Individuals with the Histone Deacetylase Inhibitor Panobinostat Results in Increased Numbers of Regulatory T Cells and Limits Ex Vivo Lipopolysaccharide-Induced Inflammatory Responses.
Treatment of HIV-Infected Individuals with the Histone Deacetylase Inhibitor Panobinostat Results in Increased Numbers of Regulatory T Cells and Limits Ex Vivo Lipopolysaccharide-Induced Inflammatory Responses.
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DOI：
10.1128/msphere.00616-17
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发表时间：
2018-01
期刊：
影响因子：
4.8
通讯作者：
Tolstrup M
中科院分区：
文献类型：
--
作者：
Brinkmann CR;Højen JF;Rasmussen TA;Kjær AS;Olesen R;Denton PW;Østergaard L;Ouyang Z;Lichterfeld M;Yu X;Søgaard OS;Dinarello C;Tolstrup M
组蛋白脱乙酰酶抑制剂治疗对HIV感染者免疫系统的影响尚不清楚。对一项临床试验的结果进行了分析，其中15名艾滋病毒感染者接受了12剂Panobinostat，发现这对T细胞激活状态和调节性T细胞抑制标记的表达都有重大影响，并降低了单核细胞对炎症刺激的反应性水平。这些变化得到了全球基因表达分析的证实。总而言之，这些结果表明，Panobinostat对先天和获得性免疫反应有多种影响。重要的是，所有的影响都是暂时的，进一步的Panobinostat治疗并不会导致HIV感染者基因表达模式的长期持续变化。组蛋白脱乙酰酶抑制物(HDACi)调节所有细胞的转录活性，包括天然免疫细胞和获得性免疫细胞。因此，我们的目标是在临床IIa潜伏期逆转试验中评估HDACi Panobinostat治疗HIV感染患者的免疫学效果。应用流式细胞仪检测T细胞活化(CD69、CD38、HLA-DR)及调节性T细胞(Tregs)表面CD39、CTLA4表达的变化。进行全血刺激，并使用Luminex测量细胞因子反应。用Affymetrix HTA 2.0基因芯片检测纯化的外周血单个核细胞(PBMC)的基因表达。我们发现，在给药24小时后，表达CD69的CD_4~+和CD_8~+T细胞的比例增加(P<；0.01)，在第4天，共表达CD_4~+T细胞的CD_(38+)和CD_(18)-DR~+细胞的比例增加(P=0.02)。同时，Tregs的比例增加了40%(P=0.003)。Treg CTLA4MFI增加25%(P=0.007)，CD39MFI增加12%(P=0.02)。内毒素诱导的炎症反应(IL-1β[IL-1β]、IL-6、IL-12p40和肿瘤坏死因子α[α])在给药后4天显著下调。最后，Panobinostat诱导了整体基因表达模式的显著变化(折叠式变化，>；1.5；假发现率[FDR]-校正P，<；0.05)。重要的是，在Panobinostat治疗和随访后，免疫功能的测量恢复到基线，显示对总体基因表达没有持续的影响。组蛋白脱乙酰酶抑制剂治疗对HIV感染者免疫系统的影响尚不清楚。对一项临床试验的结果进行了分析，其中15名艾滋病毒感染者接受了12剂Panobinostat，发现这对T细胞激活状态和调节性T细胞抑制标记的表达都有重大影响，并降低了单核细胞对炎症刺激的反应性水平。这些变化得到了全球基因表达分析的证实。总而言之，这些结果表明，Panobinostat对先天和获得性免疫反应有多种影响。重要的是，所有的影响都是暂时的，进一步的Panobinostat治疗并不会导致HIV感染者基因表达模式的长期持续变化。
The effect of treatment with histone deacetylase inhibitors on the immune system in HIV-infected individuals is not clear. Analysis of results from a clinical trial in which 15 HIV-infected individuals received 12 doses of panobinostat identified a significant impact on both T cell activation status and regulatory T cell suppressive marker expression and a reduced level of monocytic responsiveness to inflammatory stimuli. These changes were substantiated by global gene expression analysis. Collectively, the results suggest that panobinostat has multiple effects on innate and adaptive immune responses. Importantly, all the effects were transient, and further panobinostat treatment did not cause persistent long-term changes in gene expression patterns in HIV-infected individuals. Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex. Gene expression in purified peripheral blood mononuclear cells (PBMCs) was evaluated using an Affymetrix HTA 2.0 gene chip. We found that proportions of CD4+ and CD8+ T cells expressing CD69 increased 24 h after initial panobinostat administration (P < 0.01), followed by an increase in the proportions of CD38+ HLA-DR+-coexpressing CD4+ T cells on day 4 (P = 0.02). Concurrently, proportions of Tregs increased by 40% (P = 0.003). Treg CTLA4 median fluorescent intensity (MFI) increased by 25% (P = 0.007), and CD39 MFI on CD39+ Treg increased by 12% (P = 0.02). Lipopolysaccharide (LPS)-induced inflammatory responses (interleukin-1β [IL-1β], IL-6, IL-12p40, and tumor necrosis factor alpha [TNF-α]) in whole blood were significantly downregulated 4 days after initial dosing. Lastly, panobinostat induced significant changes in the overall gene expression pattern (fold change, >1.5; false-discovery-rate [FDR]-corrected P, <0.05). Importantly, measures of immune function returned to baseline after panobinostat treatment and follow-up revealed no sustained effect on overall gene expression. IMPORTANCE The effect of treatment with histone deacetylase inhibitors on the immune system in HIV-infected individuals is not clear. Analysis of results from a clinical trial in which 15 HIV-infected individuals received 12 doses of panobinostat identified a significant impact on both T cell activation status and regulatory T cell suppressive marker expression and a reduced level of monocytic responsiveness to inflammatory stimuli. These changes were substantiated by global gene expression analysis. Collectively, the results suggest that panobinostat has multiple effects on innate and adaptive immune responses. Importantly, all the effects were transient, and further panobinostat treatment did not cause persistent long-term changes in gene expression patterns in HIV-infected individuals.