Low-Dose 5-Aza and DZnep Alleviate Acute Graft-Versus-Host Disease With Less Side Effects Through Altering T-Cell Differentiation.
Low-Dose 5-Aza and DZnep Alleviate Acute Graft-Versus-Host Disease With Less Side Effects Through Altering T-Cell Differentiation.
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DOI：
10.3389/fimmu.2022.780708
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发表时间：
2022
影响因子：
7.3
通讯作者：
Ren HY
中科院分区：
文献类型：
--
作者：
Wang QY;Liu HH;Dong YJ;Liang ZY;Yin Y;Liu W;Wang QY;Wang Q;Sun YH;Xu WL;Han N;Li Y;Ren HY
既往研究表明，低甲基化剂（HMAs）可减轻急性移植物抗宿主病（aGvHD），但影响异基因造血干细胞移植（allo-HSCT）后的植入。两种不同的HMA在较低剂量下的组合可能会克服这个问题。本研究旨在评价两种HMA-阿扎胞苷（5-Aza）和组蛋白H3 K27甲基转移酶抑制剂3-去氮普兰诺星（DZNep）-联合应用预防allo-HSCT后aGvHD的疗效并探讨其可能的机制。我们首先优化了单独和组合5-Aza和DZNep处理的浓度，以通过评估T细胞增殖、活力和分化来确保对活化的T细胞没有明显的毒性。然后建立aGvHD的小鼠模型以评估5-Aza、DZNep及其组合对aGvHD的预防功效。观察其对T细胞的免疫调节作用及造血重建情况。此外，进行RNA测序（RNA-seq）以鉴定潜在的分子机制。5-Aza与DZNep联合应用较单独应用能更有效地抑制Th 1/Tc 1细胞的生成，增加调节性T细胞的生成。在allo-HSCT小鼠模型中，与单一药剂相比，体内施用5-Aza与DZNep可增强aGvHD的预防效果。机制研究表明，体内联合应用5-Aza和DZNep可增强抑制Th 1/Tc 1的产生，增加Th 2/Tc 2的比例，并诱导Tc-as体外分化。RNA-seq分析揭示了细胞因子和趋化因子途径作为用5-Aza和DZNep的组合缓解aGvHD的一种机制。5-Aza和DZNep的组合可以通过影响细胞因子和趋化因子途径影响供体T细胞分化来增强aGvHD的预防效果。本研究揭示了使用不同表观遗传试剂组合的有效预防aGvHD的措施。
Previous studies showed that hypomethylating agents (HMAs) could alleviate acute graft-versus-host disease (aGvHD), but affect engraftment after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The combination of two different HMAs in lower doses might overcome this problem. This study aimed to evaluate the treatment effect of the combination of two HMAs—azacitidine (5-Aza) and histone H3K27 methyltransferase inhibitor 3-deazaneplanocin (DZNep)—for the prophylaxis of aGvHD after allo-HSCT and to explore the possible mechanisms. We first optimized the concentrations of individual and combinational 5-Aza and DZNep treatments to ensure no obvious toxicities on activated T cells by evaluating T-cell proliferation, viability, and differentiation. A mouse model of aGvHD was then established to assess the prophylactic efficacy of 5-Aza, DZNep, and their combination on aGvHD. The immunomodulatory effect on T cells and the hematopoietic reconstruction were assessed. Additionally, RNA sequencing (RNA-seq) was performed to identify the underlying molecular mechanisms. Compared with single treatments, the in vitro application of 5-Aza with DZNep could more powerfully reduce the production of T helper type 1 (Th1)/T cytotoxic type 1 (Tc1) cells and increase the production of regulatory T cells (Tregs). In an allo-HSCT mouse model, in vivo administration of 5-Aza with DZNep could enhance the prophylactic effect for aGvHD compared with single agents. The mechanism study demonstrated that the combination of 5-Aza and DZNep in vivo had an enhanced effect to inhibit the production of Th1/Tc1, increase the proportions of Th2/Tc2, and induce the differentiation of Tregs as in vitro. RNA-seq analysis revealed the cytokine and chemokine pathways as one mechanism for the alleviation of aGvHD with the combination of 5-Aza and DZNep. The combination of 5-Aza and DZNep could enhance the prophylactic effect for aGvHD by influencing donor T-cell differentiation through affecting cytokine and chemokine pathways. This study shed light on the effectively prophylactic measure for aGvHD using different epigenetic agent combinations.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
4.3
作者：
Cao, Yi-Geng;He, Yi;Han, Ming-Zhe
通讯作者：
Han, Ming-Zhe
DOI：
10.1084/jem.20021127
发表时间：
2003-01-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan HW;Kurago ZB;Stewart CA;Wilson MJ;Martin MP;Mace BE;Carrington M;Trowsdale J;Lutz CT
通讯作者：
Lutz CT
影响因子：
7.3
作者：
Jiang H;Fu D;Bidgoli A;Paczesny S
通讯作者：
Paczesny S
影响因子：
20.3
作者：
Bucher, Christoph;Koch, Lisa;Blazar, Bruce R.
通讯作者：
Blazar, Bruce R.