Low-Dose 5-Aza and DZnep Alleviate Acute Graft- Versus -Host Disease With Less Side Effects Through Altering T-Cell Differentiation

• Published in: Frontiers in immunology Vol. 13; p. 780708
• Main Authors: Wang, Qing Ya, Liu, Hui Hui, Dong, Yu Jun, Liang, Ze Yin, Yin, Yue, Liu, Wei, Wang, Qing Yun, Wang, Qian, Sun, Yu Hua, Xu, Wei Lin, Han, Na, Li, Yuan, Ren, Han Yun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 24.02.2022
• Subjects: acute graft-versus-host disease (aGvHD); Adenosine - analogs & derivatives; Animals; Cytokines - metabolism; Disease Models, Animal; epigenetic; Graft vs Host Disease - drug therapy; Graft vs Host Disease - prevention & control; Hematopoiesis; Hematopoietic Stem Cell Transplantation - adverse effects; Histone Methyltransferases; histone modification; hypomethylation agents; Immunology; Mice; mouse model; acute graft-versus-host disease (aGvHD); histone modification; hypomethylation agents; mouse model; epigenetic
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.780708

Previous studies showed that hypomethylating agents (HMAs) could alleviate acute graft- -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 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, 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 had an enhanced effect to inhibit the production of Th1/Tc1, increase the proportions of Th2/Tc2, and induce the differentiation of Tregs as . 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.