Histone deacetylase inhibitor affected CD4+CD25+Foxp3+ cells in a mouse model of acute graft versus host disease

doi:10.3969/j.issn.2095-4344.2014.49.007

Abstract

Abstract:

BACKGROUND: Prevention and treatment of graft versus host disease and elevation of graft survival rate are core problems needed to be solved in allogenic hematopoietic stem cell transplantation. Thus, it is necessary to find a new immunosuppressant. Recent studies showed that histone deacetylase inhibitor has immunomodulatory effects.

OBJECTIVE: To observe the effects of histone deacetylase inhibitor SAHA on acute graft versus host disease in mice and the immunomodulatory effects.

METHODS: C57BL/6(H-2b)→BALB/C(H-2d) was selected as donor and recipient of complete allotransplantation. At 3, 5, 7, 9 and 11 days after transplantion, mice in the treatment group were intraperitoneally given SAHA

(35 mg/kg) (0.2 mL). Mice in the control group were intraperitoneally given sterile water 0.2 mL/time. Flow cytometry, real-time quantitative PCR and pathology were used to compare the clinical manifestations, survival time and CD4⁺CD25⁺Foxp3⁺ cell percentage of acute graft versus host disease in mice of both groups.

RESULTS AND CONCLUSION: In the treatment group, the time of acute graft versus host disease was delayed and the extent was reduced and survival time was longer compared with the control group. Survival rate was significantly higher in the treatment group than in the control group (P < 0.05). After transplantation, the proportions of CD4⁺CD25⁺Foxp3⁺ cells gradually increased with prolonged time in the treatment group. On the contrary, the proportions of CD4⁺CD25⁺Foxp3⁺ cells gradually decreased with prolonged time in the control group (P < 0.05). Above data suggested that SAHA delayed the occurrence of acute graft versus host disease and lessened the severity of acute graft versus host disease possibly through elevating the proportion of CD4⁺CD25⁺Foxp3⁺ cells.

中国组织工程研究杂志出版内容重点：肾移植；肝移植；移植；心脏移植；组织移植；皮肤移植；皮瓣移植；血管移植；器官移植；组织工程

全文链接：

Key words: hematopoietic stem cell transplantation, graft vs host disease, histone deacetylases, models, animal

CLC Number:

R318

Zhu Jie-lin, Zhang Peng. Histone deacetylase inhibitor affected CD4⁺CD25⁺Foxp3⁺ cells in a mouse model of acute graft versus host disease [J]. Chinese Journal of Tissue Engineering Research, 2014, 18(49): 7908-7913.

Figures/Tables 3

2.1 实验动物数量分析 20只急性移植物抗宿主病模型小鼠随机分为治疗组及对照组，每组10只。因为移植后观察4周，至实验截止后处死全部受鼠，观察期内濒死小鼠即取组织送病检。 2.2 小鼠急性移植物抗宿主病评分及生存曲线变化移植后第1周：治疗组与对照组均出现轻微的体质量下降。移植后第2周：对照组小鼠均出现少食少动、消瘦、弓背、精神倦怠等急性移植物抗宿主病表现，本周内死亡小鼠4只；治疗组小鼠也出现上述症状，但程度较对照组轻微，本周内死亡小鼠1只。移植后第3周：对照组小鼠急性移植物抗宿主病明显加重，出现严重弓背、活动度降低、脱毛、肛周出血等症状，本周内死亡小鼠3只；治疗组小鼠出现中度耸毛，活动度尚可，本周内死亡小鼠2只。移植后第4周：对照组小鼠急性移植物抗宿主病仍呈进行性加重，本周内死亡小鼠3只；治疗组小鼠症状较第3周未有明显变化，本周内死亡小鼠1只。治疗组与对照组小鼠急性移植物抗宿主病评分结果见表2，生存时间见图1。 2.3 小鼠肝脏、脾脏的病理学变化治疗组小鼠病理表现较对照组病变轻。对照组主要病理改变：①肝脏表现为肝细胞肿胀变性，肝门静脉区大量分叶核细胞和淋巴细胞浸润及伴有局部片状性坏死；肝血窦和中央静脉扩张瘀血。②脾脏病变为脾小结结构破坏，边界不清楚(图2，3)。 2.4 CD4+CD25+Foxp3+细胞在外周血中阳性百分率变化治疗组小鼠外周血CD4+CD25+Foxp3+细胞阳性百分率移植后随时间延长呈逐渐递增趋势；对照组小鼠外周血CD4+CD25+Foxp3+细胞阳性百分率随时间延长呈逐渐递减趋势。移植后+7 d SAHA治疗组小鼠CD4+CD25+Foxp3+细胞比例与对照组差异无显著性意义(P > 0.05)；移植后+14，21 d治疗组CD4+CD25+Foxp3+细胞比例均高于对照组，差异有显著性意义(P < 0.05，见表3及图4)。 2.5 SAHA 对小鼠外周血Foxp3 mRNA表达水平的影响采用公式2??Ct计算治疗组与对照组小鼠外周血Foxp3 mRNA的相对表达水平，治疗组与对照组相比仍维持较高水平(0.85±0.20，0.26±0.10，P < 0.01)。 "

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