浙江大学Lu-yang Yu等研究人员合作发现，人羊膜上皮干细胞是预防急性移植物抗宿主病的候选细胞疗法。该研究于2024年5月27日在线发表于国际一流学术期刊《中国药理学报》。

研究人员表示，移植物抗宿主病（GVHD）是供体T细胞通过识别宿主异体抗原而激活产生的一种免疫学疾病，是同种异体造血干细胞移植（allo-HSCT）应用的主要限制因素。传统的免疫抑制剂可以缓解GVHD，但会产生严重的副作用。因此，探索替代治疗策略是非常必要的。人羊膜上皮干细胞（hAESC）具有特殊的免疫调节特性，最近被认为是细胞疗法的理想来源。

研究人员基于之前开发的cGMP级hAESC产品，评估了hAESC在治疗GVHD中的作用。通过尾静脉注射huPBMC建立了人源化小鼠急性GVHD（aGVHD）模型。为了预防或治疗急性GVHD，小鼠分别在输注PBMC后的第1天或第7天注射了hAESC。研究表明，输注hAESC能明显缓解疾病表型，提高aGVHD小鼠的存活率，并改善aGVHD靶器官的病理损伤。研究人员证实，hAESC能直接诱导CD4⁺ T细胞极化，其中Th1和Th17亚群下调，Treg亚群升高。相应地，在有hAESC存在的情况下，一系列促炎细胞因子的水平降低，而抗炎细胞因子的水平上调。

研究人员发现，hAESC以旁分泌模式调节CD4⁺亚群极化，其中TGFβ和PGE2被选择性分泌，分别介导Treg升高和Th1/Th17抑制。此外，移植的hAESC还能抑制白血病细胞的生长，从而保持移植物抗白血病（GVL）效应。更有趣的是，在HSCT患者中输注hAESC显示出潜在的抗GVHD作用，且无安全性问题，证实了临床前研究中的免疫调节机制。研究人员认为，输注hAESC是治疗HSCT后GVHD的一种很有前景的策略，而且不会影响GVL的效果。该临床试验已在www.clinicaltrials.gov注册，注册号为 #NCT03764228。

附：英文原文

Title: Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease

Author: Yang, Peng-jie, Zhao, Xiang-yu, Kou, Yao-hui, Liu, Jia, Ren, Xiang-yi, Zhang, Yuan-yuan, Wang, Zhi-dong, Ge, Zhen, Yuan, Wei-xin, Qiu, Chen, Tan, Bing, Liu, Qin, Shi, Yan-na, Jiang, Yuan-qing, Qiu, Cong, Guo, Li-he, Li, Jin-ying, Huang, Xiao-jun, Yu, Lu-yang

Issue&Volume: 2024-05-27

Abstract: Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFβ and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.

DOI: 10.1038/s41401-024-01283-y

Source: https://www.nature.com/articles/s41401-024-01283-y