Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Most patients with AA respond to immunosuppressive therapy (IST), usually as antithymocyte globulin (ATG) and cyclosporine (CsA), but some relapse on CsA withdrawal or require long-term administration of CsA to maintain blood counts. Recent research has found that rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved a satisfactory effect in clinical application. At present, many studies have confirmed that eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then, whether Rapa combined Elt in the treatment of AA will acquire better efficacy than a single drug application remains unclear. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation (TBI) and allo-lymphocyte infusion. In our study, we tested the efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. It showed that treatment with Rapa in combination Elt in the AA mouse model ameliorated pancytopenia and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. However, there was no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice after the therapy of Rapa combined with Elt compared with Rapa alone. Furthermore, the secretion of IL-10 of Tregs in AA mice increased significantly after the therapy of Rapa combined with Elt, but there was no significant difference in the number of Treg cells. We did not observe the difference in the curative effect of the Rapa group and CsA group, but for IL-10/Tregs ratio, the Rapa group was superior to the CsA group. And the IFN-r secretion of CD8+T cells in AA mice decreased significantly after the combination therapy of Rapa and Elt than Rapa alone. Compared with the AA group, the level of plasma IFN-γ, IL-2, and TNF-α decreased significantly (), but IL-10, IL-4, IL-5, and IL-1β increased significantly in the Rapa group (). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO, and TNF-α, the therapy of Rapa combined with Elt showed a more significant effect than Rapa alone in AA mice. To some extent, this study had shown a relatively better synergistic effect in murine models of immune-mediated bone marrow failure after the combination therapy of Rapa and Elt, which was a promising clinical utility in SAA treatment.

中文翻译：

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雷帕霉素联合艾曲波帕在免疫介导的骨髓衰竭小鼠模型中的有效性。

严重再生障碍性贫血（SAA）是一种罕见的疾病，其特征在于严重的全血细胞减少症和骨髓衰竭。大多数AA患者对免疫抑制疗法（IST）都有反应，通常以抗胸腺细胞球蛋白（ATG）和环孢素（CsA）的形式出现，但在停用CsA时会复发或需要长期服用CsA来维持血球计数。最近的研究发现，雷帕霉素（Rapa）在免疫介导的骨髓衰竭的小鼠模型中是一种有效的疗法。但是，它在临床应用中没有取得令人满意的效果。目前，许多研究已经证实，Eltrombopag（ELT）联合IST可以提高AA患者的疗效。然后，尚不清楚Rapa联合Elt治疗AA是否会比单药治疗获得更好的疗效。在这个研究中，通过全身照射（TBI）和同种异体淋巴细胞输注构建免疫攻击介导的AA小鼠模型。在我们的研究中，我们在免疫介导的骨髓衰竭小鼠模型中测试了Rapa联合Elt作为新疗法的功效。结果表明，在AA小鼠模型中用Rapa联合Elt进行治疗可改善全血细胞减少症，并延长了动物的生存时间，其方式与单独使用CsA和Rapa的标准剂量相当。然而，与单独使用Rapa相比，Rapa联合Elt治疗后，AA小鼠对NK细胞及其子集，mDC和CD4 + / CD8 +比的数量和功能没有明显改善。此外，Rapa联合Elt治疗后，AA小鼠Tregs的IL-10分泌显着增加，但是Treg细胞的数量没有显着差异。我们没有观察到Rapa组和CsA组在疗效上的差异，但是就IL-10 / Tregs比而言，Rapa组优于CsA组。与单独使用Rapa相比，Rapa和Elt联合治疗后AA小鼠CD8 + T细胞的IFN-r分泌明显减少。与AA组相比，血浆IFN-γ，IL-2和TNF- α明显降低（），但Rapa组的IL-10，IL-4，IL-5和IL- 1β显着增加（）。至于IL-10，IL-12p70，IL-2，IL-6，KC / GRO和TNF- α，在AA小鼠中，Rapa联合Elt的治疗比单独使用Rapa具有更显着的作用。在某种程度上，这项研究显示了在Rapa和Elt联合治疗后，在免疫介导的骨髓衰竭小鼠模型中具有相对较好的协同作用，这在SAA治疗中具有广阔的临床应用前景。