Abstract
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 (P < 0.05), but IL-10, IL-4, IL-5, and IL-1β increased significantly in the Rapa group (P < 0.05). 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.
Highlights
Aplastic anemia (AA) is a rare and heterogeneous disorder
The focus in the clinical development of the novel nontransplant therapies for severe aplastic anemia (SAA) has been on intensifying immunosuppressive therapy (IST), usually as antithymocyte globulin (ATG) and cyclosporine (CsA), which have dramatically changed the course of this illness, with the 10-year survival rate of patients being about 70% [3]
An immune attack-mediated AA mouse model was constructed by total body irradiation (TBI) and allo-lymphocyte infusion [13]
Summary
Aplastic anemia (AA) is a rare and heterogeneous disorder. It is defined as pancytopenia with hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis [1, 2]. Feng et al [8] had reported that rapamycin effectively treated immune-mediated murine BM failure as compared to the standard-dose CsA, which showed a high efficacy in suppressing Th1 immune responses, eradicating pathogenic CD8+ T cells. Elt had received FDA approval for the treatment of SAA in recent years, based on phase I/II dose-escalation trial of a single agent Elt for patients failing one or more treatment cycles with ATG/CsA and the efficacy within clinical trials exploring its role in the first-line therapy in addition to standard IST [10,11,12]. Based on the above research, we tested the efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure, whether a better curative effect can be achieved compared to the standard dose of CsA and Rapa alone. We will discuss new insights into the possible efficacy of Rapa combined with Elt in BMF mouse, which may further improve the efficacy of AA patients
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