The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure
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 admin...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2020/1798795 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832560054784491520 |
|---|---|
| author | Shaoxue Ding Xiaowei Liang Tian Zhang Rong Fu |
| author_facet | Shaoxue Ding Xiaowei Liang Tian Zhang Rong Fu |
| author_sort | Shaoxue Ding |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a85e074725104f199515b5b591a01fbb |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-a85e074725104f199515b5b591a01fbb2025-02-03T01:28:30ZengWileyJournal of Immunology Research2314-88612314-71562020-01-01202010.1155/2020/17987951798795The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow FailureShaoxue Ding0Xiaowei Liang1Tian Zhang2Rong Fu3Department of Hematology, Tianjin Medical University General Hospital, Tianjin, ChinaDepartment of Hematology, Tianjin Medical University General Hospital, Tianjin, ChinaDepartment of Hematology, Tianjin Medical University General Hospital, Tianjin, ChinaDepartment of Hematology, Tianjin Medical University General Hospital, Tianjin, ChinaSevere 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.http://dx.doi.org/10.1155/2020/1798795 |
| spellingShingle | Shaoxue Ding Xiaowei Liang Tian Zhang Rong Fu The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure Journal of Immunology Research |
| title | The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure |
| title_full | The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure |
| title_fullStr | The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure |
| title_full_unstemmed | The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure |
| title_short | The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure |
| title_sort | effectiveness of rapamycin combined with eltrombopag in murine models of immune mediated bone marrow failure |
| url | http://dx.doi.org/10.1155/2020/1798795 |
| work_keys_str_mv | AT shaoxueding theeffectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT xiaoweiliang theeffectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT tianzhang theeffectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT rongfu theeffectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT shaoxueding effectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT xiaoweiliang effectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT tianzhang effectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure AT rongfu effectivenessofrapamycincombinedwitheltrombopaginmurinemodelsofimmunemediatedbonemarrowfailure |