Article ; Online: Withaferin-A alleviates acute graft versus host disease without compromising graft versus leukemia effect.
International immunopharmacology
2023 Volume 121, Page(s) 110437
Abstract: Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from ... ...
| Abstract | Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from Withania somnifera (Ashwagandha), is known to have anti-inflammatory, anti-proliferative and immunomodulatory properties. The efficacy of WA for the prevention and treatment of aGvHD was evaluated using a murine model of alloHSCT. Prophylactic administration of WA to mice mitigated the clinical symptoms of aGvHD and improved survival significantly compared to the GvHD control [HR = 0.07 (0.01-0.35); P < 0.001]. Furthermore, WA group had better overall survival compared to standard prophylactic regimen of CSA + MTX [HR = 0.19 (0.03-1.1), P < 0.05]. At the same time, WA did not compromise the beneficial GvL effect. In addition, WA administered to animals after the onset of aGvHD could reverse the clinical severity and improved survival, thus establishing its therapeutic potential. Our findings suggest that WA reduced the systemic levels of Th1, Th2 and Th17 inflammatory cytokine and increased the anti-inflammatory cytokine IL-10 levels significantly (P < 0.05). WA also inhibited lymphocytes migration to gut, liver, skin and lung and protected these organs from damage. Ex-vivo, WA inhibited proliferation of human peripheral blood mononuclear cells (hPBMCs), modulated immune cell phenotype and decreased cytokine release. In addition, WA inhibited pJAK2 and pSTAT3 protein levels in mouse splenocytes and hPBMCs. In conclusion, our study demonstrates the utility of WA for the prevention and treatment of aGvHD, which should be further evaluated in a clinical setting. |
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| MeSH term(s) | Humans ; Animals ; Mice ; Graft vs Leukemia Effect ; Leukocytes, Mononuclear ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Cytokines/therapeutic use ; Leukemia/drug therapy ; Anti-Inflammatory Agents/therapeutic use ; Acute Disease |
| Chemical Substances | Cytokines ; Anti-Inflammatory Agents |
| Language | English |
| Publishing date | 2023-06-11 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 2043785-7 |
| ISSN | 1878-1705 ; 1567-5769 |
| ISSN (online) | 1878-1705 |
| ISSN | 1567-5769 |
| DOI | 10.1016/j.intimp.2023.110437 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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