Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway.
Publication/Presentation Date
7-1-2020
Abstract
Acute Graft versus Host Disease (aGVHD) is a frequent and serious complication in patients receiving allogeneic bone marrow transplantation (allo-BMT) and often requires rigorous prophylaxis. The current treatment regimens for aGVHD are associated with several side effects which necessitates the development of novel interventions that prevent aGVHD without precluding graft-versus-tumor effects. In the present study, we show that treatment of donor graft with plant steroidal lactone Withaferin A (WA) prior to transplantation markedly reduced aGVHD mediated damage in target organs without compromising the graft-versus.-tumor activity of the transplanted lymphocytes. WA abrogated post-transplant cytokine storm associated with allo-activation of donor lymphocytes. This was attributed to the ability of WA to inhibit early signaling events in T-cell activation including lymphoblast formation and activation of AKT/mTOR pathway. Mortality and morbidity related to allo-transplantation was significantly reduced in recipients of WA treated donor splenocytes compared to recipient of vehicle treated donor splenocytes. Further, WA treatment did not have any effect on reconstitution of lymphoid and myeloid lineages in recipients, resulting in stable and complete donor chimerism. In agreement with previous reports showing the effectiveness of WA in a mouse model of partial chimerism, our data further establishes that WA is able to attenuate aGVHD in an MHC-mismatched high dose chemo-conditioned murine model without compromising engraftment. This study provides compelling scientific basis for possible application of WA for prevention and treatment of aGVHD in patients receiving allo-BMT.
Volume
84
First Page
106575
Last Page
106575
ISSN
1878-1705
Published In/Presented At
Mehta, M., Gohil, D., Khattry, N., Kumar, R., Sandur, S., Sharma, D., Checker, R., Agarwal, B., Jha, D., Majumdar, A., & Gota, V. (2020). Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway. International immunopharmacology, 84, 106575. https://doi.org/10.1016/j.intimp.2020.106575
Disciplines
Medicine and Health Sciences
PubMedID
32416453
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article