GSK3 inhibition prevents lethal GVHD in mice

Klamer, Guy, Shen, Sylvie, Song, Emma, Rice, Alison M., Knight, Robert, Lindeman, Robert, O'Brien, Tracey A. and Dolnikov, Alla (2013) GSK3 inhibition prevents lethal GVHD in mice. Experimental Hematology, 41 1: 39-55. doi:10.1016/j.exphem.2012.09.005


Author Klamer, Guy
Shen, Sylvie
Song, Emma
Rice, Alison M.
Knight, Robert
Lindeman, Robert
O'Brien, Tracey A.
Dolnikov, Alla
Title GSK3 inhibition prevents lethal GVHD in mice
Journal name Experimental Hematology   Check publisher's open access policy
ISSN 0301-472X
1873-2399
Publication date 2013-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.exphem.2012.09.005
Volume 41
Issue 1
Start page 39
End page 55
Total pages 17
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2014
Language eng
Abstract Graft-versus-host disease (GVHD) is a major contributor to transplant-related mortality and morbidity after allogeneic stem cell transplantation. Despite advancements in tissue-typing techniques, conditioning regimens, and therapeutic intervention, the incidence rate of GVHD remains high. GVHD is caused by alloreactive donor T cells that infiltrate and destroy host tissues (e.g., skin, liver, and gut). Therefore, GVHD is prevented and treated with therapeutics that suppress proinflammatory cytokines and T-cell function (e.g., cyclosporine, glucocorticoids). Here we report that the small molecule inhibitor of glycogen synthase kinase 3, 6-bromoindirubin 3'-oxime (BIO), prevents lethal GVHD in a humanized xenograft model in mice. BIO treatment did not affect donor T-cell engraftment, but suppressed their activation and attenuated bone marrow and liver destruction mediated by activated donor T cells. Glycogen synthase kinase 3 inhibition modulated the Th1/Th2 cytokine profile in vitro and suppressed activation of signal transducers and activators of transcription 1 and 3 signaling pathways both in vitro and in vivo. Importantly, human T cells derived from BIO-treated mice were able to mediate anti-tumor effects in vitro, and BIO did not affect stem cell engraftment and multilineage reconstitution in a mouse model of transplantation. These data demonstrate that inhibition of glycogen synthase kinase 3 can potentially abrogate GVHD without compromising the efficacy of transplantation.
Keyword Transplant-related mortality
Allogeneic stem cell transplantation
Graft-versus-host disease (GVHD)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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