title: GSK3 inhibition prevents lethal GVHD in mice.
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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Klamer
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.forename: Emma
authors.initials: E
authors.lastname: Song
authors.forename: Alison M
authors.initials: AM
authors.lastname: Rice
authors.forename: Robert
authors.initials: R
authors.lastname: Knight
authors.forename: Robert
authors.initials: R
authors.lastname: Lindeman
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
authors.forename: Alla
authors.initials: A
authors.lastname: Dolnikov
mesh_terms: D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C579143:3,6-bromoindirubin 3'-oxime; D007211:Indoles; C489427:MYC protein, human; D010091:Oximes; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D038362:Glycogen Synthase Kinase 3