RT Journal Article
SR Electronic
T1 Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: Evidence from an experimental murine model
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.182717
DO 10.1124/jpet.111.182717
A1 Pandey, Rupal
A1 Hegde, Venkatesh L
A1 Nagarkatti, Mitzi
A1 Nagarkatti, Prakash
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/06/14/jpet.111.182717.abstract
AB Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT is often accompanied by severe and lethal complications from graft-versus-host disease (GVHD), in which activated donor T cells recognize histocompatibility antigenic mismatches and cause significant toxicity in the recipient. In the current study, we tested the hypothesis that activation of cannabinoid receptors on donor-derived T cells may prevent GVHD. We tested the effect of delta-9-tetrahydrocannabinol (THC) in an acute model of GVHD that was induced by transferring parental C57Bl/6 (B6) spleen cells into (C57B1/6 X DBA/2) F1(BDF1) mice. Transfer of B6 cells into BDF1 mice produced severe acute GVHD in the recipient, characterized by lymphoid hyperplasia, weight loss, Thl cytokine production and mortality. THC administration led to early recovery from body weight loss, reduced tissue injury in the liver and intestine, as well as complete survival. THC treatment reduced the expansion of donor-derived effector T cells and blocked the killing of host-derived immune cells while promoting Foxp3+ Tregs. Impaired hematopoiesis seen during GVHD was rescued by treatment with THC. The ability of THC to reduce the clinical GVHD was reversed, at least in part, by administration of CB1 and CB2 antagonists thereby demonstrating that THC-mediated amelioration of GVHD was cannabinoid receptor-dependent. Our results demonstrate for the first time that targeting cannabinoid receptors may constitute a novel treatment modality against acute GVHD.