Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA.
J Pharmacol Exp Ther. 2011 Sep;338(3):819-28. doi: 10.1124/jpet.111.182717. Epub 2011 Jun 14.
Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life-threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT often is 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 Δ(9)-tetrahydrocannabinol (THC) in an acute model of GVHD that was induced by transferring parental C57BL/6 (B6) spleen cells into (C57BL/6 × DBA/2) F(1)(BDF1) mice. Transfer of B6 cells into BDF1 mice produced severe acute GVHD in the recipient, characterized by lymphoid hyperplasia, weight loss, T helper l 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(+) regulatory T cells. 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 cannabinoid receptor (CB) 1 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.
异基因造血细胞移植（HCT）被广泛用于治疗患有危及生命的恶性和非恶性血液疾病的患者。然而，异基因 HCT 常伴有严重和致命的移植物抗宿主病（GVHD）并发症，其中激活的供体 T 细胞识别组织相容性抗原不匹配，并导致受者发生显著毒性。在本研究中，我们检验了这样一个假设，即供体来源的 T 细胞上的大麻素受体的激活可能预防 GVHD。我们通过将亲代 C57BL/6（B6）脾细胞转移到（C57BL/6×DBA/2）F1（BDF1）小鼠中，检测了 Δ(9)-四氢大麻酚（THC）在急性 GVHD 模型中的作用。将 B6 细胞转移到 BDF1 小鼠中，会在受者中产生严重的急性 GVHD，其特征为淋巴细胞增生、体重减轻、辅助性 T 细胞 l 细胞因子产生和死亡率。THC 给药导致体重减轻的早期恢复，减少肝和肠组织损伤，并实现完全存活。THC 治疗减少了供体来源效应 T 细胞的扩增，并阻断了宿主来源免疫细胞的杀伤，同时促进了 Foxp3+调节性 T 细胞。在 GVHD 期间观察到的造血功能受损被 THC 治疗挽救。通过给予大麻素受体（CB）1 和 CB2 拮抗剂，至少部分逆转了 THC 降低临床 GVHD 的能力，从而表明 THC 介导的 GVHD 改善是大麻素受体依赖性的。我们的结果首次证明，靶向大麻素受体可能构成一种针对急性 GVHD 的新型治疗模式。
