Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil.
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
J Pharmacol Exp Ther. 2021 May;377(2):273-283. doi: 10.1124/jpet.120.000479. Epub 2021 Mar 3.
Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor , and interferon (IFN). CCL3 and IFN levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB) receptors on CD4 and forkhead box P3 cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB) receptor expression on CD4 and forkhead box P3 cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.
大麻二酚（CBD）是一种具有显著抗炎作用的高度脂溶性植物大麻素。本研究旨在评估 CBD 对急性移植物抗宿主病（aGVHD）小鼠的治疗作用及其作用机制。通过将 C57BL-6j 骨髓细胞和脾细胞移植到 Balb-c 小鼠中诱导 aGVHD。接受治疗的小鼠每天接受 CBD 治疗，治疗通过减少炎症和损伤并促进肠道、回肠和肝脏的免疫调节，降低了小鼠的死亡率。对肠道的分析表明，CBD 治疗降低了 C-C 基序趋化因子配体（CCL）2、CCL3、CCL5、肿瘤坏死因子和干扰素（IFN）的水平。肝脏中 CCL3 和 IFN 的水平也降低了。从机制上讲，CBD 还增加了肠道中 CD4 和叉头框 P3 细胞上的大麻素受体 2（CB）受体的数量，这可能解释了促炎细胞因子和趋化因子的减少。CB 受体拮抗剂降低了 CBD 治疗小鼠的存活率，表明该受体参与了 CBD 的作用。此外，CBD 治疗不会干扰移植物抗白血病反应。CBD 治疗通过部分由 CB 受体相互作用介导的抗炎和免疫调节作用来保护 aGVHD 小鼠。总的来说，我们的研究表明，CBD 作为治疗 aGVHD 的一种有前途的方法，在接受骨髓移植的患者中具有潜在的治疗应用。
本研究首次提供了大麻二酚（一种无精神活性作用的植物大麻素）在移植物抗宿主病中诱导免疫调节的机制。增强 CD4 和叉头框 P3 细胞上的肠道大麻素受体 2（CB）受体表达并增加这些调节性细胞的数量，大麻二酚可降低促炎细胞因子并提高移植物抗宿主病小鼠的存活率。这种作用依赖于 CB 受体的激活。此外，大麻二酚不干扰移植物抗白血病反应，这是避免原发性疾病复发的主要反应。
