Cannabidiol Enhances Intestinal Cannabinoid Receptor Type 2 Receptor Expression and Activation Increasing Regulatory T Cells and Reduces Murine Acute Graft-versus-Host Disease without Interfering with the Graft-versus-Leukemia Response
Cannabidiol Enhances Intestinal Cannabinoid Receptor Type 2 Receptor Expression and Activation Increasing Regulatory T Cells and Reduces Murine Acute Graft-versus-Host Disease without Interfering with the Graft-versus-Leukemia Response
复制标题
大麻二酚增强肠大麻素受体2型受体表达和活化增加调节性T细胞并减少小鼠急性移植物抗宿主病而不干扰移植物抗白血病反应
DOI：
10.1124/jpet.120.000479
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发表时间：
2021-05-01
影响因子：
3.5
通讯作者：
Miranda e Castor, Marina Gomes
中科院分区：
文献类型：
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作者：
Berg, Barbara Betonico;Soares, Jaqueline Silva;Miranda e Castor, Marina Gomes
大麻二酚（CBD）是一种高脂类植物大麻素，具有显着的抗炎作用。本研究的目的是评估 CBD 在治疗患有急性移植物抗宿主病（aGVHD）的小鼠中的作用和作用机制。 aGVHD 通过将 C57BL-6j 的骨髓细胞和脾细胞移植到 Balb-c 小鼠中来诱导。受体小鼠每天接受 CBD 治疗，这种治疗通过减少炎症和损伤以及促进空肠、回肠和肝脏的免疫调节来降低小鼠死亡率。对空肠和回肠的分析表明，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α和干扰素γ（IFNγ）的水平。肝脏中 CCL3 和 IFNg 水平也降低。从机制上讲，CBD还增加了肠道CD4（+）和叉头盒P3（+）细胞上大麻素受体2型（CB2）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。 CB2 受体的拮抗剂降低了 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 治疗似乎可以通过部分由 CB2 受体相互作用介导的抗炎和免疫调节作用来保护 aGVHD 小鼠。总而言之，我们的研究表明 CBD 代表了治疗 aGVHD 的一种有趣方法，在接受骨髓移植的患者中具有潜在的治疗应用。 意义声明这项研究首次提供了大麻二酚（一种不具有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。大麻二酚可增强 CD4(+) 和叉头盒 P3(+) 细胞上肠道 2 型大麻素受体 (CB2) 受体的表达并增加这些调节细胞的数量，从而减少促炎细胞因子并提高移植物抗宿主病小鼠的存活率。该效应依赖于 CB2 受体激活。此外，大麻二酚不会干扰移植物抗白血病反应，这是避免原发性疾病复发的核心反应。
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 alpha, and interferon gamma (IFN gamma). CCL3 and IFNg levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4(+) and forkhead box P3(+) cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 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 CB2 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 STATEMENTThis 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 (CB2) 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 CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.