Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy.
Department of Discovery and Preclinical Development, Corbus Pharmaceuticals, Inc., Norwood, MA, USA.
Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12768. doi: 10.1111/nan.12768. Epub 2021 Oct 21.
Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist able to exert potent anti-inflammatory effects, but its role on T cells remains unknown.
The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE).
Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing-remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT-PCR. EAE mice were treated with lenabasum, and clinical score and neuroinflammation were evaluated.
Lenabasum significantly reduced TNF-a production from CD4+ T cells and CD8+ T cells in a dose-dependent manner in both HS and RRMS patients. In MS patients, lenabasum also reduced activation marker CD25 and inhibited IL-2 production from both T cell subsets and IFN-γ and IL-17 from committed Th1 and Th17 cells, respectively. These effects were blocked by the pretreatment with selective CB2 inverse agonist SR144528. In vivo treatment of EAE mice with lenabasum significantly ameliorated disease severity, reduced neuroinflammation and demyelination in spinal cord.
Lenabasum exerts potent T cell-mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS.
利纳巴斯umab 是一种合成大麻素受体 2（CB2）激动剂，能够发挥强大的抗炎作用，但它对 T 细胞的作用尚不清楚。
本研究旨在探讨利纳巴斯umab 在 T 淋巴细胞亚群中的抗炎机制及其在实验性自身免疫性脑脊髓炎（EAE）中的体内治疗效果。
从 17 名健康受试者（HS）和 25 名复发缓解型多发性硬化症（RRMS）患者的单核细胞中提取出来，在有或没有利纳巴斯umab 的情况下进行激活，并通过流式细胞术和 qRT-PCR 进行分析。用利纳巴斯umab 治疗 EAE 小鼠，并评估临床评分和神经炎症。
利纳巴斯umab 在 HS 和 RRMS 患者中均以剂量依赖性方式显著降低 CD4+T 细胞和 CD8+T 细胞中 TNF-a 的产生。在 MS 患者中，利纳巴斯umab 还降低了 CD25 激活标志物的表达，并抑制了两种 T 细胞亚群的 IL-2 产生以及 Th1 和 Th17 细胞的 IFN-γ和 IL-17 产生，这些作用均被选择性 CB2 反向激动剂 SR144528 的预处理所阻断。在 EAE 小鼠体内治疗中，利纳巴斯umab 显著改善了疾病严重程度，减少了脊髓中的神经炎症和脱髓鞘。
利纳巴斯umab 发挥了强大的 T 细胞介导的免疫调节作用，提示 CB2 是一种有前途的药理学靶点，可以对抗 MS 中的神经炎症。
