Potent T cell‐mediated anti‐inflammatory role of the selective CB2 agonist lenabasum in multiple sclerosis

• Published in: Neuropathology and applied neurobiology 2022-02, Vol.48 (2), p.e12768-n/a
• Main Authors: Tiberi, Marta, Evron, Tama, Saracini, Stefano, Boffa, Laura, Mercuri, Nicola Biagio, Chintalacharuvu, Subba R., Atamas, Sergei P., Chiurchiù, Valerio
• Format: Article
• Language: English
• Subjects: Adult; Animals; Anti-Inflammatory Agents - pharmacology; Apoptosis - drug effects; Cannabinoid CB2 receptors; cannabinoid receptor; Cannabinoid Receptor Agonists - pharmacology; CD25 antigen; CD4 antigen; CD8 antigen; Cell Survival - drug effects; cytokines; Demyelination; Dronabinol - analogs & derivatives; Dronabinol - pharmacology; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; Female; Flow cytometry; Helper cells; Humans; Immunomodulation; Inflammation; Interferon; Inverse agonists; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Male; Mice; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - immunology; Patients; Receptor, Cannabinoid, CB2 - agonists; Spinal cord; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; Th1; Th17; Tumor necrosis factor
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12768

Background 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. Objectives 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). Methods 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. Results 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. Conclusion Lenabasum exerts potent T cell‐mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS. With the aim of selectively targeting the neuroprotective and anti‐inflammatory cannabinoid receptor type‐2 (CB2) as a pharmacological strategy to treat multiple sclerosis (MS), we tested the role of lenabasum, a selective agonist for this receptor, on T lymphocytes from MS patients, the key subsets that are crucially involved in the autoreactive responses against myelin. Lenabasum exerted potent effects in reducing cytokine production from CD4 and CD8 T cells and from committed Th1 and Th17 cells by modulating their respective transcriptional programs. Oral administration of lenabasum in the experimental mouse model of multiple sclerosis attenuated disease severity by reducing immune cell infiltration and promoting remyelination in spinal cord. CB2 agonists can be exploited as promising therapeutics to treat MS.