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Potent immunomodulatory activity of a highly selective cannabinoid CB2 agonist on immune cells from healthy subjects and patients with multiple sclerosis

Published:December 22, 2016DOI:https://doi.org/10.1016/j.jneuroim.2016.12.009

      Highlights

      • COR167 inhibits proliferation of normal and MS immune cells.
      • COR167 shifts Th1 towards Th2 phenotype and down-regulates IL-4, IL-5 and Th17 phenotype.
      • COR167 reduces in vitro cell trafficking through human brain endothelium.
      • Cannabinoid CB2 receptor is a pharmacological target to counteract neuroinflammation.

      Abstract

      COR167, a novel CB2-selective high affinity agonist, was found to significantly inhibit, in a dose-dependent manner, the proliferation of both peripheral blood mononuclear cells and myelin basic protein-reactive T cell lines from normal healthy subjects and patients with relapsing-remitting multiple sclerosis (MS). In MS, a significantly higher inhibition was observed in patients on treatment with disease modifying drugs compared to those naive to treatment. The inhibitory activity of COR167 was exerted through a mixed mechanism involving atypical and incomplete shift of Th1 phenotype towards Th2 phenotype associated with slight reduction of IL-4 and IL-5 as well as strongly reduced levels of Th17-related cytokines. COR167 was also able to reduce in vitro migration of stimulated immunocompetent cells through human brain endothelium associated with a significant reduction of levels of several chemokines. These findings demonstrate that COR167 exerts potent immunomodulatory effects and confirm the cannabinoid CB2 receptor as a novel pharmacological target to counteract neuroinflammation.

      Graphical abstract

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      References

        • Aharoni R.
        Immunomodulation neuroprotection and remyelination - the fundamental therapeutic effects of glatiramer acetate: a critical review.
        J. Autoimmun. 2014; 54: 81-92
        • Ashton J.C.
        • Glass M.
        The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration.
        Curr. Neuropharmacol. 2007; 5: 73-80
        • Baker D.
        • Pryce G.
        • Croxford J.L.
        • Brown P.
        • Pertwee R.G.
        • Huffman J.W.
        • Layward L.
        Cannabinoids control spasticity and tremor in a multiple sclerosis model.
        Nature. 2000; 404: 84-87
        • Benito C.
        • Romero J.P.
        • Tolón R.M.
        • Clemente D.
        • Docagne F.
        • Hillard C.J.
        • Guaza C.
        • Romero C.
        Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis.
        J. Neurosci. 2007; 27: 2396-2402
        • Benito C.
        • Tolón R.M.
        • Pazos M.R.
        • Núñez E.
        • Castillo A.I.
        • Romero J.
        Cannabinoid CB2 receptors in human brain inflammation.
        Br. J. Pharmacol. 2008; 153: 277-285
        • Cascio M.G.
        • Bolognini D.
        • Pertwee R.G.
        • Palazzo E.
        • Corelli F.
        • Pasquini S.
        • Di Marzo V.
        • Maione S.
        In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB2 receptor inverse agonists.
        Pharmacol. Res. 2010; 61: 349-354
        • Centonze D.
        • Mori F.
        • Koch G.
        • Buttari F.
        • Codecà C.
        • Rossi S.
        • Cencioni M.T.
        • Bari M.
        • Fiore S.
        • Bernardi G.
        • Battistini L.
        • Maccarrone M.
        Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis.
        Neurol. Sci. 2009; 30: 531-534
        • Cioni C.
        • Turlizzi E.
        • Zanelli U.
        • Oliveri G.
        • Annunziata P.
        Expression of tight junction and drug efflux transporter proteins in an in vitro model of human blood-brain barrier.
        Front. Psych. 2012; 3: 47
        • Collison L.W.
        • Chaturvedi V.
        • Henderson A.L.
        • Giacomin P.R.
        • Guy C.
        • Bankoti J.
        • Finkelstein D.
        • Forbes K.
        • Workman C.J.
        • Brown S.A.
        • Rehg J.E.
        • Jones M.L.
        • Ni H.T.
        • Artis D.
        • Turk M.J.
        • Vignali D.A.
        IL-35-mediated induction of a potent regulatory T cell population.
        Nat. Immunol. 2010; 11: 1093-1101
        • Comabella M.
        • Imitola J.
        • Weiner H.L.
        • Khoury S.J.
        Interferon-beta treatment alters peripheral blood monocytes chemokine production in MS patients.
        J. Neuroimmunol. 2002; 126: 205-212
        • Correa F.
        • Docagne F.
        • Mestre L.
        • Clemente D.
        • Hernangomez M.
        • Loria F.
        • Guaza C.
        A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells.
        Biochem. Pharmacol. 2009; 77: 86-100
        • De Santi L.
        • Cantalupo L.
        • Tassi M.
        • Raspadori D.
        • Cioni C.
        • Annunziata P.
        Higher expression of BDNF receptor gp145trkB is associated with lower apoptosis intensity in T cell lines in multiple sclerosis.
        J. Neurol. Sci. 2009; 277: 65-70
        • Dittel B.N.
        Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor.
        Br. J. Pharmacol. 2008; 153: 271-276
        • Ehrhart J.
        • Obregon D.
        • Mori T.
        • Hou H.
        • Sun N.
        • Bai Y.
        • Klein T.
        • Fernandez F.
        • Tan J.
        • Shytle R.D.
        Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation.
        J. Neuroinflammation. 2005; 2: 29
        • Galiegue S.
        • Mary S.
        • Marchand J.
        • Dussossoy D.
        • Carriere D.
        • Carayon P.
        • Bouaboula M.
        • Shire D.
        • Le Fur G.
        • Casellas P.
        Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations.
        Eur. J. Biochem. 1995; 232: 54-61
        • Graham E.S.
        • Angel C.E.
        • Schwarcz L.E.
        • Dunbar P.R.
        • Glass M.
        Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry.
        Int. J. Immunopathol. Pharmacol. 2010; 23: 25-34
        • Grimsey N.L.
        • Goodfellow C.E.
        • Dragunow M.
        • Glass M.
        Cannabinoid receptor 2 undergoes Rab5-mediated internalization and recycles via a Rab11-dependent pathway.
        Biochim. Biophys. Acta. 2011; 1813: 1554-1560
        • Hedegaard C.J.
        • Krakauer M.
        • Bendtzen K.
        • Lund H.
        • Sellebjerg F.
        • Nielsen C.H.
        T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis.
        Immunology. 2008; 125: 161-169
        • Hohnocki K.
        • Inoue A.
        • Koh C.S.
        Elevated serum levels of IFN-gamma, IL-4 and TNF alpha/unelevated serum levels of IL-10 in patients with demyelinating diseases during the acute stage.
        J. Neuroimmunol. 1998; 87: 27-32
        • Hussain R.F.
        • Nouri A.M.
        • Oliver R.T.
        A new approach for measurement of cytotoxicity using colorimetric assay.
        J. Immunol. Methods. 1993; 160: 89-96
        • Imitola J.
        • Chitnis T.
        • Khoury S.J.
        Cytokines in multiple sclerosis: from bench to bedside.
        Pharmacol. Ther. 2005; 106: 163-177
        • Jaerve A.
        • Müller H.W.
        Chemokines in CNS injury and repair.
        Cell Tissue Res. 2012; 349: 229-248
        • Jean-Gilles L.
        • Feng S.
        • Tench C.R.
        • Chapman V.
        • Kendall D.A.
        • Barrett D.A.
        • Constantinescu C.S.
        Plasma endocannabinoid levels in multiple sclerosis.
        J. Neurol. Sci. 2009; 287: 212-215
        • Keserü G.
        • Makara G.M.
        Hit discovery and hit-to-lead approaches.
        Drug Discov. Today. 2006; 11: 741-748
        • Kieseier B.C.
        The mechanism of action of interferon-β in relapsing multiple sclerosis.
        CNS Drugs. 2011; 25: 491-502
        • Killestein J.
        • Hoogervorst E.L.J.
        • Reif M.
        • Kalkers N.F.
        • van Loenen A.C.
        • Staats P.G.M.
        • Gorter R.W.
        • Uitdehaag B.M.
        • Polman C.H.
        Safety, tolerability, and efficacy of orally administered cannabinoids in MS.
        Neurology. 2002; 58: 1404-1407
        • Kuwabara T.
        • Ishikawa F.
        • Yasuda T.
        • Aritomi K.
        • Nakano H.
        • Tanaka Y.
        • Okada Y.
        • Lipp M.
        • Kakiuchi T.
        CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells.
        J. Immunol. 2009; 183: 2513-2521
        • Malfitano A.M.
        • Laezza C.
        • D'Alessandro A.
        • Procaccini C.
        • Saccomanni G.
        • Tuccinardi T.
        • Manera C.
        • Macchia M.
        • Matarese G.
        • Gazzerro P.
        • Bifulco M.
        Effects on immune cells of a new 1,8-naphthyridin-2-one derivative and its analogues as selective CB2 agonists: implications in multiple sclerosis.
        PLoS One. 2013; 8: 62511
        • Maresz K.
        • Pryce G.
        • Ponomarev E.D.
        • Marsicano G.
        • Croxford J.L.
        • Shriver L.P.
        • Ledent C.
        • Cheng X.
        • Carrier E.J.
        • Mann M.K.
        • Giovannoni G.
        • Pertwee R.G.
        • Yamamura T.
        • Buckley N.E.
        • Hillard C.J.
        • Lutz B.
        • Baker D.
        • Dittel B.N.
        Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.
        Nat. Med. 2007; 13: 492-497
        • McDonald W.I.
        • Compston A.
        • Edan G.
        • Goodkin D.
        • Hartung H.P.
        • Lublin F.D.
        • McFarland H.F.
        • Paty D.W.
        • Polman C.H.
        • Reingold S.C.
        • Sandberg-Wollheim M.
        • Sibley W.
        • Thompson A.
        • van den Noort S.
        • Weinshenker B.Y.
        • Wolinsky J.S.
        Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis.
        Ann. Neurol. 2001; 50: 121-127
        • Moreno Torres I.
        • Sanchez A.J.
        • Garcia-Merino A.
        Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis.
        Expert. Rev. Neurother. 2014; 14: 1243-1250
        • Ni X.
        • Geller E.B.
        • Eppihimer M.J.
        • Eisenstein T.K.
        • Adler M.W.
        • Tuma R.F.
        Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model.
        Mult. Scler. 2004; 10: 158-164
        • Pacher P.
        • Hasko G.
        Endocannabinoids and cannabinoid receptors in ischaemia–reperfusion injury and preconditioning.
        Br. J. Pharmacol. 2008; 153: 252-262
        • Pasquini S.
        • Botta L.
        • Semeraro T.
        • Mugnaini C.
        • Ligresti A.
        • Palazzo E.
        • Maione S.
        • Di Marzo V.
        • Corelli F.
        Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo.
        J. Med. Chem. 2008; 51: 5075-5084
        • Pearce-Pratt R.
        • Phillips D.M.
        • Bourinbaiar A.S.
        Simple colorimetric cell-cell adhesion assay using biotinylated lymphocytes.
        J. Immunol. Methods. 1991; 140: 159-165
        • Pertwee R.G.
        Emerging strategies for exploiting cannabinoid receptor agonists as medicines.
        Br. J. Pharmacol. 2009; 156: 397-411
        • Pröbstel A.K.
        • Sanderson N.S.
        • Derfuss T.
        B cells and autoantibodies in multiple sclerosis.
        Int. J. Mol. Sci. 2015; 16: 16576-16592
        • Racke M.K.
        • Bonomo A.
        • Scott D.E.
        • Cannella B.
        • Levine A.
        • Raine C.S.
        • Shevach E.M.
        • Röcken M.
        Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.
        J. Exp. Med. 1994; 180: 1961-1966
        • Ramirez S.H.
        • Haskó J.
        • Skuba A.
        • Fan S.
        • Dykstra H.
        • McCormick R.
        • Reichenbach N.
        • Krizbai I.
        • Mahadevan A.
        • Zhang M.
        • Tuma R.
        • Son Y.J.
        • Persidsky Y.
        Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.
        J. Neurosci. 2012; 32: 4004-4016
        • Sánchez López A.J.
        • Román-Vega L.
        • Ramil Tojeiro E.
        • Giuffrida A.
        • García-Merino A.
        Regulation of cannabinoid receptor gene expression and endocannabinoid levels in lymphocyte subsets by interferon-β: a longitudinal study in multiple sclerosis patients.
        Clin. Exp. Immunol. 2015; 179: 119-127
        • Schagger H.
        • Von Jagow G.
        Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in he range from 1 to 100 kDa.
        Anal. Biochem. 1987; 166: 368-379
        • Szczuciński A.
        • Losy J.
        Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies.
        Acta Neurol. Scand. 2007; 115: 137-146
        • Tada H.
        • Shibo O.
        • Kuroshima K.
        • Koyama M.
        • Tsukamoto K.
        An improved colorimetric assay for interleukin-2.
        J. Immunol. Methods. 1986; 93: 157-165
        • Takatsu K.
        • Tominaga A.
        • Hamaoka T.
        Antigen-induced T cell-replacing factor (TRF). I. Functional characterization of a TRF-producing helper T cell subsetand genetic studies on TRF production.
        J. Immunol. 1980; 124: 2414-2422
        • Tzartos J.S.
        • Friese M.A.
        • Craner M.J.
        • Palace J.
        • Newcombe J.
        • Esiri M.M.
        • Fugger L.
        Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.
        Am. J. Pathol. 2008; 172: 146-155
        • Vignali D.A.
        • Kuchroo V.K.
        IL-12 family cytokines: immunological playmakers.
        Nat. Immunol. 2012; 13: 722-728
        • Vitetta E.S.
        • Ohara J.
        • Myers C.D.
        • Layton J.E.
        • Krammer P.H.
        • Paul W.E.
        Serological, biochemical, and functional identity of B cell stimulatory factor 1 and B cell differentiation factor for IgG1.
        J. Exp. Med. 1985; 162: 1726-1731
        • Zajicek J.
        • Fox P.
        • Sanders H.
        • Wright D.
        • Vickery J.
        • Nunn A.
        • Thompson A.
        • U.K. MS Research Group
        Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomized placebo-controlled trial.
        Lancet. 2003; 362: 1517-1526