Sisay Sofia, Pryce Gareth, Jackson Samuel J, Tanner Carolyn, Ross Ruth A, Michael Gregory J, Selwood David L, Giovannoni Gavin, Baker David
Neuroimmunology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
PLoS One. 2013 Oct 9;8(10):e76907. doi: 10.1371/journal.pone.0076907. eCollection 2013.
Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.
内源性大麻素和一些植物性大麻素可与CB1和CB2大麻素受体、瞬时受体电位香草酸受体1（TRPV1）以及孤儿G蛋白受体55（GPR55）结合。使用C57BL/10和C57BL/6（Cnr2(tm1Zim)）CB2大麻素受体基因敲除小鼠的研究表明，在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）模型中，其具有免疫增强作用。然而，在Biozzi ABH小鼠中进行的其他EAE研究往往未能显示出CB2受体激动或拮抗对抑制T细胞自身免疫的任何治疗效果。研究了遗传背景对与内源性大麻素系统相关基因敲除小鼠中EAE诱导的影响。结果发现，在用髓鞘少突胶质细胞糖蛋白35 - 55肽进行主动诱导后，C57BL/6.GPR55基因敲除小鼠所患疾病的严重程度较低，尤其是雌性小鼠。相比之下，C57BL/6.CB2（Cnr2(Dgen)）受体基因敲除小鼠所患疾病的严重程度增加，这与基因和药理学上不同的Cnr2(tm1Zim)小鼠一致。然而，当将敲除基因培育到ABH小鼠背景中并用脊髓自身抗原诱导EAE时，CB2受体缺失的免疫增强作用消失。同样，在ABH背景下的CB1受体和瞬时受体电位香草酸受体1基因敲除小鼠，在EAE的疾病发病率和严重程度方面，未表现出免疫易感性的改变，这与一些C57BL/6小鼠研究中所报道的情况不同。此外，在ABH小鼠背景下GPR55的免疫调节影响很小。虽然镇静剂量的四氢大麻酚可诱导免疫抑制，但这与CB1受体介导的效应有关，而非CB2受体介导的效应。这些数据支持了这样一个事实，即非精神活性剂量的药用大麻对MS中的免疫反应影响很小。重要的是，这为一些转基因/基因敲除研究以及其他在低EAE易感性背景下疾病进程和易感性不一致的研究的转化价值增添了一份谨慎。
