Commissariat à l'Énergie Atomique (CEA), Molecular Imaging Research Center (MIRCen), 92260 Fontenay-aux-Roses, France.
CEA, INSERM, Université Paris-Sud, U1184, IDMIT Department, Fontenay-aux-Roses 92265, France.
EBioMedicine. 2019 Sep;47:492-505. doi: 10.1016/j.ebiom.2019.08.052. Epub 2019 Sep 3.
Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation.
We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4 lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen).
rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a DCs or CD163 cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4 T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4CD25FOXP3CD39 regulatory lymphocytes and favoured an upsurge in systemic TGFβ and IL-8 upon rhMOG re-administration in vivo.
We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.
自身免疫性脱髓鞘疾病（ADD）是由于针对脑抗原的自身反应性细胞和体液免疫反应引起的神经功能障碍的主要原因。通过适当的免疫调节，可以治愈慢性 ADD。
我们实施了一个临床前方案，以在实验性自身免疫性脑脊髓炎（EAE）的食蟹猴模型中促进对髓鞘少突胶质细胞糖蛋白（MOG）的免疫耐受，其中重组人 MOG（rhMOG）的给药会引发由 MOG 自身反应性 CD4 淋巴细胞和抗 MOG IgG 介导的脑炎症。对于免疫疗法，我们使用了一种针对树突状细胞-唾液酸糖蛋白受体（DC-ASGPR）的重组抗体（Ab），该抗体与 MOG 或对照抗原 PSA（前列腺特异性抗原）融合。
rhMOG 和抗-DC-ASGPR-MOG 分别在食蟹猴皮肤中的 CD1a DC 或 CD163 细胞中被检测到。皮内给予抗-DC-ASGPR-MOG，但不给对照抗-DC-ASGPR-PSA，可预防 EAE。该治疗可防止对照中观察到的 CD4 T 细胞活化和促炎细胞因子的产生。此外，抗-DC-ASGPR-MOG 的给药诱导了 MOG 特异性 CD4CD25FOXP3CD39 调节性淋巴细胞，并在体内重新给予 rhMOG 时促进了全身性 TGFβ 和 IL-8 的增加。
我们表明，抗-DC-ASGPR-MOG 的递呈允许抗原特异性适应性免疫调节以防止对 MOG 的免疫耐受的突破。我们的发现为针对自身抗原的治疗性疫苗铺平了道路，这些自身抗原与抗 MOG 自身抗体相关的 ADD 等严重的脑脊髓炎具有长期缓解作用。
这项工作得到了法国 ANR（ANR-11-INBS-0008 和 ANR-10-EQPX-02-01）、NIH（NIH 1 R01 AI 105066）、贝勒斯科特和怀特医疗保健系统资助和罗氏研究合作资助的支持。
