Division of Immunogenetics and Cellular Immunology, Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; and
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032.
J Immunol. 2021 Feb 1;206(3):554-565. doi: 10.4049/jimmunol.2000265. Epub 2020 Dec 23.
Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS that is characterized by demyelination, axonal loss, gliosis, and inflammation. The murine model of MS is the experimental autoimmune encephalopathy (EAE) induced by immunization of mice with myelin oligodendrocyte glycoprotein (MOG) Ig-like transcript 3 (ILT3) is an inhibitory cell surface receptor expressed by tolerogenic human dendritic cells. In this study, we show that the recombinant human ILT3.Fc protein binds to murine immune cells and inhibits the release of proinflammatory cytokines that cause the neuroinflammatory process that result in paralysis. Administration of ILT3.Fc prevents the rapid evolution of the disease in C57BL/6 mice and is associated with a profound reduction of proliferation of MOG-specific Th1 and Th17 cells. Inhibition of IFN-γ and IL-17A in mice treated with ILT3.Fc is associated with delayed time of onset of the disease and its evolution to a peak clinical score. Neuropathological analysis shows a reduction in inflammatory infiltrates and demyelinated areas in the brains and spinal cords of treated mice. These results indicate that inhibition of Th1 and Th17 development provides effective suppression of EAE and suggests the feasibility of a clinical approach based on the use of ILT3.Fc for treatment of MS. Furthermore, our results open the way to further studies on the effect of the human ILT3.Fc protein in murine experimental models of autoimmunity and cancer.
多发性硬化症（MS）是一种中枢神经系统的慢性自身免疫性疾病，其特征是脱髓鞘、轴突丢失、神经胶质增生和炎症。实验性自身免疫性脑脊髓炎（EAE）是 MS 的小鼠模型，通过用髓鞘少突胶质细胞糖蛋白（MOG）免疫球蛋白样转录物 3（ILT3）免疫接种诱导。ILT3 是一种抑制性细胞表面受体，表达于耐受性人树突状细胞。在本研究中，我们表明，重组人 ILT3.Fc 蛋白与鼠免疫细胞结合，并抑制引起神经炎症过程从而导致瘫痪的促炎细胞因子的释放。ILT3.Fc 的给药可防止 C57BL/6 小鼠疾病的快速进展，并与 MOG 特异性 Th1 和 Th17 细胞的增殖显著减少相关。在接受 ILT3.Fc 治疗的小鼠中，IFN-γ和 IL-17A 的抑制与疾病发作时间的延迟以及向峰值临床评分的进展相关。神经病理学分析显示，治疗小鼠的大脑和脊髓中的炎症浸润和脱髓鞘区域减少。这些结果表明，抑制 Th1 和 Th17 的发展提供了对 EAE 的有效抑制，并表明基于使用 ILT3.Fc 治疗 MS 的临床方法的可行性。此外，我们的结果为进一步研究人 ILT3.Fc 蛋白在自身免疫和癌症的小鼠实验模型中的作用开辟了道路。
