抑制炎性细胞逸出、浸润并配合神经营养类药物多靶点治疗多发性硬化的研究

Experimental autoimmune encephalomyelitis (EAE) is a model for Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS) in which circulating leukocytes enter the brain and spinal cord producing inflammation, myelin damage and paralysis. Drugs known to relieve inflammation and affect the immune system have become the primary focus for treat MS. However, these trestments may cause numerous side effects associated with immunosuppression.Here,we planed to daily intravenous inject an avb3-binding peptide named C16, which is not an immune-suppresant, in rodential acute single peak and chronic relapse EAE models, for interfering with the leukocyte ligand required for lymphocytes transmigration, so as to alleviating the extensive infiltration of leukocytes and macrophages in spinal cords and brains of EAE animal model.Meanwhile,the angiopoietin-1, which could reduce vascular permeability and alleviate blood vessel leakiness under inflammatory conditions, as well as regeneration gene protein 2(Reg-2), a peptide provided with the similar neuroprotective effects of ciliary neurotrophic factor (CNTF), will be co-applied in EAE models. The effects of these durgs on the disease onset, clinical scores, the inflammatory response and axonal density,neuronal death, occurrence of demyelination and behavioral deficits, as well as related molecular mechanisms will be detected, in order to exploring new potential therapeutic agents for MS treatment.

多发性硬化（multiple sclerosis，MS）是常见的自身免疫性疾病，目前尚无有效的治疗措施。既往研究一直在寻找既能减轻中枢神经系统炎症反应，又能保护受损神经元，促进神经轴突和髓鞘再生的有效治疗手段。本研究拟以整合素（integrin）及其受体为靶点，通过静脉连续注射C16多肽，阻止炎性细胞表面的整合素受体与血管内皮细胞结合，抑制炎细胞的游走，逸出和组织浸润。同时，配合使用可降低血脑屏障通透性的促血管生成素1（Ang1）和具有类神经营养因子作用的Reg-2蛋白，在实验性变态反应性脑脊髓炎(experimental allergic encephalomyelitis，EAE)动物模型上，观察对病灶斑块大小，炎性细胞浸润，病变区域神经细胞凋亡、脱髓鞘病变的程度范围，神经轴突损伤修复以及实验动物神经功能等多种指标的影响，了解其对MS病程发生发展所起到的作用，为MS的治疗寻找新的方向。

本项目在多发性硬化 发病的炎性反应上游进行干预，在前期研究细胞外基质以及相关分子与炎细胞逸出和血管外浸润关系的基础上，选择以血管内皮细胞，细胞外基质及integrin 为靶点，通过使用能保护血管内皮细胞，降低血管通透性的促血管生成素-1（Ang—1），以及能阻止炎性细胞与细胞外基质中介导跨血管壁转移的特异性分子结合来抑制炎细胞逸出和血管外浸润的C16 多肽，同时配合使用具有神经营养和髓鞘保护作用的Reg-2 蛋白，寻找到了一种既能改善局部微环境，显著减轻中枢神经系统炎症反应，又能保护受损神经元，并促进神经轴突和髓鞘再生的多靶点治疗手段。证实了两类不同靶点的药物显示明显的协同效应效果超越了任何单一给药所达到的效应。为多发性硬化 的中枢神经系统抗炎治疗提供了可能的新途径。