Ramroodi Nourollah, Khani Masood, Ganjali Zohre, Javan Mohammad Reza, Sanadgol Nima, Khalseh Roghayeh, Ravan Hadi, Sanadgol Ehsan, Abdollahi Mohammad
a Department of Neurology, Faculty of Medicine , Zahedan University of Medical Sciences , Zahedan , Iran .
b Department of Immunology, Faculty of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran .
Immunol Invest. 2015;44(7):694-712. doi: 10.3109/08820139.2015.1085391.
Some functional limitations and economic burden of therapeutic antibodies indicated that introducing of alternative therapeutic compounds with same or different mechanism of action could be worthwhile. In this regard small-molecule antagonists can have a wide range of impacts, so in this research, we examine the prophylactic effects of BIO-1211 [Very Late Antigen-4 (VLA4) blocker], in experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in comparison with commercial available medicine, Natalizumab (NTZ)].
EAE was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55) in 8-week-old C57BL/6 mice. During EAE induction, mice were separated to distinct groups and provided either BIO-1211 (5 and 10 mg/kg) or NTZ (5 mg/kg) and co-administration of these two compounds. After 21 days, neuro-inflammatory responses were analyzed using qRT-PCR, western blot, and ELISA methods. Pervade of immune cells to brain was examined by Evans blue staining and immunohistochemistry (IHC) analysis of specific markers of microglia/monocytes (CD11b) and leukocytes (CD45).
Targeted disruption of VLA4/VCAM1 interactions, by BIO-1211 agonist in mice, results in reduced cytokines expression, leukocyte trafficking, and inhibition of inflammatory responses in EAE (p < 0.01) in a dose-independent manner (data not shown). Mice treated with both BIO-1211 and NTZ exhibited a considerable depletion in the EAE clinical score, which correlated with decreased expression of TNF-α, IL-17, IFN-γ and pervade of CD11b(+) and CD45(+) cells into the cerebral cortex.
Our results indicated that BIO12-11 compound would be an useful tool to further understand the biological roles of VLA4/VCAM1 interactions, and could also be considered as EAE-suppressing agent.
治疗性抗体的一些功能限制和经济负担表明，引入具有相同或不同作用机制的替代治疗化合物可能是值得的。在这方面，小分子拮抗剂可能会产生广泛的影响，因此在本研究中，我们研究了BIO-1211[极晚期抗原-4（VLA4）阻滞剂]在多发性硬化症实验性自身免疫性脑脊髓炎（EAE）小鼠模型中的预防作用，并与市售药物那他珠单抗（NTZ）进行比较。
通过对8周龄C57BL/6小鼠皮下注射髓鞘少突胶质细胞糖蛋白（MOG35-55）诱导EAE。在EAE诱导期间，将小鼠分为不同组，分别给予BIO-1211（5和10mg/kg）或NTZ（5mg/kg）以及这两种化合物的联合给药。21天后，使用qRT-PCR、蛋白质印迹和ELISA方法分析神经炎症反应。通过伊文思蓝染色以及对小胶质细胞/单核细胞（CD11b）和白细胞（CD45）的特异性标志物进行免疫组织化学（IHC）分析，检测免疫细胞向脑内的浸润情况。
BIO-1211激动剂在小鼠中对VLA4/VCAM1相互作用的靶向破坏导致细胞因子表达降低、白细胞迁移减少，并以剂量非依赖性方式抑制EAE中的炎症反应（p<0.01）（数据未显示）。用BIO-1211和NTZ治疗的小鼠在EAE临床评分上有显著降低，这与TNF-α、IL-17、IFN-γ表达降低以及CD11b(+)和CD45(+)细胞向大脑皮层的浸润减少相关。
我们的结果表明，BIO12-11化合物将是进一步了解VLA4/VCAM1相互作用生物学作用的有用工具，也可被视为EAE抑制剂。
