Elliott E A, Cofiell R, Wilkins J A, Raine C S, Matis L A, Mueller J P
Department of Immunobiology, Alexion Pharmaceuticals, New Haven, CT 06511, USA.
J Neuroimmunol. 1997 Oct;79(1):1-11. doi: 10.1016/s0165-5728(97)00093-3.
Proteolipid protein (PLP), a transmembrane protein expressed only in the central nervous system (CNS), is a candidate target autoantigen for autoimmune-mediated demyelination. We have evaluated the effect of a recombinant form of the PLP protein, delta PLP4, in a murine model of experimental autoimmune encephalomyelitis (EAE). PLP-specific T-cell responses were observed following immunization of SJL/J, PL/J and SWR mice with delta PLP4, demonstrating processing of the protein to several distinct antigenic epitopes. Clinical EAE associated with inflammation and demyelination in the CNS also developed after sensitization of mice with delta PLP4 in adjuvant. Conversely, tolerance to delta PLP4 in adult mice and prevention of PLP peptide 139-151-induced EAE was induced by intravenous injection of soluble delta PLP4. The prevention of disease onset was paralleled by a significant reduction in demyelination and CNS inflammatory cell infiltration and diminished PLP139-151-specific T-cell proliferative responses. These results are consistent with the establishment of peripheral T-cell tolerance and reinforce the notion that recombinant myelin antigens and intravenous tolerance induction may prove useful in the modulation of the human demyelinating disease, multiple sclerosis (MS).
蛋白脂蛋白（PLP）是一种仅在中枢神经系统（CNS）中表达的跨膜蛋白，是自身免疫介导的脱髓鞘的候选靶自身抗原。我们已经在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中评估了重组形式的PLP蛋白delta PLP4的作用。用delta PLP4免疫SJL/J、PL/J和SWR小鼠后，观察到了PLP特异性T细胞反应，表明该蛋白被加工成了几个不同的抗原表位。在用佐剂中的delta PLP4致敏小鼠后，还出现了与CNS炎症和脱髓鞘相关的临床EAE。相反，通过静脉注射可溶性delta PLP4可诱导成年小鼠对delta PLP4产生耐受性，并预防PLP肽139 - 151诱导的EAE。疾病发作的预防伴随着脱髓鞘和CNS炎性细胞浸润的显著减少以及PLP139 - 151特异性T细胞增殖反应的减弱。这些结果与外周T细胞耐受性的建立一致，并强化了这样一种观念，即重组髓鞘抗原和静脉内耐受性诱导可能被证明对调节人类脱髓鞘疾病——多发性硬化症（MS）有用。
