CN111450234B - 生理盐水联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用 - Google Patents
生理盐水联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用 Download PDFInfo
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Abstract
本发明公开了生理盐水联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用。脑脊液置换联合免疫吸附治疗具有明显优点：(1)回输给患者的是自身的血浆，无需补充外源性血浆，可节约血浆资源，可防止传播传染病，还可避免血浆置换中的过敏反应、凝血机制异常、枸橼酸中毒等并发症；(2)对血浆致病因子清除选择性更高，对血浆中的有用成分丢失得更少，能有效清除各类致病抗体；(3)对于脑脊液中抗体阳性的患者，脑脊液置换可清除脑脊液中的部分抗体，再回输等量无菌生理盐水，对颅内压影响小，并发症少；(4)吸附柱可以重复使用，降低治疗成本。
Description
技术领域
本发明属于医药生物领域，具体涉及生理盐水联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用。
背景技术
自身免疫性脑炎(AE)是近年来临床上发现的一组以癫痫发作、精神行为异常和认知功能减退为特点的疾病，泛指一大类由自身免疫反应引起的中枢神经系统炎性疾病，是一种在体液免疫和细胞免疫基础上，补体、巨噬细胞和细胞因子等共同参与的自身免疫性疾病[1]。快速清除自身抗体，是AE的主要治疗方法之一。目前的一线治疗包括大剂量糖皮质激素、人血免疫球蛋白(IVIG)、血浆置换(PE)、免疫吸附(IA)，其中后三种疗法具有清除抗体作用[2]。血浆置换需要大量血浆，而血源的紧张，限制了血浆置换在临床的应用。大剂量IVIG和免疫吸附相比，使用选择性免疫吸附可以快速消除自身抗体，并避免非选择性血浆置换的缺点。最近的研究表明，免疫吸附对AE患者的疗效与PE相当[3]，甚至优于PE[4]。IA，PE和IVIG主要是直接降低血液中的抗体滴度。IA可以降低血管内自身抗体的浓度，甚至可能导致CSF中的IgG重新分布，并减少抗体和淋巴细胞进入CNS的流量[5]。但是使用IA不能直接影响CSF抗体滴度。那么如何减少CSF的抗体滴度呢？
[1]Graus F，Titulaer MJ，Balu R，et al.A clinical approach to diagnosisof autoimmune encephalitis.Lancet Neurol，2016,15:391404.
[2]FerlazzoE，Gasparini S，Sueri C，et al.Status epilepticus ofinflammatory etiology:a cohort study Neurology，2016，86(11):1076.
[3]Dogan Onugoren M,Golombeck KS,Bien C,Abu-Tair M,Brand M,Bulla-Hellwig M,Lohmann H,Munstermann D,Pavenstadt H,Tholking G,Valentin R,WiendlH,Melzer N,Bien CG.Immunoadsorption therapy in autoimmuneencephalitides.Neurology(R)neuroimmunology&neuroinflammation 2016,3(2):e207.
[4]Fassbender C,Klingel R,Kohler W.Immunoadsorption for autoimmuneencephalitis.Atherosclerosis Supplements 2017,30:257-263.
[5]Klingel R,Heibges A,Fassbender C.Neurologic diseases of thecentral nervous system with pathophysiologically relevant autoantibodies--perspectives for immunoadsorption.Atherosclerosis Supplements 2013,14(1):161-165.
发明内容
本发明的目的是提供生理盐水联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用。
优选，是生理盐水作为脑脊液的置换液联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用。
所述的血清抗体吸附剂可以是葡萄糖球菌A蛋白，如葡萄糖球菌A蛋白吸附柱。
本发明提出用脑脊液置换法减少脑脊液(CSF)的抗体滴度。血液和脑脊液是两个小室，与血液抗体滴度相比，CSF抗体滴度与脑部免疫力的严重程度更为相关。脑脊液置换可以直接降低脑脊液抗体滴度。
脑脊液置换联合免疫吸附治疗具有明显优点：(1)回输给患者的是自身的血浆，无需补充外源性血浆，可节约血浆资源，可防止传播传染病，还可避免血浆置换中的过敏反应、凝血机制异常、枸橼酸中毒等并发症；(2)对血浆致病因子清除选择性更高，对血浆中的有用成分丢失得更少，能有效清除各类致病抗体；(3)对于脑脊液中抗体阳性的患者，脑脊液置换可清除脑脊液中的部分抗体，再回输等量无菌生理盐水，对颅内压影响小，并发症少；(4)吸附柱可以重复使用，降低治疗成本。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：
脑脊液置换治疗方法：术前30min予20％甘露醇(100ml)快速静脉滴注，腰穿成功后测脑压，缓慢放脑脊液10ml，然后再向椎管内推注等量的生理盐水。20分钟后进行第二个循环，重复进行3-5个循环，共置换30-50ml脑脊液。置换过程中严密观察患者心率、脉搏及血压等指标。拔针后，使用无菌纱布覆盖，使患者去枕平卧10小时，并严密监测。间隔数天后再置换一次，共1-3次。
同时配合IA(免疫吸附)治疗方法：颈内静脉或锁骨下静脉置双腔管建立血液通道，肝素生理盐水进行预冲，静脉推注肝素钠抗凝，肝素钠首次用量20mg，追加量5mg/h，经全自动化血液净化系统将血液引出体外，血液泵流量调到110ml/min，使其通过膜式血浆分离器，将血浆分离，分离出的血浆先后进入康碧尔免疫吸附柱(广州康盛生物科技有限公司)，葡萄糖球菌A蛋白吸附柱吸附血浆，血浆泵流量30ml/min，吸附10min，洗脱予以柠檬酸洗脱液，进行磷酸缓冲液冲洗，直至吸附柱pH值恢复为7.0再进行下一周期治疗，10周期/次，2～3次/周，通过预冲、吸附、回浆、洗脱、平衡、储存等步骤，完成一个循环。通过5-10个循环，治疗再生血浆量约为3 000～4000ml，除去病理成分的血浆和血细胞再回输体内。吸附血浆总量为3600～4800ml，循环次数6～8次，血浆/血液流速30/110ml/min，时间为4～5.5h，间隔2天后进行下次治疗，每位患者行3～5次治疗。治疗过程中监测基本临床参数，如血压、脉搏、呼吸频率等。
我们已在我院用脑脊液置换联合免疫吸附治疗成功治疗2例自身免疫学脑炎患者。
病例介绍
病例1：患者，卢某，女，28岁，因“发热、头痛1月余，胡言乱语1周”入院，入院后查4-22血抗谷氨酸受体(NMDAR)抗体IgG阳性(1:1000),脑脊液抗NMDAR抗体IgG阳性(1:100)。治疗上予甲泼尼龙1.0g冲击治疗，予吗替麦考酚酯(0.5bid)免疫调节治疗，并予免疫球蛋白(0.4g/(kg·d)静脉滴注，予阿昔洛韦(0.5gq8h)抗病毒、丙戊酸钠(0.2g tid)抗癫痫、奥氮平改善精神症状治疗，患者精神状态有所好转，但仍有淡漠、认知功能障碍。
病例2：患者，李某，男，51岁，因“发作性抽搐9天，反应差5天”入院，入院后查4-18血抗GABAB受体抗体IgG阳性(1:3200)，脑脊液抗GABAB受体抗体IgG阳性(1:3200)。治疗上予甲泼尼龙1.0g冲击后逐渐减量，免疫球蛋白(0.4g/kg·d)静脉滴注5天，予抗病毒(阿昔洛韦0.5gq8h+利巴韦林0.5gq12h)、抗癫痫(开浦兰、妥泰、拉莫三嗪、舒必利)、抗感染(头孢哌酮钠舒巴坦钠、哌拉西林钠他唑巴坦)、抗真菌(氟康唑0.6gqd)、奥氮平改善精神症状治疗，免疫调节(吗替麦考酚酯0.5bid，4.22-4.28，因血小板下降停用)，患者症状无明显好转，神志仍昏睡，反复肢体抽搐，予地西泮持续滴注控制癫痫。
对上述2个病例实行脑脊液置换治疗方法同时配合IA(免疫吸附)治疗方法；
其中对两个病例实行脑脊液置换治疗方法，具体如下：
脑脊液置换参数
脑脊液置换治疗后，然后进行免疫吸附治疗方法(一般是第一天做脑脊液置换治疗，第二天再做免疫吸附治疗，交替来)，免疫吸附参数如下：
免疫吸附参数：
治疗后，其自身脑脊液和体液免疫结果如表1所示：
表1 2例自身免疫性脑炎患者脑脊液及体液免疫结果
说明：两例患者经过脑脊液置换后脑脊液细胞数下降，同时配合免疫吸附，见血中IgG水平明显下降。
治疗后其免疫吸附抗体滴度、MMSE和mRS的变化如表2所示：
表2 2例自身免疫性脑炎患者免疫吸附前后抗体滴度、MMSE和mRS变化
说明：两例患者经过脑脊液置换联合免疫吸附，脑脊液和血中的抗体滴度明显下降，患者MMSE和mRs评分改善。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (1)
1.生理盐水作为脑脊液的置换液联合血清抗体吸附剂在制备治疗自身免疫性脑炎的药物中的应用，所述的血清抗体吸附剂是葡萄糖球菌 A 蛋白。
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