CN113069469B - 调节性t细胞在制备治疗孤独症药物或细胞疗法中的应用 - Google Patents

调节性t细胞在制备治疗孤独症药物或细胞疗法中的应用 Download PDF

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CN113069469B
CN113069469B CN202110374048.9A CN202110374048A CN113069469B CN 113069469 B CN113069469 B CN 113069469B CN 202110374048 A CN202110374048 A CN 202110374048A CN 113069469 B CN113069469 B CN 113069469B
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周子凯
张小云
季旻珺
徐志鹏
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Shanghai Mental Health Center Shanghai Psychological Counselling Training Center
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Abstract

本发明涉及调节性T细胞在孤独症细胞疗法或制备孤独症药物方面的应用。通过对孤独症发病机制和调节性T细胞的针对性研究，发现对免疫异常型的孤独症模式小鼠输注调节性T细胞可以有效消除或者减轻孤独症模式小鼠的核心症状，有望在将来解决目前孤独症无法治疗的问题。

Description

调节性T细胞在制备治疗孤独症药物或细胞疗法中的应用
技术领域
本发明涉及医药技术领域，特别涉及调节性T细胞在孤独症细胞疗法或制备治疗孤独症药物中的应用。
背景技术
免疫系统(immune system)是机体执行免疫应答及免疫功能的重要系统。由免疫器官、免疫细胞和免疫分子组成。免疫系统具有识别和排除抗原性异物、与机体其他系统相互协调，共同维持机体内环境稳定和生理平衡的功能。
在免疫细胞体系中，调节性T细胞仅占人外周免疫细胞的1～3％，但却是极少数能够抑制免疫活化从而维持免疫稳态的细胞类型。
本发明描述的调节性T细胞包括不同的细胞亚群，按照免疫学通用定义为CD4+和CD25+分子同时高表达为标志物的细胞类型。
目前，在临床应用方面，已有研究表明经过分离、富集、离体扩增后的调节性T细胞经过回输后，可对异体器官移植后的排异反应、I型糖尿病等病症起到一定的治疗作用。
孤独症是一种神经发育谱系障碍，属于精神疾病；目前没有任何药物可以有效治疗该疾病。该疾病的病因及病理机制十分复杂，核心症状为社会交流障碍、语言交流障碍及重复刻板行为。
本发明发现对孤独症模式小鼠输注调节性T细胞可以有效消除或者减轻孤独症模式小鼠的核心症状。
截至目前为止，没有任何关于采用调节性T细胞治疗孤独症的报道。
发明内容
本发明的主要目的是针对以上存在的问题，提供调节性T细胞在孤独症的细胞疗法及制备治疗孤独症药物中的应用，对孤独症模式小鼠输注调节性T细胞可以有效消除或者减轻孤独症模式小鼠的症状。
为了实现上述目的，本发明提供调节性T细胞在制备治疗孤独症药物或孤独症细胞疗法的应用。
其中，治疗孤独症包括消除或者减轻孤独症的核心症状。
上述疗法或药物应至少包括调节性T细胞，调节性T细胞为活性成分，加上药学上可接受的辅料所制成的制剂，经配制用于静脉内施用。
本发明提供了一种调节性T细胞的扩增培养方法，产物可应用于制备治疗免疫异常型孤独症的制剂或药物，包括以下步骤：
(1)第0天：采用常规分选型流式细胞仪或者磁珠分选的方式从血液中分选出CD4+CD25+调节性T细胞。
(2)第0天：将调节性T细胞置于扩增培养基中，细胞密度调整为1～2×106/mL，并加入1×107/mL的CD3/CD28磁珠，并置于37℃培养箱中培养。
(3)第2-8天：每天检查细胞生长状态，当细胞密度大于2～3×108/mL时重悬细胞至1～2×106/mL，继续扩增培养。
(4)第9或10天：计算细胞数量，再次加入CD3/CD28磁珠，使细胞和磁珠个数比例达到1比1。继续扩增。
(5)第14天：离心法收集经过扩增培养的调节性T细胞。
经验证，由上述扩增培养的调节性T细胞通过静脉输注可有效治疗或缓解孤独症症状，具体地，社会交流障碍、重复刻板行为及孤独症常见伴发的焦虑症状，特别是，免疫异常型孤独症。
附图说明
图1a～1b显示社交互动(social interaction)行为学实验的结果，其中图1a中，将被试小鼠分别与陌生的同年龄(age-matched)小鼠置于检测箱内，记录被试小鼠社交互动的时间；图1b中检测被试小鼠与幼年陌生小鼠(juvenile mouse)的社交互动时间。
图2显示三厢社交实验的结果，用于检测社交倾向性，其中，被试小鼠置于三厢的中厢，一侧(厢)为空笼(E)，另一侧为装有陌生鼠的小笼(S1)，被试小鼠可以嗅探(sniffing)笼中的小鼠，通过比较被试小鼠嗅探E和S1的时间可以判断小鼠的社交倾向性。
图3a～3b显示用于检测被试小鼠的重复刻板行为的行为学测试的结果，其中，图3a为重复梳理动作(grooming)；图3b为埋弹珠(marble burying)的次数，均是公认反映重复刻板行为的行为学指标。
图4a～4b分别为旷场实验(open filed)和十字高架迷宫(elevated plus maze)的结果，用于检测小鼠的焦虑水平。由于鼠类趋暗的天性，在旷场中心和十字高架迷宫的开臂里停留的时间越短说明焦虑水平越高。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。所使用的实验方法如无特殊说明均为常规方法。该实施例采用孤独症模式小鼠，提供了一种采用上述扩增培养的调节性T细胞用于有效缓解孤独症症状的实施方案，具体操作步骤如下：
(1)使用抗凝管无菌取血，采用Ficoll密度梯度离心法制备外周血单个核细胞(PBMC)。
(2)采用StemCell公司的EasySepTM Mouse CD4+CD25+Regulatory T CellIsolation Kit，进行调节性T细胞的磁珠法分选；获得1×105个调节性T细胞。
(3)调节性T细胞的扩增培养方法，包括以下步骤：
(3-1)第0天：将调节性T细胞置于48孔板中，加入100μL扩增培养基，细胞密度调整为1×106/mL，并加入1×107/mL的CD3/CD28磁珠，置于37℃培养箱中培养。
(3-2)第2～8天：每天检查细胞生长状态，当细胞密度大于2～3×108/mL时重悬细胞至1～2×106/mL，移入培养瓶中继续扩增培养。
(3-3)第9或10天：计算细胞数量，再次加入CD3/CD28磁珠，使细胞和磁珠个数比例达到1比1。在培养瓶中继续扩增。
(3-4)第14天：离心法收集经过扩增培养的调节性T细胞，获得至少1×107个调节性T细胞。
(4)静脉输注细胞：
(4-1)采用poly(I:C)注射孕鼠诱导仔鼠产生孤独症表型。
聚肌苷酸胞苷酸[poly(I:C)]是一种合成的双链RNA(dsRNA)类似物，注射孕期母鼠，造成子代小鼠的孤独症表型；该孤独症模式小鼠具有细胞因子(cytokine)失衡、免疫细胞亚群失衡等多种免疫异常的表型(Choi,G.B.,Y.S.Yim,H.Wong,S.Kim,H.Kim,S.V.Kim,C.A.Hoeffer,D.R.Littman and J.R.Huh(2016)."The maternal interleukin-17apathway in mice promotes autism-like phenotypes in offspring."Science 351(6276):933-939；Garay,P.A.,E.Y.Hsiao,P.H.Patterson and A.K.McAllister(2013)."Maternal immune activation causes age-and region-specific changes in braincytokines in offspring throughout development."Brain,Behavior,and Immunity31:54-68；Hsiao,E.Y.,S.W.McBride,J.Chow,S.K.Mazmanian and P.H.Patterson(2012)."Modeling an autism risk factor in mice leads to permanent immunedysregulation."Proceedings of the National Academy of Sciences 109(31):12776-12781)。
在本发明中，将具有免疫指标异常的孤独症类型定义为免疫异常型孤独症。
(4-2)于仔鼠6～7周龄时尾静脉输注5×105个溶于磷酸盐缓冲液(PBS)的调节性T细胞。对照组注射同等剂量PBS。
(4-3)饲养1周后进行孤独症症状相关的动物行为学检测。
(5)孤独症相关的行为学检测。
(5-1)如图1a所示，孤独症病鼠[poly(I:C)组]与同年龄陌生小鼠(7-8周龄)的社交互动时间(social interaction time)显著低于健康对照小鼠(PBS组)。而接受调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]的社交互动时间则显著上调，接近健康对照组。说明调节性T细胞治疗可以有效缓解孤独症的社交互动缺陷。
(5-2)类似地，如图1b所示，孤独症病鼠[poly(I:C)组]与幼年陌生小鼠(3～4周龄)的社交互动时间(social interaction time)显著低于健康对照小鼠(PBS组)。而接受调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]的社交互动时间则显著上调，接近健康对照组。再次说明调节性T细胞治疗可以有效缓解孤独症的社交互动缺陷。
(5-3)如图2所示，孤独症病鼠[poly(I:C)组]嗅探三厢社交实验中的空笼(E)的时间与嗅探装有陌生鼠(S1)笼子的时间无显著差异。而健康对照小鼠(PBS组)用于嗅探装有陌生鼠(S1)笼子的时间则显著大于嗅探空笼(E)的时间。接受过调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]用于嗅探空笼(E)和嗅探装有陌生鼠(S1)笼子的时间则接近于健康对照组。说明调节性T细胞治疗可以有效缓解孤独症的社交互动缺陷。
(5-4)如图3a所示，孤独症病鼠[poly(I:C)组]用于重复梳理动作(grooming)的时间与健康对照小鼠(PBS组)相比显著增加。说明该病鼠有重复刻板动作的症状。而接受过调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]用于重复梳理动作的时间则接近于健康对照组。说明调节性T细胞治疗可以有效缓解孤独症的重复刻板行为的症状。
(5-4)如图3b所示，孤独症病鼠[poly(I:C)组]埋弹珠(marble burying)的次数显著高于健康对照小鼠(PBS组)。说明该病鼠有重复刻板动作的症状。而接受过调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]埋弹珠的次数则接近于健康对照组。说明调节性T细胞治疗可以有效缓解孤独症的重复刻板行为的症状。
(5-5)如图4a所示，在旷场实验(open filed)中孤独症病鼠[poly(I:C)组]处于旷场中心的时间(time spent in center)显著低于健康对照小鼠(PBS组)。说明该病鼠有焦虑症状。而接受过调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]处于旷场中心的时间则接近于健康对照组。说明调节性T细胞治疗可以有效缓解孤独症伴发的焦虑症状。
(5-6)如图4b所示，在十字高架迷宫(elevated plus maze)实验中，孤独症病鼠[poly(I:C)组]处于开臂的时间(time spent in open arms)显著低于健康对照小鼠(PBS组)。说明该病鼠有焦虑症状。而接受过调节性T细胞输注治疗的病鼠[poly(I:C)+Treg组]处于开臂的时间则接近于健康对照组。说明调节性T细胞治疗可以有效缓解孤独症伴发的焦虑症状。
综上，以具有免疫异常表型的、poly(I:C)构建的孤独症小鼠模型说明，采用本发明中扩增培养后的调节性T细胞可以有效治疗免疫异常型孤独症模式小鼠的社会交流障碍、重复刻板行为及孤独症常见伴发的焦虑症状。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (5)

1.调节性T细胞在制备治疗孤独症药物中的应用，其特征在于，所述的T细胞为CD4+和CD25+分子同时高表达为标志物的细胞类型，所述的孤独症为免疫异常型孤独症。
2.调节性T细胞在制备用于孤独症细胞疗法的生物制剂中的应用，其特征在于，所述的T细胞为CD4+和CD25+分子同时高表达为标志物的细胞类型，所述的孤独症为免疫异常型孤独症。
3.根据权利要求1或2所述的应用，其特征在于，所述的生物制剂或药物用于改善社会交流障碍、重复刻板行为或孤独症常见伴发的焦虑症状中的一种或多种。
4.根据权利要求1或2所述的应用，其特征在于，所述的生物制剂或药物包括活性成分调节性T细胞及药学上可接受的辅料。
5.根据权利要求1或2所述的应用，其特征在于，所述的生物制剂或药物经注射施用。
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