CN1326560C - Poly-glu,tyr在神经保护治疗中的应用 - Google Patents
Poly-glu,tyr在神经保护治疗中的应用 Download PDFInfo
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Abstract
提供了用于预防或抑制中枢神经系统(CNS)或周围神经系统(PNS)的神经元变性、或者促进CNS或PNS的神经再生、或者保护CNS细胞免遭谷氨酸毒性的方法和组合物,所述组合物包含一种选自(a)poly-Glu,Tyr和(b)已被poly-Glu,Tyr激活的T细胞的药物。
Description
发明领域
本发明涉及用于促进神经再生或者预防或抑制神经元变性以缓解神经系统(NS)的损伤、障碍或疾病效应的组合物和方法。具体地说,本发明涉及包含poly-Glu,Tyr和/或用poly-Glu,Tyr处理的活化T细胞的组合物,以保护中枢神经系统(CNS)细胞免遭谷氨酸毒性、促进神经再生或者预防或抑制由人类受治疗者的CNS或周围神经系统(PNS)内的神经损伤或疾病引起的神经元变性。本发明的组合物可以单独给予或者可以任选地以任何所需的组合给予。
缩写:CFA:完全弗氏佐剂;CNS:中枢神经系统;MBP:髓鞘碱性蛋白;MHC:主要组织相容性复合体;NS:神经系统;PBS:磷酸缓冲盐溶液;pEY:poly-Glu,Tyr;PNS:周围神经系统;Poly-Glu,Tyr:共聚物poly-Glu50Tyr50,即L-谷氨酸和L-酪氨酸的随机杂共聚物;RGC:视网膜神经节细胞。
发明背景
神经系统包括中枢神经系统(CNS)和周围神经系统(PNS)。CNS由脑脊髓和视觉系统组成;PNS由所有其它的神经元件即除脑和脊髓之外的神经和神经节组成。
神经系统的损伤可以由诸如穿透性创伤或钝器创伤的外伤性损伤或者疾病或障碍引起,所述疾病或障碍包括但不限于早老性痴呆(Alzheimer′s disease)、帕金森病(Parkinson′s disease)、亨廷顿舞蹈病(Huntington′s disease)、肌萎缩性侧索硬化(ALS)、糖尿病性神经病、老年性痴呆、中风和局部缺血。
维持CNS完整性是一个复杂的“平衡作用”,其中免疫系统控制其平衡点。在大多数组织中,免疫系统在保护、修复和愈合方面起重要的作用。在CNS中,因为其独特的免疫特权,免疫反应受到相对限制。越来越多的证据表明,哺乳动物CNS在损伤后不能实现机能恢复,反映出在受损组织和免疫系统之间的无效对话。例如,CNS和血源性巨噬细胞之间的有限通讯影响轴突切开的轴突再生的能力,而活化巨噬细胞的移植可以促进CNS的再生。
已经表明,活化T细胞进入CNS的实质,与其抗原特异性无关,但只是能够与CNS抗原反应的T细胞似乎在那里继续存在(Hickey等,1991)。与CNS白质的抗原例如髓鞘碱性蛋白(MBP)反应的T细胞在将其接种到首次用于实验的受体大鼠的数天内,可以诱发麻痹性疾病如实验性自身免疫性脑脊髓炎(EAE)(Ben-Nun,1981)。抗MBPT细胞也可能涉及人类疾病如多发性硬化(Ota等,1990)。然而,不管其致病潜力如何,在健康研究对象的免疫系统中都存在抗MBP T细·胞克隆(Pette等,1990)。正常巡视完整CNS的活化T细胞在CNS白质损伤部位瞬时累积(Hirschberg等,1998)。
CNS损伤的严重后果是,原发性损伤常常被明显未损伤或者仅被原始损伤在一定程度上损伤的相邻神经元的逐渐继发性损失所加重(McIntosh,1993)。所述原发性损伤引起胞外离子浓度改变、自由基含量升高、神经递质的释放、生长因子的耗尽和局部炎症。这些变化在最初避开所述原发性损伤的相邻神经元中触发破坏性事件级联(Lynch等,1994)。这种继发性损害由电压依赖性或激动剂门控通道的活化、离子渗漏、钙依赖性酶例如蛋白酶、脂酶和核酸酶的活化、线粒体功能障碍和能量耗尽而介导,最终导致神经元细胞死亡。直接由所述原发性损伤所引起的损失之外的神经元广泛损失已被称为“继发性变性”。
引起疾病的自我加重、甚至当原发性危险因素被除去或减弱时仍起作用的最常见的介质之一是谷氨酸,即一种能够表现出双重活性的兴奋性氨基酸:其在正常CNS中作为一种必需神经递质起关键性作用,而当其超过生理水平时却变成毒性物质。据报道,在许多CNS疾病中,谷氨酸升高。在其作为兴奋毒性化合物的作用中,谷氨酸是急性和慢性变性性疾病(包括青光眼中的视神经变性)中最常见的毒性介质之一(Pitt等,2000)。内源谷氨酸对在癫痫持续状态、脑局部缺血或创伤性脑损伤后急性发生的脑损伤造成影响。内源谷氨酸也可以引起在如肌萎缩性侧索硬化和亨廷顿舞蹈病(Huntington′S chorea)的疾病中的慢性神经变性。
对通过使用局部作用药物例如N-甲基-D-天冬氨酸(NMDA)-受体拮抗剂减弱谷氨酸的细胞毒性效应进行了深入细致的研究。在人类中,这样的化合物具有治疗精神病的作用和使其不适合作为治疗药物的其它副作用。另外,由于中和谷氨酸毒性效应可能干预其作为普遍存在的CNS神经递质的生理功能,因此该类型的常规疗法通常令人不满意。因为谷氨酸活性是正常生理功能所必不可少的,而其在急性损伤后或慢性CNS疾病中被潜在破坏,所以任何中和其有害效应的尝试应该避免在机体的其它部位消除其必需活性。
CNS损伤的另一个悲剧性后果是哺乳动物CNS中的神经元在损伤后不进行自发再生。因此,CNS损伤引起运动和感觉机能的永久性损害。
脊髓损伤不管其损伤的严重程度如何,总是最初引起称为脊髓休克的完全机能性麻痹。可以观察到脊髓休克的一些自发性恢复,从损伤后几天开始并且在3-4周内逐渐减少。损伤的严重程度越低,机能恢复效果越好。恢复程度随最初未受损组织量减去由于继发性变性的损失量而变。损伤的恢复将通过可以减少继发性变性的神经保护性治疗而改善。例如,降低谷氨酸的作用是神经保护药研发的一个常用靶。其中为此目的正在研发的药物是N-甲基-D-天冬氨酸(NMDA)-受体拮抗剂或α-氨基-3-羟基-5-甲基-4-异唑丙酸(AMPA)-受体拮抗剂。这些药物将不可避免地具有严重副作用,因为它们干扰正常CNS活性所必不可少的NMDA受体和AMPA受体的功能。最深入细致研究的NMDA-受体拮抗剂之一是MK801,MK801提供有效的神经保护但具有严重副作用。在脑局部缺血和外伤性脑损伤的动物模型中,NMDA和AMPA受体拮抗剂防止急性脑损伤并且延迟行为缺陷。正在对这类化合物进行人体试验,但治疗功效尚有待证实。可能对作用于谷氨酸传递的药物应答的其它临床病症包括癫痫、遗忘症、焦虑、痛觉过敏和精神病(Meldrum,2000)。
在本发明人的实验室中,最近发现了识别患者NS抗原的活化T细胞赋予神经保护。参见美国申请顺序号09/218,277和09/314,161以及PCT公布号WO 99/60021,所述专利的全部内容通过引用结合到本文中。更准确地讲,在部分受损视神经大鼠模型(另见Moalem等,1999)和脊髓损伤大鼠模型(另见Hauben等,2000)中显示,与MBP反应的T细胞是神经保护因子。迄今为止,人们认为,免疫细胞不参与NS修复。此外,传统上认为在CNS损伤方面的任何免疫活性对恢复有害。令人十分惊奇的是,发现NS特异性活化的T细胞可以用于保护神经系统组织免遭可能紧接在由CNS或PNS的损伤或疾病引起的损伤之后发生的继发性变性。这类NS特异性T细胞的作用机理还有待发现,但外源给予的T细胞在CNS损伤部位的大量累积提示,在损伤部位存在的T细胞在神经保护中起重要作用。然而,似乎所述累积虽然是一个必要条件,但是对于该目的仍不充分,由于非自体抗原卵清蛋白的特异性T细胞也在该部位累积,但却没有神经保护作用(Hirschberg等,1998)。
除所述NS特异性活化的T细胞之外,上面引用的美国申请和PCT公布号WO 99/60021还公开了也可以用天然或合成的NS特异性抗原或衍生自NS特异性抗原的肽来进行缓解NS损伤或疾病效应的治疗,所述天然或合成的NS特异性抗原例如MAG、S-100、β-淀粉状蛋白、Thy-1、P0、P2、神经递质受体,并且优选人MBP、人蛋白脂质蛋白(PLP)和人少突神经胶质细胞糖蛋白(MOG),而所述肽例如包含MBP的氨基酸51-70或MOG的氨基酸35-55的肽。
在本发明人的实验室中新近发现了一种由平均摩尔数为0.141、0.427、0.095和0.338的L-Ala、L-Glu、L-Lys和L-Tyr残基组成的高分子量随机合成碱性共聚物,称为共聚物1或Cop 1,并且是COPAXONE(Teva Pharmaceuticals Ltd.,以色列)的有效成分,COPAXONE是用于治疗多发性硬化的药物,能够预防或抑制CNS或PNS的神经元变性、或者促进CNS或PNS的神经再生以及保护CNS细胞免遭谷氨酸毒性。参见同时待审的美国申请顺序号09/487,793、09/620,216和09/765,644以及PCT公布号WO 01/52878和WO 01/93893,所述专利的全部内容由此通过引用结合到本文中。更准确地讲,显示了Cop 1特异性活化的T细胞在受损和非受损神经元组织中累积并且在受损视神经中预防继发性变性的破坏作用,表明用Cop 1免疫抵抗谷氨酸毒性。
为了治疗各种自身免疫病,公开了口服给予自身抗原以便获得“口服耐量”。例如,EP 359 783公开了口服给予MBP以治疗多发性硬化,而PCT国际公布号WO 91/12816、WO 91/08760和WO92/06704公开了用各种各样的自身抗原、采用口服耐量方法来治疗其它自身免疫病。在PCT公布号WO 98/30227中公开了摄入或吸入共聚物1,以实现抑制自身免疫T细胞对髓鞘抗原的应答,从而治疗多发性硬化。
共聚物poly-Glu50Tyr50,以前一般称为polyGT,而在下文也称为pEY,是L-谷氨酸和L-酪氨酸的一种随机杂共聚物,平均长100个氨基酸,在某些小鼠品系中能够激发强免疫应答(Vidovic等,1985;Vidovic和Matzinger,1988)。20多年以前表明,数个对pEY不应答的小鼠自交系以及同类抗性系,当用与免疫原性载体例如甲基化牛血清白蛋白(MBSA)复合的pEY刺激时,产生特异性空斑形成细胞(PFC)应答;预先用pEY免疫则在某些小鼠品系中对pEY-MBSA应答有致耐受性效应,并且该耐受性可以通过pEY致敏动物的脾细胞或胸腺细胞转移至正常同系受体中(Debre等,1975)。最近,已表明pEY激活鼠类表皮Vγ5/Vδ1 TCR(+)T细胞系(Seo等,2001)。这些出版物中没有一个出版物描述或提示pEY的任何有用生物活性,特别是没有应用pEY来进行神经保护。
本申请的该小节或任何其它部分中任何参考文献的引用或识别不应认为是承认这样的参考文献对于本发明可作为现有技术利用。
发明概述
现在,按照本发明,发现了poly-Glu,Tyr和经poly-Glu,Tyr活化的T细胞可以保护神经细胞免遭谷氨酸毒性和经历脊髓挫伤后的继发性变性。在大鼠脊髓挫伤后,检查了大鼠中对MBP特异性的T细胞和对poly-Glu,Tyr特异性的T细胞的自发出现。另外,用poly-Glu,Tyr主动免疫来减弱由谷氨酸毒性或脊髓的机械性损伤所诱发的神经元变性。
因此,一方面,本发明涉及一种包含药学上可接受的载体和选自(a)poly-Glu,Tyr和(b)已被poly-Glu,Tyr激活的T细胞的药物的药用组合物。
在本发明的一个实施方案中,所述药用组合物包含poly-Glu,Tyr。在另一个实施方案中,所述药用组合物包含已被poly-Glu,Tyr激活的T细胞。所述poly-Glu,Tyr特异性活化的T细胞可能最好是自体T细胞,但本发明也包括来自相关供体的同种异体T细胞或者来自HLA匹配或部分匹配、半同种异体或完全同种异体的供体的同种异体T细胞。所述自体T细胞可以是新鲜T细胞,或者是来源于保存的自体T细胞的细胞。
在本发明的另一个实施方案中,所述药用组合物可用于神经保护,即可用于预防或抑制CNS或PNS的神经元变性或者促进CNS或PNS的神经再生,尤其可用于治疗引起轴突损害或伴随有轴突损害的CNS或PNS的损伤、障碍或疾病。
在本发明的再一个实施方案中,所述药用组合物可用于保护CNS细胞或PNS细胞免遭谷氨酸毒性,尤其可用于治疗由谷氨酸毒性引起或恶化的CNS或PNS的损伤、障碍或疾病。
在一个实施方案中,所述损伤、障碍或疾病包括脊髓损伤、钝器创伤、穿透性创伤、脑外伤或对侧外伤、出血性中风或局部缺血性中风。在一个优选的实施方案中,所述损伤是脊髓损伤。
在另一个实施方案中,所述损伤、障碍或疾病包括糖尿病性神经病、老年性痴呆、早老性痴呆、帕金森病、面神经麻痹(贝尔麻痹(Bell′spalsy))、亨廷顿舞蹈病、肌萎缩性侧索硬化(ALS)、维生素缺乏症、癫痫、遗忘症、焦虑、痛觉过敏、精神病、癫痫发作、氧化性应激或阿片制剂耐受性和依赖性以及下文描述的其它障碍和疾病。
在再一个实施方案中,所述损伤、障碍或疾病与眼有关并且包括视神经病、年龄相关黄斑变性、视网膜疾病例如视网膜变性或与眼内压异常升高相关的疾病例如青光眼。在一个优选的实施方案中,所述障碍或疾病是青光眼。
在又一个实施方案中,所述损伤、障碍或疾病是自身免疫病。
另一方面,本发明涉及一种选自(a)poly-Glu,Tyr和(b)已被poly-Glu,Tyr激活的T细胞的药物在生产药用组合物中的应用。所述药用组合物将可用于如上所述的适应症。
再一方面,本发明涉及一种用于预防或抑制CNS或PNS的神经元变性、或者促进CNS或PNS的神经再生、或者保护CNS细胞免遭谷氨酸毒性的方法,所述方法包括给予有其需要的个体有效量的一种选自(a)poly-Glu,Tyr和(b)已被poly-Glu,Tyr激活的T细胞的药物。“有效量”在本文被定义为有效缓解所述CNS或PNS的损伤、障碍或疾病效应的量。
本文所用的术语“神经保护”是指CNS或PNS的损伤、障碍或疾病的变性效应的预防或抑制,包括防止持久的继发性神经变性效应,甚至当原发性危险因素被除去或减弱时防止持久的继发性神经变性效应。这种保护既包括白质的保护,又包括灰质的保护。
本文所用的术语“活化T细胞”是指包括(i)由于接触poly-Glu,Tyr而活化的T细胞和(ii)这种活化T细胞的后代。本文所用的术语“Poly-Glu,Tyr特异性活化T细胞”是指对poly-Glu,Tyr具有特异性的活化T细胞。
将所述poly-Glu,Tyr特异性活化T细胞用于促进神经再生或者预防或抑制可能紧接着原发性NS损伤而发生的继发性变性效应或者由下文描述的疾病、障碍或病症引起的神经变性过程的作用,所述疾病、障碍或病症例如但不限于青光眼、中风、局部缺血、枪伤和由危险性运动所造成的脑损伤。
鉴于所发现的对谷氨酸毒性的保护作用,所述poly-Glu,Tyr特异性活化T细胞不仅可用来提供针对与髓鞘质(白质)相关的原发性和继发性危险因素的神经保护作用,而且提供针对与神经元胞体本身(灰质)相关的原发性和继发性危险因素的神经保护作用。因此,预期poly-Glu,Tyr特异性活化T细胞对本发明目的有用。
此外,由于poly-Glu,Tyr防止谷氨酸毒性,因此其也一定具有调节活性,例如通过产生调节细胞或调节物质。就该调节活性而论,预期接种所述poly-Glu,Tyr和所述poly-Glu,Tyr特异性活化T细胞也保护白质和灰质免遭由氧化性应激和对神经细胞有害的其它源引起的损害。另外,因为该调节活性,所以本发明也可以用来保护神经细胞免患自身免疫病。
本发明的药用组合物包含治疗有效量的poly-Glu,Tyr,所述量有效激活体内或体外T细胞,其中所述活化T细胞抑制或缓解CNS或PNS的损伤、障碍或疾病效应。
在本发明的实施过程中,包括给予poly-Glu,Tyr特异性活化T细胞以缓解和治疗损伤、障碍或疾病效应的疗法可以任选地与poly-Glu,Tyr联合使用。
另外,在用与佐剂一起给予的poly-Glu,Tyr致敏后,口服给予poly-Glu,Tyr对于神经保护可能是有效的。因此,可在这种poly-Glu,Tyr的初次活化之后,且优选在用佐剂的上述初次活化后,采用口服poly-Glu,Tyr来加强所述T细胞的活性,以在损伤后立即建立决定性的T细胞应答。
在本发明的另一个实施方案中,可以建立细胞库以保存poly-Glu,Tyr-敏化T细胞,稍后在需要时用于个体的神经保护性治疗。要保存的细胞可以是从个体中获得的自体T细胞。另一方面,可以保存同种异体或半同种异体T细胞,致使存在最常见主要组织相容性复合体(MHC)-II类类型中的每种的T细胞库。
如果患者是需要治疗损伤的患者,则最好使用保存的自体T细胞;而如果自体T细胞不可利用,则可以使用与所述患者共享MHC II型分子的个体的细胞,并且预期这些细胞在该患者中是有效的。
所述细胞最好在接触poly-Glu,Tyr后以活化状态保存。然而,所述细胞也可以以静息状态保存,一旦将其解冻并制备供使用,则所述细胞就被激活。所述库的细胞系最好进行深低温保藏。所述细胞系以本领域熟知的任何方式制备。一旦将所述细胞解冻,则它们最好在注射前进行培养,以便消除无活力细胞。在这种培养期间,所述细胞可以用如同最初活化中所用的poly-Glu,Tyr抗原进行活化或再活化。另一方面,可以通过在促细胞分裂原例如伴刀豆球蛋白A存在下,或者优选在植物凝集素(PHA)存在下进行培养,来实现活化。该过程将使细胞处于甚至更高的活化状态。将所述细胞培养而占用的几天时间应该对所述患者是无害的,因为按照本发明的治疗可以在所述损伤后至多1周或更长的任何时间开始,以便仍然有效。另一方面,如果时间是关键性要素,则所述保存的细胞可以在解冻后立即给予。
附图简述
图1是一幅图,显示对以下不同抗原应答时脾细胞增殖测定的结果:卵清蛋白(Ova)、共聚物1(Cop 1)、髓鞘碱性蛋白(MBP)、MBP肽p87-99、poly-Glu,Tyr(pEY)和伴刀豆球蛋白A(Con A)。用在SPD大鼠经受脊髓挫伤后8-10天从所述大鼠中分离的脾细胞进行所述测定。确定与不含任何抗原的培养基中的脾细胞增殖相比的指数(SI=1)。
图2是一幅图,显示用pEY免疫如何显著减少由谷氨酸诱导的视网膜神经节细胞(RGC)死亡。在玻璃体内注射谷氨酸前7天以及注射后7天,对已用pEY加上完全弗氏佐剂的乳剂(CFA-pEY)或PBS加上CFA(CFA-PBS)免疫的C57BL/6J小鼠中切除的视网膜中的标记(存活)RGC数/mm2进行计数。柱状图代表与首次进行实验的视网膜相比的RGC死亡百分率的平均值±sem。
图3描绘pEY/CFA免疫对脊髓挫伤大鼠恢复的影响。该图表示在脊髓损伤后立即用pEY/CFA(方形)或CFA-PBS(对照;三角形)免疫的两组SPD大鼠中,开放场中后肢自主活动评分的平均值±sd(BBB检验,如下文实施例3.1中描述的)随脊髓损伤后时间的变化。
图4描绘用pEY活化的脾细胞的过继转移对脊髓损伤恢复的影响。该图表示在脊髓损伤后立即用经CFA-pEY活化的T细胞(SPc+pEY;方形)或经CFA-PBS处理的T细胞(对照;三角形)腹膜内注射的两组SPD大鼠中,开放场中后肢自主活动评分的平均值±sd随脊髓损伤后时间的变化。
发明详述
Poly-Glu,Tyr特异性活化T细胞是已在Poly-Glu,Tyr存在下被活化的T细胞,正如上文所描述的。本发明的这种活化T细胞可以用于治疗即缓解或抑制引起NS变性的CNS或PNS的损伤、障碍或疾病效应或者促进NS、尤其是CNS的再生。另外,由于谷氨酸是所有神经变性性疾病(无论是慢性的还是急性的)中的介质,因此计划将这样的T细胞用于保护CNS细胞免遭谷氨酸毒性以及用于治疗由谷氨酸毒性引起或恶化的疾病或病症,例如青光眼中的异常眼内压。
所述poly-Glu,Tyr特异性活化T细胞优选是自体T细胞,最优选是具有CD4和/或CD8表型的自体T细胞,但它们也可以是来自相关供体例如同胞、父母亲、孩子或HLA匹配或部分匹配的、半同种异体或完全同种异体的供体的同种异体T细胞。
除了使用从所述研究对象中分离的自体T细胞外,本发明也包括使用用于神经保护的半同种异体T细胞。这些T细胞可以制备成短期或长期细胞系以及通过常规深低温保藏法进行保存,从而用于解冻后立即给予或者在培养1-3天后给予CNS损伤的受治疗者和需要T细胞神经保护的受治疗者。
半同种异体T细胞的应用基于T细胞可以识别由外源抗原呈递细胞(APC)所呈递的特异性抗原表位,条件是APC表达限制特异性应答的T细胞群体的MHC I类或II类分子以及由所述T细胞所识别的抗原表位。因此,可以识别受治疗者MHC分子的至少一种等位基因产物、最好是HLA-DR或HLA-DQ或其它HLA分子并且是poly-Glu,Tyr表位特异性的T细胞的半同种异体群体,将能够识别受冶疗者的NS损伤部位与poly-Glu,Tyr有交叉反应的抗原并且产生所需的神经保护作用。在使所述T细胞迁移至损伤部位、在该部位累积和经历活化所需要的粘着分子、白细胞迁移分子和辅助分子中,没有或几乎没有多态性。因此,所述半同种异体T细胞将能够迁移并在需要神经保护的CNS部位累积并且将被激活以产生所需的效应。
已知半同种异体T细胞将被所述受治疗者免疫系统排斥,但是已知排斥需要大约2周才会发生。因此,所述半同种异体T细胞将具有需要发挥神经保护作用的2周概率窗。2周后,所述受治疗者的机体将排斥所述半同种异体T细胞,但是该排斥对于所述受治疗者是有利的,因为将清除所述受治疗者的外源T细胞并且防止所述活化细胞的任何事与愿违的结果。因此,所述半同种异体T细胞提供一个重要的安全性因素并且是一个优选的实施方案。
已知相对小数目的用HLA II类分子为群体中的大多数个体所共享。例如,犹太人中的约50%表达HLA-DR5基因。因此,限于HLA-DR5的与poly-Glu,Tyr表位反应的特异性T细胞库将可用于该人种中的50%。全部人群可以基本上由限于其它几种优势HLA分子例如DR1、DR4、DR2等的少数其它T细胞系覆盖。因此,可以制备单一T细胞系的功能库并将其保存,以备立即用于特定群体中的几乎任何个体。这样的T细胞库将克服从需要神经保护的受治疗者中在治疗概率的开放窗期间获得足够数目的特异性T细胞的任何技术问题。所述半同种异体T细胞将在完成其神经保护作用后被安全地排斥。本发明的该方面并不自相矛盾并且是在除使用本文所描述的自体T细胞之外使用。
所述poly-Glu,Tyr特异性活化T细胞最好是未经减毒的,虽然可以使用减毒poly-Glu,Tyr特异性活化T细胞。可以采用本领域熟知的方法,包括但不限于γ-照射例如1.5-10.0拉德(Ben-Nun等,1982);和/或通过加压处理,例如美国专利第4,996,194号(Cohen等)中描述的加压处理,来使T细胞减毒。在一个优选的实施方案中,所述poly-Glu,Tyr特异性活化T细胞如下所述进行分离。T细胞可以按照本领域已知的方法(Mor等,1995)进行分离和纯化。有关一个说明性的实例参见实施例3.2。
识别poly-Glu,Tyr的、受治疗者的循环T细胞采用已知的方法进行分离和扩充。为了获得poly-Glu,Tyr特异性活化T细胞,分离T细胞,然后通过已知的方法(参见例如Pette等,1990,所述文献通过引用全部结合到本文中)扩充所述poly-Glu,Tyr特异性活化T细胞。
在离体活化期间,所述T细胞可以通过将其培养在加入了至少一种合适的生长促进因子的培养基中进行活化。适合该目的的生长促进因子包括但不限于细胞因子,例如肿瘤坏死因子α(TNF-α)、白介素-2(IL-2)和白介素-4(IL-4)。
在一个实施方案中,所述活化T细胞内源性产生一种缓解NS损伤或疾病效应的物质。
在另一个实施方案中,所述活化T细胞内源性产生一种刺激其它细胞的物质,包括但不限于转化生长因子-β(TGF-β)、神经生长因子(NGF)、神经营养因子3(NT-3)、神经营养因子4/5(NT-4/5)、脑源神经营养因子(BDNF)、干扰素-γ(IFN-γ)和白介素-6(IL-6),其中所述其它细胞直接或间接缓解损伤或疾病效应。
在体外增殖T细胞后,将所述T细胞给予哺乳动物受治疗者。在一个优选的实施方案中,将所述T细胞给予人类受治疗者。最好利用poly-Glu,Tyr进行T细胞扩充。
经poly-Glu,Tyr活化的T细胞可以立即使用或者可以保存后待用,例如通过以下描述的深低温保藏后待用。也可以采用先前冷藏的T细胞获得Poly-Glu,Tyr特异性活化T细胞,即在将所述细胞解冻后,可以将T细胞与poly-Glu,Tyr一起孵育,最好与外周血淋巴细胞(PBL)一起孵育,以获得poly-Glu,Tyr特异性活化T细胞的制备物。
正如本领域技术人员众所周知的,所述T细胞可以在培养之前或之后进行保存,例如通过深低温保藏。可使用的低温防护剂包括但不限于二甲亚砜(DMSO)、甘油、聚乙烯吡咯烷酮、聚乙二醇、白蛋白、葡聚糖、蔗糖、乙二醇、i-赤藓醇、D-核糖醇、D-甘露醇、D-山梨醇、i-肌醇、D-乳糖、氯化胆碱、氨基酸、甲醇、乙酰胺、甘油一乙酸酯、无机盐和与羟乙基淀粉组合的DMSO以及人血清白蛋白。
冷却速率的控制是至关重要的。不同的低温防护剂和不同的细胞类型具有不同的最佳冷却速率。冷却速度对细胞的存活率和其移植潜力有影响。其中水变成冰的熔融相的热应该是最小的。可以通过用例如可编程冷冻装置或甲醇浴方法,来进行所述冷却步骤。
可编程冷冻装置可供测定最佳冷却速率并且便于标准的可再现冷却。可编程控释速率冷冻剂例如Cryomed或Planar允许将冷冻方案换算成所需的冷却速率曲线。
在充分冷冻后,将细胞快速转移至一个长期深低温的保存容器中。在一个实施方案中,可以在机械冷冻罐例如保持温度约-80℃或约-20℃冷冻罐中,将样品低温保存。在一个优选的实施方案中,将样品在液氮(-196℃)或其蒸汽中深低温保藏。由于高效液氮冷藏器的有效性,极大地简化了这样的保存,该高效液氮冷藏器类似于大热水瓶容器且具有极低真空和内部超绝缘性能,致使热渗漏和氮损失保持绝对最小。
低温冷藏活细胞的其它方法或其改进方法例如冷金属-镜像技术是可利用的并且设想可以使用。
优选将冷冻细胞快速解冻(例如保持在37-47℃的水浴中)并且在解冻后快速冷却。可能最好是处理所述细胞,以防止解冻后细胞聚集。为了防止聚集,可以使用各种方法,包括但不限于在冷冻之前或之后加入DNA酶、低分子量葡聚糖和柠檬酸、羟乙基淀粉或酸性柠檬酸葡萄糖。
所述低温防护剂如果对人有毒,则应该在治疗性使用所述解冻T细胞之前将其除去。一种除去所述低温防护剂的方法是通过稀释至无意义的浓度。
一旦将冷冻T细胞解冻并回收,则如本文关于非冷冻T细胞的描述,将其用于促进神经元再生。一旦解冻,则所述T细胞可以立即使用,假定它们在冷冻之前已被活化。然而,优选所述解冻细胞在注射到患者体内之前进行培养,以消除非活力细胞。此外,在该培养过程超过约1-3天的时期的情况下,如果所述冷冻细胞是静息T细胞或者在冷冻之前已活化T细胞而为了有助所述细胞实现更高速率激活,则可以加入合适的活化剂,以便激活所述细胞。通常,可用时间为给药之前进行这样的培养步骤创造条件,这是因为只要在损伤后1周和可能更长时间内,则可以给予所述T细胞,并且所述T细胞仍保持其神经再生作用和神经保护作用。
包含poly-Glu,Tyr或poly-Glu,Tyr活化T细胞的本发明组合物可以用于促进神经再生或者预防或抑制可能紧接在原发性NS损伤之后发生的继发性变性,所述原发性NS损伤例如脊髓损伤、钝器创伤例如由参加危险性运动所引起的那些NS损伤、穿透性创伤例如枪伤、脑外伤或对侧外伤、出血性中风、局部缺血性中风、脑局部缺血或由外科手术例如肿瘤切除术引起的损伤。
另外,这样的组合物可以用于缓解导致变性过程的疾病效应,例如在灰质或白质(或者它们两者)中由于各种疾病或障碍引起的变性,包括但不限于选自以下的损伤、障碍或疾病:老年性痴呆(包括早老性痴呆)、帕金森病综合征(Parkinsonian syndrome)(包括帕金森病)、面神经麻痹(贝尔麻痹)、亨廷顿舞蹈病、运动神经元病变(包括肌萎缩性侧索硬化)、朊病毒病(包括克-雅病(Creutzfeldt-Jakobdisease))、阿尔珀病(Alper′s disease)、巴腾病(Batten disease)、科克因综合征(Cockayne syndrome)、雷维小体病(Lewy body disease)、癫痫持续状态、腕管综合征、椎间盘突出、维生素缺乏症、癫痫、遗忘症、焦虑、痛觉过敏、精神病、癫痫发作、氧化性应激、阿片制剂耐受性和依赖性、自身免疫病,或者是与疾病相关的周围神经病例如淀粉状蛋白性多神经病、糖尿病性神经病、尿毒症性神经病、卟啉性多神经病、低血糖症、斯-拉综合征(Sjogren Larsson syndrome)、急性感觉神经病、慢性共济失调神经病、胆汁性肝硬化、原发性淀粉状蛋白病、阻塞性肺病、肢端肥大症、吸收障碍综合征、真性红细胞增多、IgA和IgG γ-球蛋白病、各种药物例如呋喃妥因、甲硝唑、异烟肼和毒素例如醇或有机磷酸酯的并发症、进行性神经病性肌萎缩(Charcot-Marie-Tooth disease)、共济失调-毛细管扩张症、弗里德赖希共济失调(Friedreich′s ataxia)、肾上腺脊髓神经病、巨轴突神经病、雷弗素姆病(Refsum′s disease)、法布莱病(Fabry′s disease)或脂蛋白血症。
另外,根据关于本发明的谷氨酸保护性方面的发现,可以按照本发明进行治疗的其它临床病症包括癫痫、遗忘症、焦虑、痛觉过敏、精神病、癫痫发作、眼内压异常升高例如青光眼、氧化性应激以及阿片制剂耐受性和依赖性。另外,本发明的谷氨酸保护性方面即治疗由谷氨酸毒性引起或恶化的损伤或疾病,则可以包括手术后治疗例如对于去除CNS的肿瘤和对CNS的其它形式的外科手术。
鉴于出人意外地发现poly-Glu,Tyr免疫可用于抵抗谷氨酸毒性的事实,预期按照本发明的poly-Glu,Tyr治疗或经poly-Glu,Tyr活化的T细胞治疗在治疗以上所列病症方面将是有效的,不仅在晚期当影响髓鞘质时而且在引起谷氨酸水平升高至毒性水平的因素攻击神经元的早期都是有效的。因此,本发明可用于由谷氨酸水平升高引起或恶化的任何适应症,即慢性或急性神经变性,包括局部缺血性中风、早老性痴呆等。
在一个优选的实施方案中,包含本发明poly-Glu,Tyr的活化T细胞或免疫组合物用于治疗其中适合促进神经再生或者预防或抑制继发性神经变性的疾病或障碍。
在一个优选的实施方案中,本发明考虑了在佐剂中给予的poly-Glu,Tyr的应用。考虑到口服给予用于神经保护的poly-Glu,Tyr(如果可行的话)总是在用poly-Glu,Tyr初次活化后给予,优选与佐剂一起给予;因此,可以在用poly-Glu,Tyr初次活化之后,采用口服poly-Glu,Tyr来增加所述T细胞的活性。
经poly-Glu,Tyr活化的T细胞也可以用来缓解由肿瘤引起的变性过程,而无需使用免疫疗法过程。用poly-Glu,Tyr活化的T细胞将在神经变性部位累积并且有助于抑制该变性。
可供按照本发明使用的药用组合物可以用一种或多种生理上可接受的载体或赋形剂以常规方式配制。所述载体在与所述组合物的其它组分相匹配的意义上必须是“可接受的”并且对其接受者而言是无害的。
列出了载体的以下范例、给药模式、剂型等,因为所述载体、给药模式、剂型等的已知可行性可以根据本发明的用途进行选择。然而,本领域普通技术人员将会知道,所选的任何特定制剂和给药模式应该首先进行测试以确定其是否达到所需的结果。因此,例如,当有效成分是poly-Glu,Tyr时,所述特定制剂和给药模式必需允许所述有效成分作为疫苗起作用,以便在体内产生出理针对该疫苗的被活化的T细胞。如果没有获得这样的免疫应答,则该特定制剂和给药模式不应该按照本发明来使用。
同样,如果有效成分是活化T细胞,则特定制剂和给药模式应该进行测试,以确保所给予的活性T细胞以活性状态进入血流,致使它们可以起按照本发明的保护作用。
术语“载体”是指随所述治疗药一起给予的稀释剂、辅料、赋形剂或溶媒。所述药用组合物中的载体可以包含结合剂,例如微晶纤维素、聚乙烯吡咯烷酮(polyvidone或聚维酮)、西黄蓍胶、明胶、淀粉、乳糖或乳糖一水合物;崩解剂,例如藻酸、玉米淀粉等;润滑剂或表面活性剂,例如硬脂酸镁或十二烷基硫酸钠;助流剂,例如胶态二氧化硅;甜味剂,例如蔗糖或糖精;和/或矫味剂,例如胡椒薄荷、水杨酸甲酯或橙味矫味剂。
给药方法包括但不限于胃肠外途径例如静脉内、腹膜内、肌内、皮下、粘膜(例如经口、鼻内、口腔含化、阴道、直肠、眼内)、鞘内、局部和皮内途径。给药可以是系统的,或者是局部的。
对于口服给药,所述药用制剂可以为液体形式例如溶液剂、糖浆剂或混悬剂,或者可以制备为供临用前用水或其它合适的溶媒重建的药品。这样的液体制剂可以按常规方法与诸如以下的药学上可接受的添加剂一起制备:悬浮剂(例如山梨醇糖浆剂、纤维素衍生物或氢化可食用脂肪)、乳化剂(例如卵磷脂或阿拉伯胶)、非水溶媒(例如杏仁油、油性酯或分级分离的植物油)和防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)。所述药用组合物可以为按常规方法与例如以下的药学上可接受的赋形剂一起制备的剂型例如片剂或胶囊剂:结合剂(例如预凝胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)、填充剂(例如乳糖、微晶纤维素或磷酸氢钙)、润滑剂(例如硬脂酸镁、滑石粉或二氧化硅)、崩解剂(例如马铃薯淀粉或羟乙酸淀粉钠)或润湿剂(例如十二烷基硫酸钠)。所述片剂可以按本领域众所周知的方法进行包衣。可以适当配制口服给药制剂,以控制所述活性化合物的释放。对于口腔含化给药,所述组合物可以为以常规方式配制的片剂或锭剂形式。当口服给予poly-Glu,Tyr时,可以将其与其它食物形式混合在一起并且以固体、半固体、悬浮剂或乳剂形式消费,并且可以将其与包括水、悬浮剂、乳化剂、香味增强剂等在内的药学上可接受的载体混合在一起。在一个实施方案中,将所述口服组合物包肠衣。包肠衣的应用是本领域众所周知的。
所述组合物可以配制用于通过注射而胃肠外给药,例如通过大剂量注射或连续输注。注射制剂可以与添加的防腐剂一起存在于单位剂型中,例如在安瓿或多剂量容器中。所述组合物可以为如油性或水性溶媒中的混悬剂、溶液剂或乳剂等形式,并且可以含有组方剂,例如悬浮剂、稳定剂和/或分散剂。或者,所述有效成分可以以粉剂形式,供使用前用合适的溶媒例如无菌无热原水重建。
也可以将所述组合物配制成直肠组合物例如栓剂或滞留灌肠剂,例如含常规栓剂基质例如可可指或其它甘油酯的栓剂或滞留灌肠剂。
对于吸入给药,可供按照本发明使用的组合物以气雾剂喷雾形式便利地传递,利用合适的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体,用加压包装或雾化器便利地传递。就加压气雾剂而论,所述剂量单位可以通过提供阀而给予计量的量来确定。可以配制含有所述化合物和合适的粉末基质例如乳糖或淀粉的粉末混合物的供吸入器或吹入器的胶囊和药筒之用,所述胶囊和药筒本身则是例如是明胶。Poly-Glu,Tyr也可以以上述形式中的某些形式通过吸入或滴鼻剂经鼻给予。此外,可以用经口吸入来将poly-Glu,Tyr传递至气管和支气管通道的粘膜内衬。
在一个优选的实施方案中,包含poly-Glu,Tyr或经poly-Glu,Tyr活化T细胞的组合物可以按照常规方法配制为适合静脉内给予人类的药用组合物。通常,用于静脉内给药的组合物为无菌等渗水性缓冲液。必要时,所述组合物可以包括增溶剂和局部麻醉药例如利多卡因,以减轻注射部位的疼痛。一般而言,所述组分或者分开提供或者混合在一起。在准备通过输注给予所述组合物的情况下,可以将其分散在含有无菌药用级水或盐水的输注瓶中。在通过注射给予所述组合物的情况下,可以提供装有注射用无菌水或盐水的安瓿,以便在给药前可将所述组分进行混合。
包含poly-Glu,Tyr的药用组合物可以任选地与佐剂按免疫的常规方式给予。这类佐剂的非限制性实例包括明矾和不完全弗氏佐剂。也可以用可代谢脂质乳剂例如英脱利匹特或力保肪宁作为以WO97/02016中公开的方式用于所述poly-Glu,Tyr疗法的溶媒,所述专利的全部内容由此通过引用结合到本文中。尽管已知这些材料引起TH1至TH2细胞因子变化,但是没有理由相信TH2细胞因子不是有效的,也许对于本发明目的甚至也是优选的。
本发明也提供一种包含一个或多个装有本发明药用组合物的一种或多种组分的容器的药用包装或试剂盒。
在一个优选的实施方案中,在NS损伤后或在检测出变性损伤后,立即将本发明的药用组合物给予哺乳动物,优选人类。本发明的治疗方法可以包括给予poly-Glu,Tyr或经poly-Glu,Tyr活化的T细胞或者它们的组合。当采用联合疗法时,可以在给予经poly-Glu,Tyr活化的T细胞之前、同时或之后给予poly-Glu,Tyr。
在一个实施方案中,将本发明的组合物与一种或多种以下组分联合给予:(a)单核吞噬细胞,优选培养的单核细胞(如在WO97/09985、WO 98/41220、US 5,800,812、US 6,117,424和US 6,267,955中描述的,所述专利通过引用全部结合到本文中),经刺激以增强其促进神经元再生的能力;和(b)神经营养因子,例如酸性成纤维细胞生长因子。
在另一个实施方案中,在胃肠外给予poly-Glu,Tyr或经poly-Glu,Tyr活化的T细胞的同时、之前或之后,将按照WO 97/09985、WO 98/41220、US 5,800,812、US 6,117,424和US 6,267,955的单核吞噬细胞注射到CNS的损伤或损害部位。
在另一个实施方案中,poly-Glu,Tyr或经poly-Glu,Tyr活化的T细胞可以以单剂量给予或者可以重复给予,优选以2周间隔重复给予,然后以连续更长的间隔每月给予1次,每季度给予1次,每6个月给予1次等。根据待治疗的病症或疾病,疗程可以持续数月、数年或者有时也长达所述个体的一生。就CNS损伤而论,所述治疗时间的范围可以在数天至数月或者甚至数年之间,直到所述病症得到稳定并且没有或仅有限发生继发性变性为止。在慢性人类疾病或帕金森病中,按照本发明的治疗性治疗可以长达终生。
正如本领域技术人员众所周知的,疗效时常取决于待治疗病症或疾病、个体的年龄和健康状况、个体的其它物理参数(例如性别、体重等)以及各种其它因素,例如个体是否摄取其它药物等。
包含本发明的poly-Glu,Tyr活化T细胞的治疗组合物的最佳剂量可以与待治疗部位的受NS损伤或疾病影响的神经纤维数目成正比。在一个实施方案中,剂量范围对于治疗影响约105根神经纤维的损伤而言,可能为约5×106细胞至约107细胞,例如在大鼠视神经的完全横切面中进行的,而对于治疗影响约106-107神经纤维的损伤而言,范围可能为约107细胞至约108细胞,例如人视神经的完全横切面。正如本领域技术人员众所周知的,T细胞的剂量可以与据认为在病灶或正在治疗的部位受影响的神经纤维数成比例地提高或降低。
为了使神经损伤后的继发性损害减至最小,患者可以通过给予poly-Glu,Tyr致敏的自体T淋巴细胞或半同种异体T淋巴细胞进行治疗。由于概率窗尚未准确确定,因此应该在原发性损伤后尽可能快地给予治疗,以使成功机会最大化,最好是在约1-2周内给予。
为了使活化所需的时间和治疗所需的时间之间无时间间隔,可以建立制备的自体T淋巴细胞的个人库,以备将来如果发生NS损伤则用于针对继发性变性的神经保护治疗。从血液中分离出T淋巴细胞,然后使其对poly-Glu,Tyr敏化。然后将所述细胞冷冻并在细胞库中按个人的姓名、身份证号和血型适当保存待用。
另外,可以将CNS的自体干细胞处理并保存,以供潜在的、在NS创伤性疾病例如局部缺血或机械性损伤事件中的患者使用以及用于治疗神经变性性疾病,例如早老性痴呆或帕金森病。另一方面,可以将半同种异体T细胞或同种异体T细胞冷冻保存在库中,以供与所述T细胞源共享一种MHC II型分子的任何个体用。
下面的实施例说明本发明的某些特征,但并不是用来限制本发明的范围。
实施例
材料和方法
动物。所有动物都按照the Institutional Animal Care and UseCommittee(IACUC)制定的规定进行管理。8-13周龄C57BL/6J品系小鼠和8-12周龄成年雄性SPD大鼠由the Animal Breeding Center ofthe Weizmann Institute of Science(Rehovot,以色列)供应,并在控制光照和温度的房间中关养。在每个实验中,让所述大鼠按年龄和体重交配。在实验之前,动物通过腹膜内给予80mg/kg氯胺酮和16mg/kg赛拉嗪而麻醉。
抗原。来自豚鼠脊髓的MBP和卵清蛋白(OVA)、poly-Glu,Tyr以及Con-A购自Sigma(St.Louis,MO)。Cop 1购自Teva Pharmaceuticals(Petah Tikva,以色列)。MBP p87-99肽在the Weizmann Institute ofScience(Rehovot,以色列)合成。
免疫。小鼠或大鼠用100μg poly-Glu,Tyr免疫,所述poly-Glu,Tyr用含有0.5mg/ml结核分枝杆菌(Mycobacterium tuberculosis)的等体积CFA乳化。将所述乳剂(总体积0.1ml)在所述小鼠的胁腹而在所述大鼠的上背的一个部位皮下注射。给对照小鼠和大鼠注射含有CFA的PBS(Difco,Detroit,Michigan,USA)。
谷氨酸注射。麻醉的小鼠或大鼠的右眼用27号针穿入巩膜上部,将装有30号针的10μl汉密尔顿(Hamilton)注射器尽可能深地插入到玻璃体(vitreal body)中。给小鼠注射总体积1μl(200 nmole)的溶于盐水中的L-谷氨酸溶液。
T细胞系。从用上述抗原免疫的Lewis大鼠获得的引流淋巴结细胞产生T细胞系(Ben-Nun等,1981)。将所述抗原溶于PBS(1mg/ml)中并用等体积的补充4mg/ml结核分枝杆菌(Difco)的不完全弗氏佐剂(IFA)(Difco Laboratories,Detroit,MI)乳化。给大鼠后足垫注射0.1ml含有所述抗原的乳剂后10天,处死该大鼠,通过外科手术取出并分离其引流淋巴结。洗涤所述细胞并用抗原(10μg/ml)在含有以下组分的刺激培养基中使其活化:补充L-谷氨酰胺(2mM)、2-巯基乙醇(5×10-5M)、丙酮酸钠(1mM)、青霉素(100IU/ml)、链霉素(100μg/ml)、非必需氨基酸(1ml/100ml)和自体血清1%(体积/体积)的Dulbecco氏改良的Eagle氏培养基(DMEM)。在37℃、98%相对湿度和10%CO2下孵育72小时后,将所述细胞转移至由以下组分组成的繁殖培养基中:DMEM、L-谷氨酰胺、2-巯基乙醇、丙酮酸钠、非必需氨基酸和抗生素(所述组分的浓度与上面的相同),并加入10%胎牛血清(FCS)(体积/体积)和10%T细胞生长因子(来源于经伴刀豆球蛋白A(ConA)刺激的脾细胞上清液)。让细胞在繁殖培养基中生长4-10天,然后在经照射的(2000拉德)胸腺细胞(107细胞/ml)存在下在刺激培养基中用其抗原(10μg/ml)再次刺激。所述T细胞系通过重复刺激和繁殖而得到扩充(Ben-Nun等,1982)。
视神经的挤压损伤:(a)使视神经经历挤压损伤。简而言之,大鼠通过腹膜内(i.p.)注射Rompun(赛拉嗪,10mg/kg;Vitamed,以色列)和Vetalar(氯胺酮,50mg/kg;Fort Dodge Laboratories,Fort Dodge,IA)而深度麻醉。采用双目镜手术显微镜,在右眼实施外侧眦切开术,并侧切结膜至角膜。分离出缩肌延髓肌后,通过钝器解剖法,暴露眼眶内视神经。采用校准后的交叉作用镊子(calibrated cross-actionforceps),使视神经经历距该眼球1-2mm的挤压损伤。对于短期试验(2周),施以轻度和重度挤压损伤,由于显示该时间是证明继发性变性和对治疗有反应的最佳时间(Yoles,1998)。未损伤对侧神经是左眼未损伤的神经;(b)麻醉小鼠或大鼠并使其在距眼球1-2mm处的视神经的眼眶内部分经历分级挤压损伤。借助于双目镜手术显微镜,切开结膜并暴露视神经。采用交叉作用校准后的镊子并特别小心地不干预血液供应,挤压视神经2秒(小鼠)或30秒(大鼠)。
通过逆向标记RGC测量大鼠视神经挤压后的继发性变性。通过在挤压损伤2周后,损伤部位远侧损伤后应用荧光亲脂性染料4-(4-(二癸基氨基)苯乙烯基)-N-甲基碘化吡啶(4-Di-10-Asp)(MolecularProbes Europe BV,荷兰),测量视神经轴突及其所附RGC的继发性变性。因为仅完整轴突可以将该染料逆向运输至其胞体,所以确保对仅在原发性损伤和继发性变性两者中存活的轴突计数,2周后,将该染料远侧应用于所述损伤部位。该方法使得能够鉴别功能仍然完好的神经元和轴突受到损伤但胞体仍有活力的神经元之间的差异,因为仅其纤维形态完好的那些神经元可以吸收损伤部位远侧的染料并将其运输至其胞体。采用该方法,标记RGC数目可靠地反映出仍有功能的神经元数目。标记和测量如下进行:第二次暴露右视神经,再次不损害视网膜血液供应。在距损伤部位远侧1-2mm处进行完全轴突切开术,而使4-Di-10-Asp的固体结晶(直径0.2-0.4mm)沉积在新实施轴突切开术的部位。施用染料5天后,处死大鼠。从眼球中剥离出视网膜,制备为扁平整体固定的4%低聚甲醛溶液,并通过荧光显微镜检查标记RGC。
小鼠视网膜神经节细胞(RCG)的标记。将RCG标记72小时,然后结束实验。麻醉小鼠并将其置于立体定位装置中。暴露颅骨并保持干燥和清洁。鉴定并标记前囟点。注射指定点位于脑表皮下2mm,前后轴中的前囟点后2.92mm且在中线外侧0.5mm。在右半球和左半球指定坐标上方的头皮中钻一个窗孔。然后采用汉密尔顿注射器,注入神经示踪染料(neurotracer dye)FluoroGold(5%的盐溶液;Fluorochrome,Denver,CO)(1μl,在每个半球均以0.5μl/min的速率注入),然后缝合伤口上的皮肤。
小鼠RGC存活率的评价。给小鼠一剂致死剂量的戊巴比妥(170mg/kg)。摘出其眼球,使视网膜脱落,并制备为扁平整体固定的低聚甲醛(4%,在PBS中)溶液。对4-6个相同大小(0.7mm2)的所选视野的标记细胞计数。所选视野与视盘的距离大致相同(0.3mm),以克服RGC密度随视盘距离不同而变化。对所述接受治疗的小鼠,由观察人员在荧光显微镜(放大倍数为800倍)下对各视野进行盲法计数。计算在每个视网膜中每视野的RGC平均数。
大鼠RGC存活率的评价。在损伤后将荧光亲脂性染料4-(4-(二癸基氨基)苯乙烯基)-N-甲基碘化吡啶(4-Di-10-Asp)(MolecularProbes Europe BV,荷兰)注入视神经头远端,来测量大鼠RGC的存活率。标记和测量如下进行:暴露视神经而不损害视网膜的血液供应。在距视神经头1-2mm处实施完全轴突切开术,而使4-Di-10-Asp的固体结晶(直径0.2-0.4mm)沉积在实施轴突切开术的部位。施用染料后5天,处死大鼠。从眼球中剥离出视网膜,制备为扁平整体固定的4%低聚甲醛溶液,然后通过荧光显微镜术检查标记RGC。在IOP实验动物中,所述神经节细胞被逆向运输的葡聚糖四甲基罗丹明(DTMR)(Molecular Probes,OR)标记。3000 MW DTMR的结晶适合于距眼球约2-3mm的视神经切口末端。24小时后,将视网膜进行整体固定并标记8个区中的神经节细胞,每个四分体中的2个(距视盘边缘0.66-1.103mm)在放大400倍下进行固定。
组织学分析。给小鼠注射谷氨酸或盐水后7天,通过注射一剂致死剂量的戊巴比妥(170mg/kg),处死小鼠,摘出其眼球并将其于4℃固定在甲醛(4%,在PBS中)溶液中达48小时。将切片(厚10μm)包埋在石蜡中并用苏木精和曙红(H&E)染色。
大鼠眼压过高的产生/大鼠眼内压的升高。雄性Lewis大鼠用氯胺酮(15mg/kg)、乙酰丙嗪(1.5mg/kg)和赛拉嗪(0.3mg/kg)的混合物麻醉。通过肢体和巩膜静脉的激光凝固法,实现眼内压(IOP)升高。大鼠接受2次激光治疗,间隔1周,用蓝绿氩激光(1瓦特持续0.2秒,在这两次治疗中传递50μm上总共130-150个点;Cohere
nt,Palo Alto,CA)治疗。在给大鼠肌内注射3.0mg/kg兽用安定药乙酰丙嗪并将0.5%普鲁卡因局部用于眼中以麻醉角膜后,采用TONO-PEN(Mentor,Norwell,MA),一周测量IOP一次。
实施例1.受挫伤动物生理性T细胞的所有组成成分
麻醉SPD大鼠,通过椎板切除术,以T8水平暴露其脊髓。诱导麻醉后1小时,采用NYU冲击器(Basso等,1995和1996),使一根10g杆从50mm的高度落在椎板切除的脊髓上。
脊髓挫伤后8-10天,处死大鼠,然后切取其脾脏并挤压使其通过一个细孔金属丝筛网。将经洗涤的细胞(2×106/ml)以三个复份在平底微量滴定板装有0.2ml含DMEM的增殖培养基的各孔中进行培养,所述DMEM补充L-谷氨酰胺(2mM)、2-巯基乙醇(5×10-5 M)、丙酮酸钠(1
mM)、青霉素(100IU/ml)、链霉素(100μg/ml)、非必需氨基酸和加有抗原(15μg/ml)或Con A(1.25μg/ml)的1%(vol/vol)自体大鼠血清以及经照射的胸腺细胞(2000拉德,2×106细胞/ml)。通过测量72小时培养的最后16小时加入的[3H]胸苷(1μCi/孔)的掺入,测定不同抗原即Ova、Cop1、MBP、87-99、poly-Glu,Tyr和Con A的增殖反应。确定与不含抗原的培养基中腺细胞增殖相比的脾细胞增殖指数(SI)(SI=1表示对所述抗原无增殖反应,即无任何抗原的增殖)。该参数是受挫动物中生理性T细胞所有组成成分的特征。Con-A是阳性对照。图1中的结果表明,在脊髓受挫伤的大鼠中,大量出现对poly-Glu,Tyr比对Cop-1或MBP有更高反应的T细胞。
实施例2.保护视神经纤维免遭谷氨酸毒性
为了弄清楚poly-Glu,Tyr是否可以影响更普遍的神经保护远离由谷氨酸诱导的毒性引起的有害环境条件,进行以下实验。
将兴奋性神经递质谷氨酸注射到C57B1/6J小鼠眼的玻璃体中,引起视神经神经元胞体的剂量依赖性死亡。以前的研究表明,RGC死亡发作被延迟(在注射谷氨酸后被延迟超过24小时)并且像细胞凋亡一样。
在本实验中,8周龄雄性C57B1/6J小鼠在注射谷氨酸前7天,用100μg在CFA中乳化的poly-Glu,Tyr进行皮下免疫。一组小鼠同时用在CFA中乳化的PBS进行免疫,以消除免疫的非特异性效应,而一组未免疫的小鼠用作对照。所有这三组小鼠都接受将谷氨酸(400nmole)注射到右眼玻璃体中。左眼不接受注射并用作完整对照。注射谷氨酸后7天,切取眼球并测定RGC存活率。
所述poly-Glu,Tyr免疫小鼠、所述PBS免疫小鼠和所述未免疫小鼠的完整视网膜中计数的RGC/mm2平均数分别为2796±165、2874±197和2807±42,表明免疫对对侧完整眼球中的RGC存活无影响。因此,综合考虑所有这三个实验组中完整视网膜的RGC/mm2平均值,并将其看作100%RGC存活(0%毒性)。
图2中描绘的结果表明,与用PBS免疫(t-检验,p=0.007)或未免疫(t-检验,p=0.01)相比,用poly-Glu,Tyr的CFA(CFA-EY)溶液免疫小鼠显著降低谷氨酸诱导的RGC死亡。后两组之间的RGC存活率没有差异(t-检验,p=0.71)。
实施例3.脊髓损伤的神经保护
低胸水平的急性不完全脊髓损伤引起后肢自主活动的立即丧失,该自主活动在损伤后前12天内自发恢复并且稳定在有缺陷的运动能力上。运动机能康复的量是从脊髓休克恢复的正面效应和损伤的纵向和腹侧扩散的负面效应的总和。目的在于通过神经保护减少损伤扩散的治疗方案将导致就后肢自主活动而言向好的方向恢复。
在以下实验中,测试用poly-Glu,Tyr主动免疫或被动免疫对脊髓挫伤后后肢自主活动的影响。
3.1用poly-Glu,Tyr主动免疫:poly-Glu,Tyr/CFA免疫对大鼠从脊髓挫伤中恢复的影响
采用NYU冲击装置,使一根10g杆从50mm的高度以T8水平落在已暴露的椎板切除的脊髓上,给经麻醉的12只SPD雄性大鼠造成脊髓的挫伤性损伤。所用的NYU冲击装置可供用于每只动物,以测定所述杆的轨道以及使其与经暴露的脊髓接触,以达到一致的损伤。
由于脊髓休克,因此大鼠后肢的运动技能最初消失,但随时间恢复,达到一种有缺陷的自主活动稳定状态。这种由所述损伤引起的缺陷的量可以用适当神经保护性治疗来降低。
将大鼠按其冲击误差(impact errors)分为2组(每组6只大鼠),以实现相似的组。在一组中,大鼠在其上背用PBS/CFA(三角形)进行皮下免疫。在另一组中,大鼠用pEY/CFA(100μg/大鼠,方形)进行皮下免疫。这两个组都在损伤后立即免疫,并且7天后,这两个组都接受与第一次免疫相同的第二次免疫。采用Basso等人1995年研究出的评分方法(按照the Basso,Beattie,Bresnahan(BBB)LocomotorRating Scale,对走动活动进行评分(范围为0-21)),对所述大鼠后肢运动技能进行评分,然后研究这两个实验组中后肢自主活动的动力学和量。一周大约两次,通过将大鼠放在由模制塑料光面防滑地板制成的圆形罩(直径90cm,墙壁高7cm)的中间达4分钟,评价所述大鼠在开放场中的躯干、尾巴和后肢的运动能力。图3中所描绘的结果表明,用pEY(方形)治疗的大鼠比经PBS治疗的大鼠的恢复趋势要好。
3.2用poly-Glu,Tyr被动免疫
为了检查poly-Glu,Tyr特异性T细胞在脊髓损伤后是否也提供神经保护,进行以下实验。
为了制备所述T细胞,4只SPD大鼠在其下背用pEY/CFA(125μg/大鼠)进行皮下免疫。7天后,收获其脾细胞,并通过用注射器的柱塞在金属丝筛网上挤压所述脾脏,制备单细胞悬浮液。所述脾细胞在与pEY(10μg/ml)一起培养3天后被活化。收获所述细胞,用PBS洗涤并计数。
另一组12只雄性SPD大鼠进行外科手术,如以上实施例3.1中描述的方法,采用重10g的杆,使其从50mm高度落下,以T7水平挫伤其脊髓。挫伤后,立即将所述大鼠按其冲击误差分为2个同样的组。一组静脉内接受0.5ml PBS,而另一组接受用pEY(30×106/0.5ml PBS/大鼠)活化的脾细胞。运用开放场BBB评分,对所述大鼠的机能恢复进行评分。
图4中所描绘的结果表明,用用pEY(方形)活化的脾细胞治疗的大鼠比对照组(三角形)的恢复情况要好。
参考文献
Basso等,″A sensitive and reliable locomotor rating scale for openfield testing in rats(一种灵敏可靠的用于大鼠开放场实验的运动评定量表)″,
J.Neurotrauma 12(1):1-21(1995)
Basso等,″Graded histological and locomotor outcomes after spinalcord contusion using the NYU weight-drop device versus transection(使用NYU落重法装置与横断术,脊髓挫伤后的组织学分级结果和运动结果)″,
Exp.Neurol.139(2):244-256(1996)
Ben-Nun等,″The rapid isolation of clonable antigen-specific Tlymphocyte lines capable of mediating autoi
mmune encephalomyelitis(能够介导自身免疫性脑脊髓炎的可克隆抗原特异性T淋巴细胞系的快速分离)″,
Eur.J.Immunol.11(3):195-199(1981)
Ben-Nun等,″Experimental autoimmune encephalomyelitis(EAE)mediated by T cell lines:process of selection of lines and characterizationof the cells(由T细胞系介导的实验性自身免疫性脑脊髓炎(EAE):细胞系的选择过程及其表征)″,
J.Immunol.129(1):303-308(1982)
Debre等,″Genetic control of specific immune suppression.II.H-2-linked dominant genetic control of immune suppression by the randomcopolymer glutamic acid50-L-tyrosine50(GT)(特异性免疫抑制的遗传控制:II.随机共聚物L-谷氨酸50-L-酪氨酸50(GT)免疫抑制的H-2-连锁显性遗传控制)″,
J.Exp.Med.142(6):1447-54(1975)
Hauben等,″Autoimmune T cells as potential neuroprotective forspinal cord contusion(作为脊髓损伤的潜在神经保护药的自身免疫性T细胞)″,
Lancet 355:286-287(2000)
Hickey,W.F.等,″T-lymphocyte entry into the central nervoussystem(进入中枢神经系统的T淋巴细胞)″,
J.Neurosci.Res.28(2):254-260(1991)
Hirschberg等,″Accumulation of passively transferred primed T cellsindependently of their antigen specificity following central nervoussystem trauma(中枢神经系统创伤后不依赖于其抗原特异性的被动转移的致敏T细胞的累积)″
J.Neuroimmunol.89(1-2):88-96(1998)
Lynch等,″Secondary mechanisms in neuronal trauma(神经元创伤的次级机制),
Curr.Opin.Neurol.7(6):510-516(1994)
McIntosh,T.K.,″Novel pharmacologic therapies in the treatment ofexperimental traumatic brain injury:a review(治疗实验性外伤性脑损伤的新药理疗法:综述)″,
J.Neurotrauma 10(3):215-261(1993)
Meldrum,″Glutamate as a neurotransmitter in the brain:review ofphysiology and pathology(作为脑中神经递质的谷氨酸:生理学和病理学综述)″,
J.Nutr.130:(4S Suppl):1007S-1015S(2000)
Moalem等,″Autoimmune T cells protect neurons from secondarydegeneration after central nervous system axotomy(自身免疫性T细胞保护神经元免遭中枢神经系统轴突切开术后的继发性变性)″,
Nat. Med.5:49-55(1999a)
Mor等,″Pathogenicity of T cells responsive to diverse crypticepitopes of myelin basic protein in the Lewis rat(Lewis大鼠中对髓鞘碱性蛋白的多样性隐藏表位应答的T细胞的致病性)″,
J.Immunol.155(7):3693-3699(1995)
Ota等,″T-cell recognition of an immunodominant myelin basicprotein epitope in multiple sclerosis(多发性硬化中免疫显性髓鞘碱性蛋白表位的T细胞识别)″,
Nature346(6280):183-187(1990)
Pette等,″Myelin basic protein-specific T lymphocyte lines from MSpatients and healthy individuals(来自MS患者和健康个体的髓鞘碱性蛋白特异性T淋巴细胞系)″,
Proc.Natl.Acad.Sci.USA 87(2):7968-7972(1990)
Pitt等,″Glutamate excitotoxicity in a model of multiple sclerosis(多发性硬化模型中的谷氨酸兴奋毒性)″,
Nat Med.6:67-70(2000)
Seo等,″Activation of murine epidermal V gamma 5/V delta 1-TCR(+)T cell lines by Glu-Tyr polypeptides(鼠类表皮Vγ5/Vδ1-TCR(+)T细胞系被Glu-Tyr多肽激活)″,
J.Invest.Dermatol.116(6):880-885(2001)
Vidovic等,Recessive T cell response to poly(Glu50Tyr50)possiblycaused by self tolerance(可能由自身耐受性引起的对poly(Glu50Tyr50)的隐性T细胞应答)″,
J.Immunol.134(6):3563-68(1985)
Vidovic和Matzinger,″Unresponsiveness to a foreign antigen can becaused by self-tolerance(对外源抗原无反应性可由自身耐受性引起)″,Nature 336:222(1988)
Yoles等,″Degeneration of spared axons following partial whitematter lesion:implications for optic nerve neuropathies(部分白质损伤后未损伤轴突的变性:视神经神经病的本质)″,
Exp.Neurol.153:1-7(1998)
Claims (9)
1.poly-Glu,Tyr在制备药物组合物中的应用,其中所述药物组合物用于治疗CNS或PNS损伤、障碍或疾病,从而预防或抑制神经元变性;或者用于促进神经再生;或者用于治疗由谷氨酸毒性引起或恶化的CNS或PNS损伤、障碍或疾病。
2.权利要求1的应用,其中所述药物组合物用于预防或抑制CNS或PNS损伤的变性效应和对原发性神经系统损伤后可能出现的继发性神经变性效应提供保护。
3.权利要求2的应用,其中所述损伤是脊髓损伤、钝器创伤、穿透性创伤、脑外伤或对侧外伤、出血性中风或者局部缺血性中风、脑局部缺血或外科手术引致的损伤。
4.权利要求3的应用,其中所述损伤是脊髓损伤。
5.权利要求1的应用,其中所述药物组合物用于治疗由谷氨酸毒性引起或恶化的CNS或PNS障碍或疾病。
6.权利要求5的应用,其中所述障碍或疾病与眼有关。
7.权利要求6的应用,其中所述与眼有关的障碍或疾病为非动脉炎性视神经病、年龄相关性黄斑变性、视网膜疾病或与眼内压异常升高相关的疾病。
8.权利要求7的应用,其中所述视网膜疾病为视网膜变性。
9.权利要求7的应用,其中所述与眼内压异常升高相关的疾病是青光眼。
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EP1827108B1 (en) * | 2004-11-29 | 2015-04-08 | Yeda Research And Development Co., Ltd. | Induction of neurogenesis and stem cell therapy in combination with copolymer 1 |
US9220813B2 (en) * | 2005-04-18 | 2015-12-29 | Holy Cross Hospital, Inc. | Cell therapy for limiting overzealous inflammatory reactions in tissue healing |
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US20120171172A1 (en) * | 2009-09-04 | 2012-07-05 | Maria Siemionow | Methods Of Engineering Neural Tissue |
USRE49251E1 (en) | 2010-01-04 | 2022-10-18 | Mapi Pharma Ltd. | Depot systems comprising glatiramer or pharmacologically acceptable salt thereof |
WO2011080733A1 (en) | 2010-01-04 | 2011-07-07 | Mapi Pharma Limited | Depot systems comprising glatiramer or a pharmacologically acceptable salt thereof |
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EP3600553A4 (en) | 2017-03-26 | 2020-09-02 | Mapi Pharma Ltd. | GLATIRAMER DEPOT SYSTEMS FOR TREATMENT OF PROGRESSIVE FORMS OF MULTIPLE SCLEROSIS |
Citations (1)
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---|---|---|---|---|
WO1999034827A1 (en) * | 1998-07-21 | 1999-07-15 | Yeda Research And Development Co. Ltd. | Activated t-cells and their uses |
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HK1064951A1 (en) | 2005-02-08 |
JP4434729B2 (ja) | 2010-03-17 |
DE60229639D1 (de) | 2008-12-11 |
KR20040032825A (ko) | 2004-04-17 |
US6835711B2 (en) | 2004-12-28 |
CN1547482A (zh) | 2004-11-17 |
AU2002345323B2 (en) | 2006-12-21 |
EP1406650A1 (en) | 2004-04-14 |
MXPA03011926A (es) | 2004-03-26 |
CA2451521A1 (en) | 2003-01-09 |
ATE412419T1 (de) | 2008-11-15 |
JP2005502616A (ja) | 2005-01-27 |
CA2451521C (en) | 2011-05-17 |
NZ530261A (en) | 2006-06-30 |
US20030003082A1 (en) | 2003-01-02 |
IL159535A0 (en) | 2004-06-01 |
ES2315371T3 (es) | 2009-04-01 |
EP1406650B1 (en) | 2008-10-29 |
DK1406650T3 (da) | 2009-03-02 |
WO2003002140A1 (en) | 2003-01-09 |
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