CN110420223A - 一种含有骨髓间质干细胞的注射剂 - Google Patents
一种含有骨髓间质干细胞的注射剂 Download PDFInfo
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- CN110420223A CN110420223A CN201910830407.XA CN201910830407A CN110420223A CN 110420223 A CN110420223 A CN 110420223A CN 201910830407 A CN201910830407 A CN 201910830407A CN 110420223 A CN110420223 A CN 110420223A
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- stem cell
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Abstract
本发明提供了一种含有骨髓间质干细胞的注射剂，本发明的一种含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成，无毒副作用，安全性好，该注射剂由于有林格氏液的存在补充机体所需要的钠钾元素，甘氨酸可以清除机体内自由基，促进干细胞分泌因子的旁分泌作用，硒化黄芪多糖和香菇多糖可以延长干细胞分泌因子的持续作用时间，同时增强机体非特异性免疫功能。
Description
技术领域
本发明涉及干细胞技术领域，具体涉及一种含有骨髓间质干细胞的注射剂。
背景技术
1.骨髓间质干细胞功能
骨髓中包含两种完全不同的干细胞：造血干细胞和间质干细胞（mesenchymal stemcells，MSCs），前者维持造血, 而后者则构成了骨髓造血的微环境。这两种独立而且完全不同的干细胞不仅共存而且在功能上互相协作, 共同完成成人体内血液系统的再造。除骨髓外，其他组织也存在少量MSCs，但成人中骨髓中含量最多，约占其有核细胞0.001～0.01%，因此骨髓是较为适合的MSCs来源。
1970年Friedenstein通过成纤维细胞集落形成单位试验在体外证明了MSCs的存在；经过长期的研究, 人们对其功能已有了比较深入的了解。骨髓MSCs为多潜能的成体基质细胞，能分化为多种间质起源的组织，如成骨、软骨和脂肪细胞；在特殊环境下，还能横向分化为肌细胞、神经细胞、血管内皮细胞、肝胰细胞等多种其他组织细胞。MSCs对多种损伤组织具有替代修复作用，植入体内后可在多种造血以外的组织如肺、骨、软骨和皮肤等处定位和分布。
除了分化作用外，骨髓MSCs还具有较强的免疫调控能力，对T、B、树突状细胞和NK细胞均有调节性抑制作用。研究表明，MSCs可抑制T细胞增殖，引起T细胞分化停滞，并可抑制T细胞活化，下调相应肽段对幼稚性（naive）及记忆性抗原特异T细胞效应，诱导T细胞失能(anergy) ；此外MSCs还可诱导产生调节性T细胞来进行调控。MSCs可抑制B细胞增殖（B细胞/MSCs为1:1时作用最强，而达1:5或1:10时作用消失），抑制B细胞分化并影响B细胞趋化（与MSCs共培养后B细胞表达趋化因子CXCR4、CXCR5和CXCR7受体减少，从而出现趋化能力缺陷）。对于树突状细胞，MSCs可抑制其增殖及分化成熟，可阻止单核细胞和骨髓前体细胞分化为树突状细胞，抑制CD1a、CD40、CD80、CD86及HLA-DR上调，使细胞维持未成熟状态；MSCs还可改变其细胞因子分泌能力，从而影响树突状细胞功能。MSCs同样能够抑制NK细胞的增殖，其表面存在多种成分可影响NK细胞活化（包括NKG2D配体如MICA、ULBPs和DNAM-1配体如PVR、nectin-2）。
2.间质干细胞应用现状
MSCs可在造血干细胞niche中分泌细胞因子起支持作用，并且降低外周血单个核细胞同种免疫刺激活性，从而促进造血干细胞移植后造血系统重建。2000年，首项临床试验显示，28例女性乳腺癌患者在接受自体造血干细胞移植时给予MSCs单次输注，其造血恢复加快且无副反应。2005年另一项多中心研究也显示46例患者同时行异基因造血干细胞和MSCs治疗后多数造血恢复加快，未发现副作用。
2004年，Le Blanc报道首个MSCs治疗移植物抗宿主病(GVHD)病例，患儿为淋巴细胞白血病患者，MSCs由其母亲提供，于造血干细胞移植70天和170天时分别输注1次，患儿症状改善，胆红素水平下降。2008年，Le Blanc报道了MSCs治疗重度难治性GVHD II期临床研究结果，共治疗55例患者，结果30例患者完全缓解，另9例部分缓解。目前III期研究正在进行中。
MSCs可同时修复心肌和血管组织、具有免疫调节活性，并且具有易培养扩增满足移植需要的特点，这使其在心血管疾病治疗中存在理论价值，目前已应用于心肌梗塞、心肌缺血、心功能衰竭的治疗。经心肌直接注入是最常用的治疗方式，初步研究显示可改善心脏射血分数，提高患者生存率，但其疗效和安全性尚有待对照研究加以证实。
MSCs在神经系统疾病（如多发性硬化、肌萎缩侧索硬化）、成骨不全、皮肤创伤也有一些初步应用。由于MSCs的靶向性，在动物研究中已有用于肿瘤治疗的报道。
3. 自身免疫性疾病常规治疗
自身免疫性疾病(autoimlnune disease)是指以自身免疫应答反应导致组织器官损伤和相应功能障碍为主要发病机制的一类疾病。是临床上常见的一大类疾病，目前已被公认的自身免疫性疾病至少有30多种。根据自身免疫反应对组织器官造成损伤的范围，通常将自身免疫病分器官特异与非器官特性两大类。
临床上常见的自身免疫性疾病包括：结缔组织疾病：类风湿关节炎(RA)、幼年特发性关节炎(JIA)、系统性红斑狼疮(SLE)、干燥综合征(SS)、多肌炎/皮肌炎(PM/DM)、硬皮病(SSC)、系统性血管炎；神经肌肉疾病：多发性硬化症(MS)、重症肌无力(MG)、脱髓鞘疾病；内分泌性疾病：原发性贤上腺皮质萎缩、慢性甲状腺炎、青少年型糖尿病；消化系统疾病：慢性非特异性溃疡性结肠炎(Crohn病)、慢性活动性肝炎、恶性贫血与萎缩性胃炎；泌尿系统疾病：自身免疫性肾小球肾炎、肺肾出血性综合征；血液系统疾病：自身免疫性溶血性贫血、原发性血小板减少性紫癜 (ITP)、特发性白细胞减少症。
自身免疫性疾病的常规治疗方法有：
（1）肾上腺皮质激素：是多数自身免疫性疾病最常用的治疗药物，具有较快抑制免疫反应和较强的抗炎作用。近年采用的激素冲击疗法提高了危重症的缓解率，但是激素也有不少副作用，长期应用可以抑制下丘脑-垂体-肾上腺系统，垂体前叶分泌促肾上腺皮质激素的量明显减少，使肾上腺皮质素分泌减少，皮质腺出现萎缩，从而患者需要长期服用激素维持治疗，并且他们的应激能力减弱，容易出现感冒及各种感染，在受到外伤、冷风刺激、精神刺激、手术治疗其它疾病等应激状态时，由于体内激素的分泌不足，一方面可能诱发自身免疫性疾病发生或加重，另一方面会出现疲乏无力，食欲减退，低血糖反应，肌肉关节疼痛等肾上腺皮质分泌激素不足的症状。此外，激素还可导致肥胖、多毛、高血压、青光眼、糖尿病、消化道溃疡、出血、精神症状、骨质疏松、股骨头坏死等。
（2）免疫抑制剂：自身免疫反应对多数自身免疫性疾病的发生发展有密切关系，除激素外，临床工作中往往还需应用1－数种免疫抑制剂以控制患者病情发展。常用的免疫抑制剂有环磷酰胺、硫唑嘌呤、甲氨喋呤、霉酚酸酯等，这些药物的主要副作用有胃肠道反应、血液系统损害、泌尿系统反应、影响生育、脱发、增加肿瘤发生率等。大剂量人体免疫球蛋白静脉注射通过抗体封闭作用治疗激素和免疫抑制剂不能控制的难治性患者，国内外均有成功经验, 但此法对不同的病人疗效差异很大，也有一定的毒副作用，价格昂贵，应用受限。
（3）造血干细胞移植：尽管给予了激素和免疫抑制剂治疗，仍有不少病人病情得不到控制或不能耐受常规治疗带来的严重不良反应，这促使临床工作者不断探索新的治疗方法。造血干细胞移植（HSCT）是近十余年来发展起来的一项治疗手段，在治疗自身免疫性疾病时主要采用了自体HSCT方式，其治疗原理有两方面，一是在预处理时，通过大剂量化疗或全身照射摧毁患者的异常免疫系统，对自身免疫性疾病起缓解作用；二是移植的自体外周血干细胞以重建正常的免疫系统，在免疫重建中阻断自身抗体的产生或诱导对自身抗原的免疫耐受。根据最新统计，目前全世界有近1000例难治性自身免疫性疾病患者接受了HSCT，其中包括SSc 190例，SLE 86例，PM/DM 14例，RA 86例，MS 368例，克罗恩病21例。由于自体免疫疾病自体HSCT后仍有部分患者病情不能控制，部分病例在术后复发，加之移植治疗风险较高，相关死亡率约为7％，高于非自身免疫性疾病（3％），制约了该技术的广泛应用。移植相关死亡率与具体病种相关，从高到低依次为SSc、SLE、MS和RA；病例选择、支持治疗、预处理方案、是否去移植物中的淋巴细胞等也影响患者的存活率。
发明内容
为了解决上述问题，本发明提供了一种含有骨髓间质干细胞的注射剂，所述的注射剂可以有效的对系统性红斑狼疮、系统性硬化症、混合性结缔组织病、类风湿关节炎、多发性肌炎/皮肌炎、自身免疫性溶血性贫血、炎性肠病、白塞病、原发性胆汁性肝硬化等在内的一大类疾病有良好的治愈性。
本发明的目的在于提供一种含有骨髓间质干细胞的注射剂，其技术点在于：所述的含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成。
在本发明的有的实施例中，每1L所述血清中含有以下组分：
林格氏液 30~50mL
葡萄糖 6~10g
甘氨酸 5~10g
硒化黄芪多糖 2~5g
香菇多糖 3~6g
骨髓间质干细胞 5~9g。
在本发明的有的实施例中，所述的林格氏液为含有氯化钠、氯化钾和氯化钙的混合液，每100mL的所述林格氏液含有氯化钠850mg、氯化钠30mg、氯化钙33mg。
在本发明的有的实施例中，所述的硒化黄芪多糖的制备方法为：取5~6kg的II型黄芪多糖加入到50~60mL的脱水吡啶中，用磁力搅拌器搅拌，搅拌10~15min，然后分三次滴入含硒试剂-SeOCl2，每次滴入1~3L的SeOCl2后，充分搅拌，在常温下反应1h，分离除杂后得到所述的硒化黄芪多糖。
在本发明的有的实施例中，所述的含硒试剂-SeOCl2中含硒5~6wt％。
在本发明的有的实施例中，所述的香菇多糖的制备方法为：将香菇依次进行干燥、粉碎、浸泡、水提得到香菇多糖粗提物，然后将香菇多糖粗提物依次用氯苯、氯化钙、草酸铵、胰蛋白酶、Sevage试剂进行除蛋白，然后醇沉，最后采用丙酮进行分级沉淀，得到所述香菇多糖。
在本发明的有的实施例中，所述的骨髓间质干细胞的制备方法为：将骨髓去除残留血液，剪碎，用胶原酶消化，然后再加入胰酶消化，消化液用筛网过滤，去除未消化组织，将过滤后的消化液用磷酸缓冲液稀释，离心，获得细胞，将细胞接种于培养基内进行培养，得到大量骨髓间充质干细胞。
与现有技术相比，本发明的有益效果：
本发明的一种含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成，无毒副作用，安全性好，该注射剂由于有林格氏液的存在补充机体所需要的钠钾元素，甘氨酸可以清除机体内自由基，促进干细胞分泌因子的旁分泌作用，硒化黄芪多糖和香菇多糖可以延长干细胞分泌因子的持续作用时间，同时增强机体非特异性免疫功能。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
本发明的一种含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成。
其中，每1L血清中含有以下组分：
林格氏液 40mL
葡萄糖 8g
甘氨酸 7.5g
硒化黄芪多糖 3.5g
香菇多糖 4.5g
骨髓间质干细胞 7g。
其中，林格氏液为含有氯化钠、氯化钾和氯化钙的混合液，每100mL的所述林格氏液含有氯化钠850mg、氯化钠30mg、氯化钙33mg。
其中，硒化黄芪多糖的制备方法为：取5.5kg的II型黄芪多糖加入到55mL的脱水吡啶中，用磁力搅拌器搅拌，搅拌12.5min，然后分三次滴入含硒试剂-SeOCl2，每次滴入2L的SeOCl2后，充分搅拌，在常温下反应1h，分离除杂后得到所述的硒化黄芪多糖。
其中，含硒试剂-SeOCl2中含硒5.5wt％。
其中，香菇多糖的制备方法为：将香菇依次进行干燥、粉碎、浸泡、水提得到香菇多糖粗提物，然后将香菇多糖粗提物依次用氯苯、氯化钙、草酸铵、胰蛋白酶、Sevage试剂进行除蛋白，然后醇沉，最后采用丙酮进行分级沉淀，得到所述香菇多糖。
其中，骨髓间质干细胞的制备方法为：将骨髓去除残留血液，剪碎，用胶原酶消化，然后再加入胰酶消化，消化液用筛网过滤，去除未消化组织，将过滤后的消化液用磷酸缓冲液稀释，离心，获得细胞，将细胞接种于培养基内进行培养，得到大量骨髓间充质干细胞。
实施例2
本发明的一种含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成。
其中，每1L血清中含有以下组分：
林格氏液 30mL
葡萄糖 6g
甘氨酸 5g
硒化黄芪多糖 2g
香菇多糖 3g
骨髓间质干细胞 5g。
其中，林格氏液为含有氯化钠、氯化钾和氯化钙的混合液，每100mL的所述林格氏液含有氯化钠850mg、氯化钠30mg、氯化钙33mg。
其中，硒化黄芪多糖的制备方法为：取5kg的II型黄芪多糖加入到50mL的脱水吡啶中，用磁力搅拌器搅拌，搅拌10min，然后分三次滴入含硒试剂-SeOCl2，每次滴入1L的SeOCl2后，充分搅拌，在常温下反应1h，分离除杂后得到所述的硒化黄芪多糖。
其中，含硒试剂-SeOCl2中含硒5wt％。
其中，香菇多糖的制备方法为：将香菇依次进行干燥、粉碎、浸泡、水提得到香菇多糖粗提物，然后将香菇多糖粗提物依次用氯苯、氯化钙、草酸铵、胰蛋白酶、Sevage试剂进行除蛋白，然后醇沉，最后采用丙酮进行分级沉淀，得到所述香菇多糖。
其中，骨髓间质干细胞的制备方法为：将骨髓去除残留血液，剪碎，用胶原酶消化，然后再加入胰酶消化，消化液用筛网过滤，去除未消化组织，将过滤后的消化液用磷酸缓冲液稀释，离心，获得细胞，将细胞接种于培养基内进行培养，得到大量骨髓间充质干细胞。
实施例3
本发明的一种含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成。
其中，每1L血清中含有以下组分：
林格氏液 50mL
葡萄糖 10g
甘氨酸 10g
硒化黄芪多糖 5g
香菇多糖 6g
骨髓间质干细胞 9g。
其中，林格氏液为含有氯化钠、氯化钾和氯化钙的混合液，每100mL的所述林格氏液含有氯化钠850mg、氯化钠30mg、氯化钙33mg。
其中，硒化黄芪多糖的制备方法为：取6kg的II型黄芪多糖加入到60mL的脱水吡啶中，用磁力搅拌器搅拌，搅拌15min，然后分三次滴入含硒试剂-SeOCl2，每次滴入3L的SeOCl2后，充分搅拌，在常温下反应1h，分离除杂后得到所述的硒化黄芪多糖。
其中，含硒试剂-SeOCl2中含硒6wt％。
其中，香菇多糖的制备方法为：将香菇依次进行干燥、粉碎、浸泡、水提得到香菇多糖粗提物，然后将香菇多糖粗提物依次用氯苯、氯化钙、草酸铵、胰蛋白酶、Sevage试剂进行除蛋白，然后醇沉，最后采用丙酮进行分级沉淀，得到所述香菇多糖。
其中，骨髓间质干细胞的制备方法为：将骨髓去除残留血液，剪碎，用胶原酶消化，然后再加入胰酶消化，消化液用筛网过滤，去除未消化组织，将过滤后的消化液用磷酸缓冲液稀释，离心，获得细胞，将细胞接种于培养基内进行培养，得到大量骨髓间充质干细胞。
最后应当说明的是，以上实施例仅用以说明本发明的技术方案，而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细地说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (7)
1.一种含有骨髓间质干细胞的注射剂，其特征在于：所述的含有骨髓间质干细胞的注射剂主要由血清、林格氏液、葡萄糖、甘氨酸、硒化黄芪多糖、香菇多糖和骨髓间质干细胞混合而成。
2.根据权利要求1所述的一种含有骨髓间质干细胞的注射剂，其特征在于：每1L所述血清中含有以下组分：
林格氏液 30~50mL
葡萄糖 6~10g
甘氨酸 5~10g
硒化黄芪多糖 2~5g
香菇多糖 3~6g
骨髓间质干细胞 5~9g。
3.根据权利要求1或者2所述的一种含有骨髓间质干细胞的注射剂，其特征在于：所述的林格氏液为含有氯化钠、氯化钾和氯化钙的混合液，每100mL的所述林格氏液含有氯化钠850mg、氯化钠30mg、氯化钙33mg。
4.根据权利要求1或者2所述的一种含有骨髓间质干细胞的注射剂，其特征在于：所述的硒化黄芪多糖的制备方法为：取5~6kg的II型黄芪多糖加入到50~60mL的脱水吡啶中，用磁力搅拌器搅拌，搅拌10~15min，然后分三次滴入含硒试剂-SeOCl2，每次滴入1~3L的SeOCl2后，充分搅拌，在常温下反应1h，分离除杂后得到所述的硒化黄芪多糖。
5.根据权利要求4所述的一种含有骨髓间质干细胞的注射剂，其特征在于：所述的含硒试剂-SeOCl2中含硒5~6wt％。
6.根据权利要求1或者2所述的一种含有骨髓间质干细胞的注射剂，其特征在于：所述的香菇多糖的制备方法为：将香菇依次进行干燥、粉碎、浸泡、水提得到香菇多糖粗提物，然后将香菇多糖粗提物依次用氯苯、氯化钙、草酸铵、胰蛋白酶、Sevage试剂进行除蛋白，然后醇沉，最后采用丙酮进行分级沉淀，得到所述香菇多糖。
7.根据权利要求1或者2所述的一种含有骨髓间质干细胞的注射剂，其特征在于：所述的骨髓间质干细胞的制备方法为：将骨髓去除残留血液，剪碎，用胶原酶消化，然后再加入胰酶消化，消化液用筛网过滤，去除未消化组织，将过滤后的消化液用磷酸缓冲液稀释，离心，获得细胞，将细胞接种于培养基内进行培养，得到大量骨髓间充质干细胞。
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