CN111447950B - 活性调节剂 - Google Patents
活性调节剂 Download PDFInfo
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- CN111447950B CN111447950B CN201880077151.3A CN201880077151A CN111447950B CN 111447950 B CN111447950 B CN 111447950B CN 201880077151 A CN201880077151 A CN 201880077151A CN 111447950 B CN111447950 B CN 111447950B
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Abstract
本发明涉及作为用于调节CD300b依赖性吞噬作用的活性的方式的活性调节剂、以及用于治疗或预防与该活性有关的疾病或病症的药剂,该活性调节剂包含CD300a结合性物质,调节巨噬细胞中的CD300b依赖性吞噬信号。
Description
技术领域
本发明涉及包含CD300a结合性物质的活性调节剂及缺血性疾病用药剂。
背景技术
以老龄化、生活习惯的欧美化等为背景,我国存在大量的缺血性疾病患者,占据死亡原因的前位,并且成为医疗经济方面的负担。缺血性疾病是由心脏、脑等脏器中的血管的一时性或持续性的栓塞或狭窄引起的急剧的血流减少导致的氧、营养缺乏状态引发的疾病,作为缺血性疾病的代表性疾病,可例举例如心肌梗塞、脑梗塞等。
已知凋亡是与机体内稳态的维持等有关的细胞死亡机制之一,发生于暴露在恶化的机体内环境、例如由上述缺血性疾病引起的氧、营养缺乏状态等之下的细胞。发生了凋亡的细胞通过被巨噬细胞等吞噬细胞识别而受到吞噬处理,被迅速除去。
巨噬细胞等通过迅速的吞噬来除去凋亡细胞,这对缺血性疾病的病理发展的抑制作出很大贡献。细胞发生了凋亡的情况下,通过引诱巨噬细胞来将凋亡细胞从体内除去(清除),可减轻周围的细胞和组织的负担。这样的凋亡细胞清除未能正常发生的情况下,凋亡细胞及其内容物蓄积在周围,从而对周围的细胞和组织造成负担,引起周边组织的损伤。如此,巨噬细胞对凋亡细胞的吞噬对于维持机体的稳态是极为重要的。
已知发生了凋亡的细胞会将磷脂酰丝氨酸(PS:phosphatidylserine)暴露在细胞表面,该磷脂酰丝氨酸在正常细胞中是存在于细胞膜内侧的磷脂。已知对于巨噬细胞等吞噬细胞,该PS介入到所谓的“吞食我(eat me)”信号中,通过由巨噬细胞识别凋亡细胞上的PS,巨噬细胞将凋亡细胞吞噬(非专利文献1、2)。
作为巨噬细胞中接收“吞食我”信号的因子之一,已知属于受体酪氨酸激酶家族的Mer酪氨酸激酶(MerTK)。MerTK通过其配体gas6和protein6与凋亡细胞表面的PS结合,从而使巨噬细胞的吞噬作用亢进。例如,有人发现由MerTK缺失小鼠制备的巨噬细胞不能吞噬凋亡细胞(非专利文献3)。
此外,也有报道称,受体家族蛋白CD300家族的成员CD300b(CLM7/LMIR5)识别凋亡细胞表面的PS作为配体,调节凋亡细胞的吞噬作用(非专利文献4)。
另一方面,关于同样是CD300受体家族的成员CD300a,本发明人报道,通过作为免疫***细胞的肥大细胞等中的CD300a与PS结合,免疫***抑制性信号的传导亢进(专利文献1),即使巨噬细胞的CD300a与PS结合,也不会促进吞噬(非专利文献5)。
现有技术文献
专利文献
专利文献1:国际公开第2013/077186号
非专利文献
非专利文献1:V.A.Fadok等,J Immunol 148,2207Apr 1,1992
非专利文献2:J.Savill,I.Dransfield,C.Gregory,C.Haslett,Nat Rev Immunol2,965,2002
非专利文献3:Nishi等,Mol.Cell.Biol.April 2014vol.34no.8 1512-1520
非专利文献4:Murakami等,Cell Death and Differentiation(2014)21,1746-1757
非专利文献5:Nakahashi-Oda等,J.Exp.Med.,209,1493-1503
发明内容
发明所要解决的技术问题
本发明阐明CD300b依赖性吞噬作用的活化控制机制,其目的是提供作为用于调节该CD300b依赖性吞噬作用的活性的方式的活性调节剂、以及用于治疗或预防与该活性有关的疾病或病症的药剂。
解决技术问题所采用的技术方案
本发明人为了阐明巨噬细胞的吞噬作用中的CD300b依赖性吞噬作用的活化控制机制反复进行了认真研究,结果得到了如下发现:通过与PS结合而活化的CD300a抑制巨噬细胞的CD300b依赖性吞噬作用。
本发明人还认为,在机体内发生缺血的情况下,CD300b依赖性吞噬作用受到CD300a的抑制,由于该缺血而发生了凋亡的细胞及其胞内物质蓄积在组织内,这成为缺血性疾病发生或恶化的原因。由此想到,可以通过使用抗CD300a抗体来调节CD300a的活性、控制CD300b依赖性吞噬作用来治疗缺血性疾病,抗CD300a抗体可以成为用于治疗缺血性疾病的工具,从而完成了本发明。
通过基于这些发现而完成的本发明,可提供例如下述[1]~[9]所示的活性调节剂及药剂。
[1]一种活性调节剂,其包含CD300a结合性物质,用于调节巨噬细胞中的CD300b依赖性吞噬信号。
[2][1]所述的活性调节剂,其中,所述CD300a结合性物质是抑制巨噬细胞中CD300a的活性的物质。
[3][1]或[2]所述的活性调节剂,其中,所述CD300a结合性物质是阻断CD300a与磷脂酰丝氨酸的结合的物质。
[4][1]~[3]中任一项所述的活性调节剂,其中,所述CD300a结合性物质是抗体或肽。
[5][1]~[3]中任一项所述的活性调节剂,其中,所述CD300a结合性物质是抗CD300a抗体。
[6][5]所述的活性调节剂,其中,所述抗CD300a抗体是CD300a中和抗体。
[7][5]或[6]所述的活性调节剂,其中,所述抗CD300a抗体是抗CD300a单克隆抗体。
[8]一种缺血性疾病用药剂,其中含有[1]~[7]中任一项所述的活性调节剂。
[9][8]所述的缺血性疾病用药剂,其中,所述缺血性疾病用药剂是用于治疗或预防选自缺血性心脏疾病、缺血性脑疾病、缺血性肠疾病、缺血性肾疾病、四肢缺血、视网膜缺血、缺血性肺疾病和脊髓缺血的一种以上的药剂。
发明的效果
通过本发明,可提供以调节与巨噬细胞的CD300b依赖性吞噬作用有关的信号传导为特征的活性调节剂及缺血性疾病用药剂。
附图说明
图1所示为参考例1中得到的流式细胞仪分析的结果。用抗MerTk抗体+对照抗体处理的细胞群的结果以圆形表示,用抗MerTk抗体+抗CD300a抗体处理的细胞群的结果以方形表示。
图2A是表示参考例2中进行肾缺血处理、进行再灌注处理24小时后的CD300afl/fl小鼠(对照小鼠)和CD300afl/flLysm-Cre小鼠中的尿素氮(BUN)和肌酐(Cre)的血清中浓度的测定值的图。图2B是表示对各小鼠进行肾缺血处理、再灌注处理后的生存率的图。
图3是参考例3中的肾缺血处理前(未处理(naive))、肾缺血处理和再灌注处理24小时后和72小时后的CD300afl/fl小鼠(对照小鼠)和CD300afl/flLysm-Cre小鼠的肾脏组织切片中的苏木精-伊红染色的染色图像,以及缺血处理和再灌注处理24小时后的TUNEL染色的染色图像。
图4是表示实施例1中进行肾缺血处理、进行再灌注处理24小时后的尿素氮(BUN)和肌酐(Cre)的血清中浓度的测定值的图。抗CD300a抗体给药组以三角形表示,非给药组以方形表示。
图5是表示参考例4中进行了短暂性脑缺血处理的CD300afl/flLysm-Cre小鼠和CD300afl/fl小鼠(对照小鼠)中的神经学发现的评分的图。
图6是表示实施例2中进行了短暂性脑缺血处理的小鼠中的神经学发现的评分的图。抗CD300a抗体给药组以方形表示,非给药组以圆形表示。
图7A是表示实施例3中进行了短暂性脑缺血处理的小鼠中的神经学发现的评分的图。抗CD300a抗体给药组以方形表示,非给药组以圆形表示。图7B是表示实施例3中制作的抗CD300a抗体给药或非给药小鼠的大脑组织标本中的苏木精-伊红染色的染色图像及其分析结果的图。
图8是表示参考例5中用CD300afl/flLysm-Cre小鼠和野生型小鼠(C57BL/6J)制作的心肌梗塞模型的生存率的图。
具体实施方式
本发明的活性调节剂及缺血性疾病用药剂的特征是,调节巨噬细胞中的CD300b依赖性吞噬信号。具体而言,涉及通过调节CD300b依赖性吞噬信号传导,利用吞噬来除去(清除)缺血部位的凋亡细胞。
下面对本发明的活性调节剂及缺血性疾病用药剂进行详细说明。
本说明书中的“缺血”是指由于血管的狭窄或栓塞、供给组织的动脉血量减少、由此导致组织的氧和营养等的缺乏状态,“缺血性部位”是指由于缺血而导致动脉血量减少、其结果是营养和氧等减少的状态的部位。
如果因缺血而发生了凋亡的细胞上的PS使得巨噬细胞表面的CD300b活化,则CD300b与作为衔接子分子的DAP12缔合。其结果是,通过DAP12的ITAM(免疫受体酪氨酸活化基序,immunoreceptor tyrosine-based activating motif)中存在的酪氨酸被磷酸化,具有SH2结构域的Syk家族激酶被募集并活化,激活其下游的PI3K/Akt通路,从而使巨噬细胞的吞噬作用亢进。
另一方面,CD300a与PS结合并活化,从而经由其胞内区的ITIM(免疫受体酪氨酸抑制基序,Immunoreceptor tyrosine-based inhibitory motif)序列来募集酪氨酸磷酸酶SHP-1。其结果是,通过阻断上述DAP12的ITAM中存在的酪氨酸的磷酸化,来抑制CD300b依赖性吞噬信号。
<活性调节剂>
本发明的”活性调节剂”的特征是,包含CD300a结合性物质,调节巨噬细胞中的CD300b依赖性吞噬信号。具体而言,本发明的活性调节剂通过该活性调节剂中所包含的CD300a结合性物质与CD300a的结合,来阻断(中和)CD300a与PS的结合,从而促进CD300b依赖性吞噬信号传导。
<CD300a结合性物质>
上述CD300a结合性物质优选是阻断巨噬细胞中CD300a的活性的物质,更优选是阻断CD300a与PS的结合的物质。阻断CD300a的活性的物质无特别限定,优选抗体或肽,更优选抗CD300a抗体。
<抗CD300a抗体>
本发明的活性调节剂中使用的抗CD300a抗体是特异性识别CD300a作为抗原的抗体。抗CD300a抗体可以是游离的抗体,也可以是直接或间接固定有其它任意物质(例如辅助药剂等)的抗体。上述活性调节剂中所含的可以是特定的一种单克隆抗体,也可以是两种以上单克隆抗体的组合(或多克隆抗体),从特异性的角度来看优选含有一种单克隆抗体。
上述抗CD300a抗体只要是发挥本发明的作用效果的抗体、即具有阻断或抑制CD300a与PS的结合的作用(中和作用)的抗体即可,无特别限定,特别优选针对CD300a的中和抗体。中和抗体可通过公知的方法制备。选择单克隆抗体作为上述抗CD300a抗体的情况下,一般通过使用CD300a的免疫、杂交瘤的制备、筛选、培养、回收的步骤来制备抗CD300a单克隆抗体。从中选择具有CD300a与PS的适当的中和作用、发挥本发明的作用效果的合适的单克隆抗体即可。
选择多克隆抗体作为上述抗CD300a抗体的情况下,作为多克隆抗体,可使用将包括抗原分子的表位在内的特定的序列部分作为免疫抗原制成的常规的多克隆抗体,但不限于此,例如也可以使用两种以上的单克隆抗体的混合物作为多克隆抗体的替代品(同等品)。另外,产生抗体的动物(免疫动物)的种类无特别限定,与以往同样地从小鼠、大鼠、豚鼠、兔、山羊、绵羊等中选择即可。
上述抗CD300a抗体只要是具有阻断或抑制CD300a与PS的结合的作用(中和作用)、发挥本发明的作用效果的抗体即可,不一定要像天然的抗体那样具有全长,也可以是抗体片段或衍生物。即,本说明书中的用语“抗体”不仅包含全长的抗体,也包含抗体片段(Fab片段或F(ab')2等)、嵌合抗体(人源化抗体等)、多功能抗体等衍生物。
<肽>
本发明中,作为CD300a结合性物质使用的肽优选是阻断巨噬细胞中CD300a的活性的肽,更优选是阻断CD300a与PS的结合的肽。例如,优选选择与CD300a特异性结合的肽,具体而言,优选能够成为CD300a的配体的、阻断巨噬细胞中CD300a的活性的肽。
<缺血性疾病用药剂>
本发明的“缺血性疾病用药剂”含有上述活性调节剂作为有效成分。通过利用该活性调节剂来促进CD300b依赖性吞噬信号传导,缺血部位中的凋亡细胞通过吞噬被迅速除去(清除),因此可抑制凋亡细胞在组织内的蓄积,能够进行缺血性疾病的治疗或预防。
另外,“治疗”不仅包括疾病或症状的治愈,也包括其缓解(减轻),“预防”不仅包括将疾病或症状防患于未然,也包括在疾病或症状治愈后防止其复发。
本发明的缺血性疾病用药剂的给药对象可以是人,也可以不是人(例如小鼠等哺乳类),优选是人,更优选是罹患有缺血性疾病或有罹患可能性的人。
本发明的缺血性疾病用药剂的对象疾病“缺血性疾病”是指由于动脉的狭窄或栓塞、组织持续缺血的状态,或者是指由该缺血引起的不良状态,而不论有无主观症状。作为缺血性疾病无特别限定,可例举例如心绞痛和心肌梗塞等缺血性心脏疾病、脑梗塞和烟雾病等缺血性脑疾病、肾衰竭等缺血性肾疾病、缺血性大肠炎和肠系膜动脉栓塞症等缺血性肠疾病、坏疽和闭塞性动脉硬化症等四肢缺血、糖尿病视网膜病变等视网膜缺血、缺血性肺疾病、脊髓缺血、或者有它们的征兆的状态等。
本发明的缺血性疾病用药剂的给药部位可根据作为给药对象的疾病或病症来选择,无特别限定。例如,可以通过向血中给药来全身性给药,也可以在发生缺血部位的粘膜下组织和***或其附近给药,也可以在发生缺血的部位直接给药。作为给药方法,口服给药、非口服给药均可,优选非口服给药,例如可进行静脉注射、皮下注射、局部注入、脑室内给药等,最优选静脉注射、即全身给药。
本发明的缺血性疾病用药剂可以单独给药,也可以和其它药剂如血栓溶解药等组合使用。
本发明的缺血性疾病用药剂的给药量无特别限定,从经济上的角度和极可能避免副作用的角度来看,在可获得需要的治疗效果的范围内越少越好。具体而言,优选根据疾病的程度、患者的体重、年龄、性别适当选择,根据改善的程度等适当增减。此外,给药次数优选为每天1次~数次。
同样地,本发明的缺血性疾病用药剂中所含的抗CD300a抗体的量也可以适当选择。例如,相对于给药的人或动物1kg为10~100mg,优选为20~50mg。
本发明的缺血性疾病用药剂的形态无特别限定,例如优选以所需的粘度和含有成分的浓度溶解或分散在稀释剂中的溶液或分散液,可以按照常规方法用滤器过滤灭菌,也可以通过掺入杀菌剂等而无菌化。此外,可以是用时配制的形态,例如也可以通过冷冻干燥法等配制成固体制剂,在使用前溶解或分散于稀释剂后再给药。
本发明的“缺血性疾病用药剂”根据需要还可以含有药学上可接受的添加剂。例如可以含有稀释剂、载体或赋形剂。
药学上可接受的添加剂只要不违反本发明的目的就没有特别限定,可例举例如稀释剂、载体、赋形剂、稳定剂、保存剂、缓冲剂、表面活性剂等乳化剂、着色剂、粘稠剂、二元醇类等溶解助剂、氯化钠和甘油等等渗剂等。
作为具体的添加剂的例子,可例举乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、***胶、磷酸钙、惰性褐藻酸类、黄蓍胶、明胶、硅酸钙、结晶纤维素、聚乙烯吡咯烷酮、纤维素、水糖浆、水、水/乙醇、水/乙二醇、水/聚乙烯、高渗盐水、乙二醇、丙二醇、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油或硬质脂肪等脂肪性物质、或者它们的合适的混合物。
可以非口服给药的形态应当是已经过灭菌的、未加入生理学上不可接受的药剂的形态,并且为了将给药时的刺激或其它副作用控制在最小限度而应当是摩尔渗透压浓度低的形态,因此溶液优选是等渗的,或者是略微高渗的,例如应当是高渗盐水(生理盐水)。
实施例
下面,基于实施例对本发明的优选方式进行更具体的说明,但本发明并不限定于这些实施例。
[参考例1]
从野生型小鼠(C57BL/6J)摘取胸腺并分离胸腺细胞,向其中加入10μM***,培养12小时以诱导凋亡,进而用pHrodo(商标)染料标记。
另一方面,摘取野生型或CD300b KO小鼠的腹腔渗出细胞,培养30分钟以使巨噬细胞贴壁在培养皿上。
将1.5×106个上述标记胸腺细胞和1.5×105个巨噬细胞在20ng/ml的抗MerTk中和抗体(2B10C42,百进生物科技公司(Biolegend))和抗CD300a抗体(TKA139,中外制药株式会社(中外製薬株式会社))的存在下、或者在20ng/ml的抗MerTk抗体(2B10C42,百进生物科技公司)和1ng/ml的对照抗体(IC17-mouse IgG1 sFc,中外制药株式会社)的存在下培养90分钟。然后,用流式细胞仪(BD FACSAria(商标),BD生物科学公司(BDバイオサイエンス社))测定抗CD11b抗体(M1/70,TONBO生物科学公司(TONBO bioscience))和抗F4/80抗体(BM8,百进生物科技公司)呈阳性的总巨噬细胞数以及pHrodo阳性细胞数。然后,算出后者相对于前者的比例,将该数值作为吞噬了凋亡细胞的巨噬细胞的比例(FlowJo(注册商标),佛罗乔有限责任公司(FlowJo LLC))。
结果示于图1。
来源于CD300b KO小鼠的巨噬细胞与WT巨噬细胞相比,凋亡细胞的吞噬率显著降低,而不论有无抗CD300a抗体。
这里,在由抗CD300a抗体中和了CD300a的细胞中,WT巨噬细胞中的凋亡细胞的吞噬率显著亢进,而CD300b KO巨噬细胞中未见吞噬率的亢进。
因此可知,由CD300b导致的巨噬细胞的吞噬作用在抗CD300a抗体的作用下亢进。
[参考例2]
通过CD300afl/fl小鼠(筑波大学生命科学动物资源中心(筑波大学生命科学動物資源センター)制)和Lysm-Cre小鼠(杰克逊实验室公司(Jackson laboratory社))的交配,制成巨噬细胞特异性的CD300a条件性基因敲除小鼠,即CD300afl/flLysm-Cre小鼠。
将8-14周龄的CD300afl/fl小鼠(对照小鼠)和CD300afl/flLysm-Cre小鼠分别在麻醉下开腹,用夹子将双侧肾动脉栓塞(肾缺血处理)。
栓塞25分钟或35分钟后,移除夹子,解除栓塞(再灌注处理),关腹。
针对各小鼠,分别测定再灌注处理24小时后的尿素氮(BUN)和肌酐(Cre)的血清中浓度。
此外,针对栓塞35分钟后进行再灌注处理的小鼠,一并进行处理后的生存率的持续观察。
结果示于图2。
由这些结果可知,在巨噬细胞中缺失CD300a的小鼠中,与对照相比,肾缺血处理后的急性肾损伤得到抑制,生存率也得以维持。
[参考例3]
将通过与参考例2同样的方法制备的CD300afl/flLysm-Cre小鼠和CD300afl/fl小鼠(对照小鼠)的双侧肾动脉分别栓塞30分钟后,通过与参考例2同样的方法进行再灌注处理。摘取再灌注处理后24小时、72小时的肾脏,按照常规方法制备组织标本,进行苏木精-伊红染色或TUNEL染色(Apoptag,密理博公司(Millipore))。
结果示于图3。可知在巨噬细胞中缺失CD300a的小鼠中,与对照相比,肾缺血处理后的组织中的凋亡得到抑制,并且凋亡细胞在组织内的蓄积也得到抑制。
[实施例1]
对野生型小鼠(C57BL/6J)经静脉给予20mg/kg的对照抗体(IC17-mouse IgG1sFc,中外制药株式会社)或抗CD300a抗体(TKA139,中外制药株式会社)。给药3小时后,通过与参考例2同样的方法进行肾缺血处理和30分钟后的再灌注处理,进而分别测定24小时后的尿素氮(BUN)和肌酐(Cre)的血清中浓度。
结果示于图4。可知通过预先给予小鼠抗CD300a抗体,可抑制肾缺血处理后的急性肾损伤。
[参考例4]
针对通过与参考例2同样的方法制备的CD300afl/flLysm-Cre小鼠和CD300afl/fl小鼠(对照小鼠),分别在麻醉下切开颈部,从颈动脉***带硅涂层的单丝导管(Doccol公司(Doccol Corporation))并留置,将右大脑中动脉栓塞(短暂性脑缺血处理),从而制成大脑中动脉栓塞(MCAO:right middle cerebral artery occlusion)模型(Shichita等,NatMed 2016)。栓塞处理60分钟后,拔去导管,使脑血流再灌注,将手术创口闭合。
此后对小鼠持续进行多天观察,针对神经学发现,参考Bederson等、Stroke 1986,基于以下神经学评分进行评价。
0:无明显症状、1:前肢弯曲、2:虽然不转圈但从侧方一推就容易倒下、3:转圈、4:强制性转圈、5:几乎动弹不得、6:死亡。
结果示于图5。可知用在巨噬细胞中缺失CD300a的小鼠制备的MCAO模型小鼠中,与用对照小鼠制备的MCAO模型小鼠相比,由脑缺血引起的神经损伤程度较轻。
[实施例2]
针对野生型小鼠(C57BL/6J),通过与参考例4同样的方法进行短暂性脑缺血处理。处理60分钟后,经静脉给予20mg/kg的对照抗体(IC17-mouse IgG1 sFc,中外制药株式会社)或抗CD300a抗体。然后,针对各小鼠中的神经学发现,基于与参考例4同样的评分进行评价。
结果示于图6。可知在给予抗CD300a抗体的小鼠组中,与给予对照抗体的小鼠组相比,由短暂性脑缺血处理引起的神经损伤程度较轻。由此提示,利用抗CD300a抗体可预防由脑梗塞等脑缺血引起的神经损伤。
[实施例3]
针对野生型小鼠(C57BL/6J),通过与参考例4同样的方法进行短暂性脑缺血处理。处理3小时后,选择上述神经学评分为3(转圈)的小鼠,分别经静脉给予20mg/kg的对照抗体或抗CD300a抗体,针对随后的神经学发现,基于参考例4所示的神经学评分进行评价。
在抗CD300a抗体给药后第5天处死小鼠,摘取大脑,制备大脑组织标本,进行苏木精-伊红染色,用光学显微镜(基恩士公司(keyence社))观察,测量梗塞区域的面积。
结果示于图7。可知在给予抗CD300a抗体的小鼠组中,与给予对照抗体的小鼠组相比,神经学评分得到大幅改善,并且由染色结果可知,梗塞区域的面积显著减小。
由此提示,利用抗CD300a抗体可治疗由脑梗塞等脑缺血引起的神经损伤。
[参考例5]
针对通过与参考例2同样的方法制备的CD300afl/flLysm-Cre小鼠和野生型小鼠(C57BL/6J),分别在全身麻醉后进行呼吸机辅助下的开胸,用6-0PROLENE(注册商标)线结扎左冠状动脉左前降支,从而制成心肌梗塞模型(Mahmoud等,Nat Prot 2014)。术后1周后,通过多普勒超声心动图确认梗塞灶,针对确认有梗塞灶的小鼠观察随后的生存率。
结果示于图8。可知用在巨噬细胞中缺失CD300a的小鼠制备的心肌梗塞模型小鼠与用对照小鼠制备的心肌梗塞模型小鼠相比,生存率显著提高。
Claims (3)
1.包含CD300a结合性物质、用于调节巨噬细胞中的CD300b依赖性吞噬信号的活性调节剂在缺血性疾病用药剂的制备中的应用,
其中,所述CD300a结合性物质是CD300a中和抗体。
2.如权利要求1所述的应用,其中,所述缺血性疾病用药剂是用于治疗或预防选自缺血性心脏疾病、缺血性脑疾病、缺血性肠疾病、缺血性肾疾病、四肢缺血、视网膜缺血、缺血性肺疾病和脊髓缺血的一种以上的药剂。
3.如权利要求1或2所述的应用,其中,所述CD300a结合性物质是抗CD300a单克隆抗体。
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