CN102307587A - Apl肽用于治疗炎症性肠病和1型糖尿病的用途 - Google Patents
Apl肽用于治疗炎症性肠病和1型糖尿病的用途 Download PDFInfo
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Abstract
本发明涉及医药领域,具体是涉及源自60kDa的人类热击蛋白的APL或其类似物在制备用于治疗克罗恩病、溃疡性结肠炎和1型糖尿病的药物组合物中的用途。该肽生物分布进入胃肠道,并且还促进诱导具有克罗恩病的患者的激活的肠固有层和外周血T细胞的凋亡。此外,该肽诱导具有1型糖尿病的患者的单核细胞的凋亡。
Description
技术领域
本发明涉及医药领域,具体是涉及APL肽(改变的肽配体,Altered Peptide Ligand,简写为APL)或其类似物用于治疗炎症性肠病(例如克罗恩病和溃疡性结肠炎)和1型糖尿病的用途。
现有技术
炎症性肠病,例如克罗恩病和溃疡性结肠炎,起源于具有针对共生菌的强烈效应子功能的肠固有层T细胞的激活。然而,导致这些淋巴细胞的慢性激活的确切机理仍然不明(Balfour R(2006)Mechanismof Disease:pathogenesis of Crohn′s disease and ulcerative colitis.Nature clinical practice.Gastroenterology and Hepatology 3(7):390-407)。
大约2x104个细菌驻留在胃肠道内,这种免疫压力代表着对免疫***的巨大刺激,需要在针对致病性生物体的适当应答与无害生物体的耐受之间进行平衡。粘膜免疫***具有数种机理来避免不必要的和不受控的炎性应答,例如通过凋亡来减少激活的T细胞(Peppelenbosch MP and van Deventer SJH(2004)T cell apoptosis andinflammatory bowel disease.Gut 53:1556-1558)。
在正常状况下,免疫***迅速清除入侵的肠细菌的感染,下调先天免疫应答并治愈受损的粘膜,而不刺激效应子T细胞应答。与此相反,遗传上易感的宿主的免疫***不能引发针对共生微生物的适当的先天应答和/或产生耐受形成性免疫应答,随后激活针对共生细菌、继而针对慢性肠炎症的致病性T细胞应答(Podolsky DK(2002)Inflammatory bowel disease.N Engl J Med 347:417-29)。
因此,由于未能适当控制由环境激发剂例如急性肠感染启动的炎性过程而导致产生炎症性肠病。对T细胞凋亡的抗性、对下调性信号的应答的缺乏和持续暴露于内腔抗原和佐剂会辅助使该炎性应答持续(Mudter J and Neurath MF(2007)Apoptosis of T cells and the controlof inflammatory bowel disease:therapeutic implications.Gut56:293-303)。
克罗恩病的特征在于巨噬细胞、嗜中性粒细胞和T细胞向肠的增强的募集,这导致共刺激和粘附分子以及与TH1(T辅助细胞1,简写为TH1)细胞应答相关的促炎性细胞因子(例如白介素(IL)-6(IL-6)和肿瘤坏死因子-α(TNF-α))和与TH17(T辅助细胞17,简写为TH17)细胞应答相关的促炎性细胞因子(例如IL-12、IL-23和IL-27)的表达的增加(Balfour R(2006)Mechanism of Disease:pathogenesis ofCrohn′s disease and ulcerative colitis.Nature clinical practice.Gastroenterology and Hepatology 3(7):390-407)。
肠内的炎性细胞的数目是由细胞的募集、增殖和通过坏死或凋亡方式发生的死亡而决定的。来自正常肠粘膜的固有层T细胞易于发生激活诱导的细胞死亡(通过Fas/FasL***),其能够控制淋巴细胞的增殖(Bu P等人(2001)Apoptosis:one of the mechanisms thatmaintains unresponsiveness of the intestinal mucosal immune system.J Immunol 166:6399-6403)。然而,有数据表明:克罗恩病患者中的固有层T细胞对于细胞凋亡具有抗性,这会导致激活的效应子TH1细胞的群体的扩增,这可能引起疾病永续和慢性炎症(Boirivant M等人(1999)Lamina propria T cells in Crohn′s disease and othergastrointestinal inflammation show defective CD2 pathroute-inducedapoptosis.Gastroenterology 116:557-565)。
克罗恩病患者的粘膜T细胞中的凋亡缺陷归因于抗凋亡分子(例如Bcl-2)与促凋亡分子(例如Bax)之间的不平衡,这延长了这些细胞的生存并导致对凋亡信号的抗性(Ina K等人(1999)Resistence ofCrohn′s disease T cells of multiple apoptotic signals is associated withBcl2/Bax mucosal imbalance.J Immunol 163:1081-90;Itoh J等人(2001)Decreased Bax expression by mucosal Tcells favours resistanceto apoptosis in Crohn′s disease.Gut 49:35-41)。另一方面,Sturm和同事研究了来自患有克罗恩病、溃疡性结肠炎的患者和健康对照的粘膜T细胞的细胞周期特征。他们证明:克罗恩病患者中的粘膜T细胞具有强大的细胞扩增能力,因为相对于患有溃疡性结肠炎的患者或健康对照的粘膜细胞具有较快的细胞周期,这可能是由于激活依赖性凋亡的缺乏造成的。这些可以解释为何克罗恩病患者的粘膜含有过量的T细胞,这表示高反应性状态并且也表示缺失对共生细菌的耐受(Sturm A等人(2004)Divergent cell cycle kinetics underlies thedistinct functional capacity of mucosal T cells in Crohn′s disease andulcerative colitis.Gut 53:1624-1631)。
这些实验证据支持以下事实:克罗恩病是这样的病症,其中细胞增殖事件超过了通过凋亡方式发生的死亡,这导致活性T细胞在炎症位点的积累,这可能是该疾病的发病中的重要因素。从这个意义上讲,用于治疗该疾病的最有力的生物试剂可能是那些诱导单核细胞和T细胞凋亡的试剂,例如,针对TNFα、IL-12或IL-6受体的抗体(Lügering等人(2001)Infliximab induces apoptosis in monocytes from patientswith chronic Crohn′s disease by using it activates to caspasedependent pathroute.Gastroenterology 121:1145-57),(Stallmach等人(2004)An interleukin 12p40-IgG2b coalition protein abrogates Tcell mediated inflammation:anti-inflammatory activity in Crohn′sdisease and experimental colitis in alive.Gut 53:339-45),(Atreya R等人(2000)Blockade of interleukin 6trans-signaling suppresses T-cellresistance against apoptosis in chronic intestinal inflammation:evidence in Crohn′s disease and experimental colitis in alive.Nat Med6:583-588)。特别地,针对TNFα的抗体是在类固醇顽固性克罗恩病患者中诱导长期缓和的重要选择。
英夫利昔单抗是嵌合单克隆抗体(AcM),其包含鼠的可变区和人类免疫球蛋白G1(IgG1)分子的恒定区,该抗体以巨大的亲和性和特异性结合并中和游离的和结合的TNFα的效应(Knight DMK等人(1993)Construction and initial characterization of a mouse-humanchimeric anti-TNF antibody.Mol Immunol 30:1443-1453)。
依那西普(Etanercept)是重组蛋白,其包含融合于人类IgG1的Fc部分的人类肿瘤坏死因子受体2(TNFR2)的可溶性部分的两个单体链(Mohler KM等人(1993)Soluble tumor necrosis factor(TNF)receptors are effective therapeutic agents in lethal endotoxemia andfunction simultaneously as both TNF carriers and TNF antagonists.JImmunol 151:1548-1561)。该分子已经成功用于治疗其它炎症性疾病,例如类风湿性关节炎(RA)(Moreland LW等人(1999)Etanercepttherapy in rheumatoid arthritis.To randomized,controlled trial.AnnIntern Med 130:478-486)。然而,与英夫利昔单抗不同,依那西普对于克罗恩病没有临床上的益处。Van den Brande和同事证明:这两种药物在治疗克罗恩病时的有效性的差异是由于英夫利昔单抗诱导单核细胞和激活的固有层T细胞发生凋亡的能力(Van de Brande JMH等人(2003)Infliximab but not Etanercept induces apoptosis in laminapropria T-Lymphocytes from patients with Crohn′s disease.Gastroenterology 124:1774-1785)。依那西普不能像英夫利昔单抗一样诱导细胞凋亡,英夫利昔单抗在克罗恩病中是有效的,这是由于其促已经被证明的促凋亡效应。
使用英夫利昔单抗和其它诱导T细胞凋亡的药物治疗克罗恩病患者时获得的临床结果提示:在粘膜T细胞腔室中恢复凋亡可能是成功治疗克罗恩病的关键因素。
到目前为止,英夫利昔单抗是用于治疗克罗恩病患者的最成功的治疗法。该治疗法在治疗具有溃疡性结肠炎的患者中也取得了令人鼓舞的效果。然而,使用该治疗法产生了一些副作用,例如在这些患者中,肺结核和支原体病的发病率增加,这是因为发生了广泛的免疫抑制(Kooloos WM.(2007)Potential role of pharmacogenetics inanti-TNF treatment of rheumatoid arthritis and Crohn′s disease.Drug Discovery Today 12:125-31)。结果是,目前主要的挑战是开发能够特异性消除致病细胞而不引起广泛的免疫抑制的治疗策略。
应此目的,为了调节免疫应答而非抑制免疫应答,过去数年已经应用了抗原特异性策略。从这个意义上,已经使用了天然自身抗原性或APL肽,在诱导外周耐受机制的条件下施用(Prakken B等人(2004)Epitope-specific immunotheraphy induces immune deviation ofproinflammatory T cells in RA.PNAS 12(101):4228-33;Ben-David H等人(2005)Down-regulation of myasthenogenic T cell response by todual altered peptide ligand via CD4+CD25+-regulated events leadingto apoptosis.PNAS 102(6):2028-33;Paas-Rozner M等人(2001)Thenature of the active suppression of responses associated withexperimental autoimmune myasthenia gravis by a dual alteredpeptide ligand administered by different routes.PNAS 98(22):12642-7)。
APL是免疫原性肽的类似物,其在与干扰或修饰完成T细胞激活的必要事件的级联的T细胞受体或主要组织相容性复合物接触的必不可少的位置处具有一个或数个置换(Bielekova B and Martin R(2001)Antigen-specific immunomodulation via altered peptide ligands.J MolMed 79:552-65)。在实验上操作肽配体的内在性质的能力允许适当地改变免疫细胞应答的性质、进程和力度。
在国际专利申请号WO 2006/032216中,要求保护了源自60kDa的人类热击蛋白(简写为Hsp60)的APL肽,以及此类肽的药物组合物用于治疗RA的用途。
1型糖尿病是自身免疫器官特异性疾病,其由破坏胰腺(产生胰岛素)的β细胞的T细胞介导,导致葡萄糖代谢的失调(Brown L andEisenbarth GS(1990)Type 1diabetes:A chronic autoimmune diseaseof human,mouse,and rat.Annu Rev Immunol 8:647-79)。该疾病的临床症状在免疫***使接近80%-90%的胰腺细胞失活以后出现。目前的治疗法旨在找到安全的、特异性的和有效的方法以在胰腺细胞发生永久性损伤之前关闭自身免疫过程,以保持胰岛素的内源性产生。“耐受性的诱导”的概念已经延伸到了1型糖尿病的治疗。Irun Cohen和同事已经要求保护了人类Hsp60肽用于诊断和治疗该疾病的用途(美国专利号6682897)。
发明内容
本发明通过提供用于治疗炎症性肠病(例如克罗恩病和溃疡性结肠炎)和1型糖尿病的新的治疗选择而解决了之前提出的问题。本发明的要义在于使用源自人类Hsp60的免疫调节性APL肽或其类似物来制备用于治疗炎症性肠病和1型糖尿病的药物组合物。该肽的序列为SIDLKDKYKNIGAKLVQLVANNTNEEA,在序列表中表示为SEQ ID NO:1。
该肽促进具有克罗恩病的患者的激活的肠固有层和外周血T细胞的凋亡的诱导,引起参与疾病的发病的T细胞克隆的抑制,而不引起使用TNFα抗体时发生的非特异性免疫抑制。使用这种免疫调节性APL肽或其类似物来治疗炎症性肠病,旨在中和引起该疾病的特征性炎性过程的T细胞的克隆。
本发明的药物组合物的特征在于其高度特异性,因为中和了致病性的激活的T细胞。这极大地促成了该制备物的安全性,因为其使副作用例如引起肺结核和支原体病的机会性感染最小化,肺结核和支原体病与由于使用药物例如英夫利昔单抗而引起的广泛的免疫抑制相关,或者与瘤性过程例如由于使用氨甲蝶呤而引起的淋巴瘤的产生相关。
使用之前提及的免疫调节肽生产用于治疗炎症性肠病的药物还具有下列优点:不依赖于其通过非肠道途径(例如真皮内、皮下或静脉内)的施用,其活性物质基本上生物分布进入胃肠道:胃、小肠和结肠。另外,肽在这些器官中保持足够发挥其生物学作用的时间。如前所述,在肠疾病中,针对共生菌的效应子T细胞的不受控的激活发生于胃肠道中。该肽的生物分布和诱导致病性内腔T细胞凋亡的能力证明了使用这种APL肽来治疗克罗恩病和溃疡性结肠病的合理性。本发明的药物组合物的用途可以延伸至其它的特征在于复发-缓解发作的炎症性疾病,其中自我反应性T细胞也具有重要作用,例如1型糖尿病。
在国际专利申请WO 2006/032216中要求保护序列表中的SEQ IDNO:1的APL肽的药物制剂用于治疗RA的用途。然而,该专利申请没有要求保护也没有启示该肽可用于治疗炎症性肠病和1型糖尿病。
炎症性肠病不被认为是自身免疫疾病,因为针对自身抗原的免疫应答不负责炎症的起始和维持,并且至少到目前为止,诱因上相关的自身抗原是未知的,这与自身免疫疾病是不同的。这些疾病的起源依赖于共生菌的存在和针对共生生物体的免疫应答。支持该事实的实验证据之一是:在无菌条件下,不能诱导实验性IBD疾病,除非使肠道菌群复原(Chandran等人(2003)Inflammatory bowel disease:dysfunction of GALT and gut bacterial flora(II).Surgeon 1:125-136;Strober等人(2002)The immunology of mucosal models ofinflammation.Annu.Rev.Immunol 20:495-549)。因此,按推测,细菌抗原激发该疾病的诱导。
在美国专利号6682897中,Irun Cohen和同事揭示了人类Hsp60肽用于诊断和治疗1型糖尿病的用途。SEQ ID NO:1的序列未包括在该专利中,并且SEQ ID NO:1的肽的类似的生物活性也未被考虑到。与这些作者不同,在本发明中,我们公开了SEQ ID NO:1的肽——源自人类Hsp60的APL肽,用于诱导参与该病症的发生的致病性T细胞的凋亡的用途。
本发明的实施例首次证明了SEQ ID NO:1的肽的性质,该性质与其生物分布进入胃肠道及其诱导T细胞的致病克隆的凋亡的能力相关,这使得该肽可用于治疗克罗恩病,溃疡性结肠炎和1型糖尿病。本领域技术人员不可能基于国际专利申请号WO 2006/032216给出的要素预测本发明中要求保护的肽的新的用途。
可以通过肽合成的常规方法来产生序列为SEQ ID NO:1的肽或其类似物,并且可以通过如下文的实施例中描述的实验中诱导的免疫应答的水平和质量来评价所述肽或其类似物。
在本发明的上下文中,术语“类似物”是指包括所描述的序列(SEQID NO:1)的一个或多个衍生物但仍然保持与所描述的肽相同的生物活性的APL肽。修饰可以是置换、删除或***单一的氨基酸,优选为置换。类似物优选将包括所描述的肽的小于9个修饰,更优选小于6个修饰,再更优选小于2个修饰。
本发明的目标还在于用于治疗炎症性肠病和1型糖尿病的药物组合物,其包含序列为SEQ ID NO:1的源自人类Hsp60的APL肽或其类似物。本发明的药物组合物中的肽的量是在宿主中产生有效免疫应答的量。有效的量是所施用的引起诱导T细胞凋亡的数量,所述T细胞凋亡显著消除克罗恩病的炎症迹象并关闭胃肠道的炎性病灶,胃肠道的炎性病灶是这些疾病的进程的特征。在治疗进程中,向患者施用的药物组合物的量可以根据一些因素变化,例如,年龄、性别、一般健康状况以及一般性的免疫应答水平。
本发明还涉及治疗炎症性肠病(例如克罗恩病和溃疡性结肠炎)和1型糖尿病的方法,包括向患者施用有效量的包含序列为SEQ IDNO:1的肽或其类似物的药物组合物。
根据本发明,在治疗炎症性肠病(例如克罗恩病和溃疡性结肠炎)和1型糖尿病的过程中,通过非肠道或粘膜途径施用药物组合物。根据本发明,通过选自下列的非肠道途径施用药物组合物:真皮内途径、皮下途径、肌内途径和静脉内途径。在另一个实施方式中,通过选自下列的粘膜途径施用药物组合物:直肠途径和经口途径。由于这些疾病的性质,APL肽或其类似物可以是以灌肠剂施用的制剂的一部分或适合于通过经口途径施用的药物形式。
附图说明
图1.SEQ ID NO:1的肽对于来自具有活性克罗恩病的患者(A)和健康供体(B)的外周血单核细胞存活性的效应。不同的字母代表阴性对照(0ug/mL)与该组中评价的每个剂量的肽之间的显著性的统计上的差异。
图2是透射电子显微镜照片,其显示了在来自克罗恩病患者的外周血单核细胞中,由SEQ ID NO:1的肽诱导的凋亡。图板A和B:未经处理的细胞(阴性对照)。图板C-H:以SEQ ID NO:1的肽(40μg/mL)处理的细胞。AV:大量的空泡形成;NF:细胞核片段化;CMC:核周浓缩和染色质迁移;ICO:完整的细胞质的细胞器;AB:凋亡小体;P AB:凋亡小体的吞噬。
图3是透射电子显微镜照片,其显示了在来自克罗恩病患者的肠固有层的单核细胞中,由SEQ ID NO:1的肽诱导的凋亡。图板A和B:未经处理的细胞(阴性对照)。图板C和D:以SEQ ID NO:1的肽(40μg/mL)处理的细胞。NF:细胞核片段化;CMC:核周浓缩和染色质迁移;AB:凋亡小体。
图4.SEQ ID NO:1的肽对于来自失活的克罗恩病患者的单核细胞的存活性的效应。在X轴上:A:未以抗-CD3抗体激活的细胞;B:以抗-CD3抗体激活的细胞。不同的字母代表阴性对照(0ug/mL)与该组中评价的每个剂量的肽之间的显著性的统计上的差异。
图5是透射电子显微镜照片,其显示了在来自1型糖尿病患者的外周血单核细胞中,由SEQ ID NO:1的肽诱导的凋亡。图板A和B:未经处理的细胞(阴性对照)。图板C和D:以SEQ ID NO:1的肽(40μg/mL)处理的细胞。NF:细胞核片段化;CMC:核周浓缩和染色质迁移;AB:凋亡小体;P AB:凋亡小体的吞噬。
图6.SEQ ID NO:1的肽在Lewis大鼠中的生物分布的研究。A:静脉内途径,0.25mg/kg体重。B:静脉内途径,1mg/kg体重。C:真皮内途径,0.25mg/kg体重。D:真皮内途径,1mg/kg体重。所分析的组织是:1:肝脏;2:脾;3:肾;4:心脏;5:肺;6:颈神经节;7:腋肱神经节;8:肠系膜神经节链;9:骨盆神经节;10:甲状腺;11:胃;12:小肠;13:大肠。
实施例
实施例1.APL肽对于来自具有活性克罗恩病的患者和健康供体的外周血单核细胞的存活性的效应
通过静脉穿刺从具有克罗恩病的患者和健康供体提取血液并收集于含有抗凝溶液(柠檬酸钠123mM,磷酸二氢钠18.5mM,柠檬酸17mM和葡萄糖141.5mM)的无菌管中。将来自每位患者的血液按1∶2稀释于1X的磷酸盐缓冲的盐溶液(简写为PBS1X)中,将5mL的此溶液加入到15mL的离心管中的3mL Ficoll-PaqueTM Plus(Amersham,Biosciences AB,Sweden)中,并在1200rpm离心30分钟。提取对应于单核细胞的环。然后,以15mL PBS 1X将细胞洗涤2次,每次洗涤之后,将细胞在900rpm离心。最后,将细胞沉淀悬浮于含有10%胎牛血清并补充了青霉素(100U/mL),链霉素(100μg/mL),25mM/L HEPES和2mM L-谷氨酰胺(均获自Gibco BRL)的RPMI 1640中。使用Neubauer计数室计数来自稀释的细胞悬浮液(1∶20稀释于补充的RPMI,1∶2在台盼蓝(Boehringer Mannheim,Germany)中)的细胞。
将单核细胞以105个细胞/孔的密度接种于平底的96孔板(Costar,USA)中,终体积为100μL,一式三份地以不同浓度的APL肽(SEQ IDNO:1)(10,40和160ug/mL)处理72小时。未经处理的细胞用作基本生长对照。
使用3-(4,5-二甲基二唑-2-基)-2,5二苯基溴化四唑(MTT,Sigma,USA)方法,按照提供商描述的程序,测定APL肽对于细胞存活性的效应。MTT被存在于代谢活性细胞中的线粒体脱氢酶还原为在组织培养基中不溶的甲臜产物。通过在562nm的吸光度测定的甲臜产物的量与培养物中的活细胞的数目直接成比例。在37℃在潮湿的5%CO2空气中培养细胞72小时后,向每个孔中加入20uL MTT(5mg/mL)。然后,将平板在相同的培养条件下温育4小时。然后,加入100uL 2-丁醇溶液(20%的十二烷基硫酸钠(SDS),50%的2-丁醇和5mL 2N的盐酸),通过轻轻的吸液使每个孔中混合均匀。然后,将平板维持在37C持续振荡30分钟,以使甲臜产物完全溶解。最后,使用96孔酶标仪记录562nm处的吸光度。
使用GraphPad Prism软件程序进行统计分析。数据表示为平均值+/-SE。所用的统计学检验是Kruskal-Wallis,其是用于多重比较的非参数检验。然后,使用Dunn检验来鉴定中位数有显著性差异的组。p<0.05的值被认为是显著性的。
如图1所示,相对于未经处理的细胞,在所有的肽的剂量,APL肽处理都显著降低了来自具有活性克罗恩病的患者的外周血单核细胞的存活性(p<0.001)。然而,使用该肽进行处理未对来自健康供体的单核细胞的存活性产生影响(在实验中评价的APL肽的任何剂量都没有)。该结果说明该肽在克罗恩病患者的细胞中诱导的细胞死亡机制的特异性。这些结果是5位具有活性克罗恩病和5位健康供体的代表性结果。
实施例2.通过透射电子显微镜检查鉴定APL肽在来自克罗恩病的患者的外周血单核细胞中诱导的细胞死亡的机理
为了鉴定APL肽(在本发明中表示为SEQ ID NO:1)在来自具有活性克罗恩病的患者的外周血单核细胞中诱导的细胞死亡是否是由凋亡介导的,通过透射电子显微镜检查(TEM)分析了样品。该技术允许显示凋亡细胞的形态上的特征,这是无可反驳的发生凋亡的标准。这些特征是:电子密集的细胞核(早期染色质的核周迁移),细胞核片段化,紊乱的和完整的细胞质细胞器,巨大且可以区分的液泡,细胞表面的变化和凋亡小体中的细胞的瓦解。通过该技术也可以观察到凋亡小体被周围细胞的吞噬(White M等人(2004)A morphologicapproach to detect apoptosis based on electron microscopy.MethodsMol Biol 285:105-11)。
在存在和不存在浓度为40ug/mL的APL肽的情况下培养从具有克罗恩病的患者的外周血分离的单核细胞(10x106个细胞)72小时。未经处理的细胞用作该测定的对照。温育72小时后,使用1%的戊二醛溶液和4%多聚甲醛(在0.1M的磷酸盐缓冲液中)将样品固定1小时。然后,以PBS 1X洗涤细胞,并以2%的四氧化锇处理1小时。然后,以0.1M的cocodilate缓冲液将细胞洗涤2次,将样品在浓度渐增的醇(30%-100%)中脱水。然后,使用环氧树脂Spurr(Spurr AR(1969)A low-viscosity epoxy resin embedding medium for electronmicroscopy.J Ultrastruct Head 26(1):31-43)渗透细胞,在70℃聚合24小时。使用超微切片机(Nova,LKB)切取超细切片(40nm),并在镍架上封片。然后,使用在甲醇中过饱和的乙酸铀酰溶液将样品染色5分钟。在Electronic Microscope JEOL/JEM 2000EX(JEOL,Japan)上进行分析。
在图2中显示了来自具有活性克罗恩病的患者的单核细胞的TEM结果。如所观察到的那样,未经处理的细胞具有正常的形态(A和B)。然而,在经APL肽(SEQ ID NO:1)处理的细胞中,可以观察到凋亡过程的特征性形态变化(C-H)。特别地,可以观察到染色质的浓缩和向核周的迁移(CMC),这是凋亡过程中发生于细胞核(N)中的最早的形态变化之一。另外,在这些样品中也观察到了细胞核片段化(NF)和凋亡小体(AB)。通过细胞碎片的存在可以知道,发生了凋亡小体的吞噬(P AB)。在图2F中观察到了细胞质细胞器保持完整(ICO),其是通过凋亡发生细胞死亡的特征。这些结果证明:这种APL肽在具有活性克罗恩病的患者的单核细胞中诱导的细胞死亡是通过凋亡介导的。
通过TEM对这些患者细胞的分析还允许鉴定单核的细胞中发生凋亡的细胞群体。该结果是可能的,因为血液的不同类型的白细胞(单核细胞(monocyte)、淋巴细胞和多形核)具有不同的形态。
在单核的细胞(mononuclear cell)中,我们鉴定出淋巴细胞是发生凋亡的群体。从形态的角度来看,淋巴细胞比单核细胞(monocyte)小,也具有圆的细胞核和较少的细胞质。此外,淋巴细胞不呈现具有松散染色质或具有马蹄形的细胞核(单核细胞(monocyte)的特征)(Junqueira LC and Carneiro J(2005)Basic Histology.Sixth edition.Editorial Masson,Barcelona,Spain).
实施例3.APL肽在来自克罗恩病患者的肠固有层单核细胞中诱导的细胞死亡机理的鉴定
在知情同意的情况下获得对应于发炎的斑的肠组织的样品。将样品保持在冷的不含镁和钙的Hank平衡盐溶液(HBSS)中。使用Bull和Bookman(Bull DMK and Bookman MA(1977)Isolation andfunctional characterization of human intestinal mucosal lymphoidcells.J Clin Invest 59:966-974)描述的二硫苏糖醇/乙二胺四乙酸/胶原酶方法,按照Van Tol和同事(Van Tol EA等人(1992)The CD56adhesion molecule is the major determinant for detecting non-majorhistocompatibility complex-restricted cytotoxic mononuclear cellsfrom the intestinal lamina propria.Eur J Immunol 22:23-29)作出的修改,从这些组织中分离固有层单核细胞。
在存在和不存在APL肽(SEQ ID NO:1)(40ug/mL)的情况下,培养来自克罗恩病患者的固有层单核细胞(10x106个细胞)72小时。通过TEM进行的分析(图3)揭示:该肽通过凋亡诱导该群体中的一大部分细胞的死亡,因为在经APL肽处理的细胞中可以观察到这种类型的细胞死亡的一些形态特征(C-E),例如:染色质向核周迁移(CMC),细胞核片段化(NF)和凋亡小体(AB)。未经处理的细胞具有正常的形态(A-B)。
实施例4.来自具有失活的克罗恩病的患者的外周血单核细胞在以抗CD3抗体激活后的存活性的降低
在37℃,在5%CO2的潮湿空气中,以抗-CD3抗体(e-Biosciences)激活来自具有失活的克罗恩病的患者的外周血单核细胞72小时。加入抗-CD3抗体引起了细胞群体中T细胞的多克隆激活。以PBS IX溶液洗涤激活的淋巴细胞,然后以不同浓度(10,40和160ug/mL)的APL肽(SEQ ID NO:1)温育(1x105个细胞)1小时。在不存在抗-CD3抗体的情况下培养72小时的外周血单核细胞用作激活测定的对照(未激活的细胞)。此后,以相同浓度的APL肽培养这些细胞。
使用如实施例1描述的MTT方法测定细胞存活性。如图4A中可以观察到的那样,APL肽不降低来自具有失活的克罗恩病患者的单核细胞的存活性。然而,该肽显著降低之前经过抗-CD3抗体激活的那些细胞的存活性(B)。该结果联同实施例1和2中所示的结果(其中该肽不影响来自健康供体的单核细胞的存活性(实施例1)和淋巴细胞被鉴定为来自具有活性克罗恩病的患者的单核细胞中发生凋亡的主要群体(实施例2))表明这种APL肽(SEQ ID NO:1)能够以高度特异性诱导致病性的激活的T细胞的凋亡。
实施例5.APL肽对于来自具有1型糖尿病的患者的外周血单核细胞的存活性的影响的评价
按照实施例1的描述,通过在Ficoll-PaqueTM PLUS上离心分离来自具有1型糖尿病患者的外周血单核细胞。以APL肽(40ug/mL)处理10x106个细胞72小时。未经处理的细胞用作该测定的对照。如图5所示,以该肽处理的细胞具有之前描述的(见实施例2)发生凋亡的细胞的形态(图板C-D)。另一方面,未经处理的细胞(图板A-B)具有正常形态。该结果证明:这种APL肽诱导来自具有1型糖尿病的患者的单核细胞的凋亡。
实施例6.APL肽(SEQ ID NO:1)在Lewis大鼠中的生物分布研究
以I125同位素标记APL肽(SEQ ID NO:1),并将其以0.25mg和1mg/Kg体重的剂量通过静脉内和真皮内途径施用至Lewis大鼠。在接种肽之后4和24小时,从每个实验组处死6只动物。测定不同器官中的放射活性水平。结果表示为%放射活性剂量/克组织。
该研究表明:这种肽生物分布进入胃肠道:胃、小肠和结肠,在这些器官中保持足以发挥其生物学机制的时间。该结果支持该肽用于治疗炎症性肠病,例如克罗恩病和溃疡性结肠炎的用途。此外,该肽可用于治疗其它自身免疫病,例如1型糖尿病,因为胃肠道是诱导外周耐受的良好位点。
Claims (15)
1.序列为SEQ ID NO:1的源自人类hsp60的APL肽或其类似物在制备用于治疗炎症性肠病和1型糖尿病的药物组合物中的用途。
2.根据权利要求1的APL肽的用途,其中所述炎症性肠病选自克罗恩病和溃疡性结肠炎。
3.根据权利要求1的APL肽的用途,其中所述药物组合物包含载体或药学上可接受的赋形剂。
4.序列为SEQ ID NO:1的源自人类hsp60的APL肽或其类似物用于诱导具有炎症性肠病和1型糖尿病的患者中的T细胞的致病性克隆的凋亡的用途。
5.根据权利要求4的APL肽的用途,其中所述炎症性肠病选自克罗恩病和溃疡性结肠炎。
6.根据权利要求1的APL肽的用途,其中所述药物组合物通过非肠道或粘膜途径施用。
7.根据权利要求6的APL肽的用途,其中所述药物组合物通过选自真皮内途径、皮下途径、肌内途径和静脉内途径的非肠道途径施用。
8.根据权利要求6的APL肽的用途,其中所述药物组合物通过选自直肠途径和经口途径的粘膜途径施用。
9.治疗炎症性肠病和1型糖尿病的方法,包括:向患者施用治疗上有效量的包含序列为SEQ ID NO:1的源自人类hsp60的APL肽或其类似物的药物组合物。
10.权利要求9的治疗方法,其中所述炎症性肠病选自克罗恩病和溃疡性结肠炎。
11.权利要求9的治疗方法,其中所述药物组合物通过非肠道或粘膜途径施用。
12.权利要求11的治疗方法,其中所述药物组合物通过选自真皮内途径、皮下途径、肌内途径和静脉内途径的非肠道途径施用。
13.权利要求11的治疗方法,其中所述药物组合物通过选自直肠途径和经口途径的粘膜途径施用。
14.用于治疗炎症性肠病和1型糖尿病的药物组合物,其包含序列为SEQ ID NO:1的源自人类hsp60的APL肽或其类似物。
15.权利要求14的药物组合物,其中所述炎症性肠病选自克罗恩病和溃疡性结肠炎。
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CN115671253A (zh) * | 2021-07-30 | 2023-02-03 | 河北菲尼斯生物技术有限公司 | Se-dr亲和肽在制备治疗风湿疾病的药物中的用途 |
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WO2024017423A1 (es) * | 2022-07-22 | 2024-01-25 | Centro De Ingenieria Genética Y Biotecnología | Péptido para el tratamiento de enfermedades relacionadas con afectaciones en la apolipoproteina ai o la transtirretina |
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CN111741763B (zh) * | 2017-12-29 | 2024-06-14 | 遗传工程与生物技术中心 | 包含apl型肽的药用组合物 |
CN115671253A (zh) * | 2021-07-30 | 2023-02-03 | 河北菲尼斯生物技术有限公司 | Se-dr亲和肽在制备治疗风湿疾病的药物中的用途 |
CN115671253B (zh) * | 2021-07-30 | 2024-02-27 | 河北菲尼斯生物技术有限公司 | Se-dr亲和肽在制备治疗风湿疾病的药物中的用途 |
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