CN112870368A - 通过抑制tl1a的功能和相关信号传导途径来减轻并逆转纤维化和炎症 - Google Patents
通过抑制tl1a的功能和相关信号传导途径来减轻并逆转纤维化和炎症 Download PDFInfo
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Abstract
本发明涉及治疗纤维化和炎性肠病的方法。在一个实施方案中,本发明通过向个体施用治疗有效剂量的TL1A抑制剂和/或DR3抑制剂治疗肠炎症。在另一实施方案中,本发明提供一种通过抑制TL1A‑DR3信号传导功能逆转个体的组织纤维化的方法。
Description
本申请是申请日为2014年03月27日、申请号为201480030128.0、发明名称为“通过抑制TL1A的功能和相关信号传导途径来减轻并逆转纤维化和炎症”的中国专利申请(其对应PCT申请的申请日为2014年03月27日、申请号为PCT/US2014/032054)的分案申请。
发明领域
本发明提供用于治疗和诊断与TL1A功能及纤维化相关的病症的方法和组合物。
背景技术
本文所有出版物以引用的方式并入,其程度如同每个单独出版物或专利申请被具体地且单独地指出是以引用的方式并入那样。下列描述包括可用于理解本发明的信息。不是承认本文提供的任何信息为现有技术或与目前要求保护的发明相关,或者任何明确或含蓄引用的出版物为现有技术。
克罗恩氏病(CD)是具有诸如补丁型透壁性炎症和纤维狭窄的病理学特征的慢性炎性病症。尽管采用有效的抗炎治疗,仍有高达20%的CD患者会发展为需要手术干预的组织并发症。调节纤维化的途径可能不同于介导炎症的那些途径。TL1A,TNF超家族的成员,与死亡结构域受体3(DR3)结合并调节适应性免疫应答。TL1A可能与CD、肠道纤维狭窄和较大手术需要有关。需要新型且有效的用于治疗与TL1A/DR3信号传导途径(signalingpathway)相关的疾病、CD以及相关并发症的疗法,包括用于逆转已形成的纤维化的疗法。
发明概述
本文各种实施方案包括治疗受试者的纤维化(fibrosis)的方法,其包括提供包含一种或多种TL1A功能抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在其它实施方案中,所述组合物包含一种或多种TL1A阻断抗体。在另一实施方案中,所述组合物包含一种或多种Dr3阻断抗体。在另一实施方案中,所述组合物包含一种或多种通过直接与TL1A结合而抑制TL1A功能的化合物。在另一实施方案中,所述组合物包含一种或多种Ifnγ(Ifngamma,干扰素γ)、IL17(白细胞介素17)、Ctgf(结缔组织生长因子)和IL31Ra(白细胞介素31受体a)的抑制剂。在另一实施方案中,所述组合物包含一种或多种Tgfβ(Tgfbeta1,转化生长因子)和Igf1(胰岛素样生长因子)的抑制剂。在另一实施方案中,所述组合物包含一种或多种IL31信号传导(signaling)的抑制剂。在另一实施方案中,施用治疗有效剂量的所述组合物使得纤维化逆转到发炎前水平。在另一实施方案中,所述纤维化为结肠纤维化。在另一实施方案中,施用治疗有效剂量的所述组合物进一步导致对受试者的肠炎症的抑制。
其它实施方案包括治疗受试者的疾病的方法,其包括提供包含IL31Ra信号传导的抑制剂的组合物,并向所述受试者施用有效剂量的所述组合物。在另一实施方案中,所述疾病为TL1A相关疾病。在另一实施方案中,所述疾病为炎性肠病(IBD)。在另一实施方案中,所述疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述疾病为小肠和大肠纤维狭窄(fibrostenosis)。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述组合物包含一种或多种TL1A抗体。在另一实施方案中,所述组合物包含一种或多种IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1信号传导的抑制剂。
其它实施方案包括诊断受试者对TL1A相关疾病的易感性的方法,其包括从所述受试者获得样本,分析所述样本以确定是否存在相对于正常个体来说是高水平的IL31Ra表达,和根据相对于正常个体来说是高水平的IL31表达的存在来诊断对所述TL1A相关疾病的易感性。在另一实施方案中,所述TL1A相关疾病为炎性肠病(IBD)。在另一实施方案中,所述TL1A相关疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述TL1A相关疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述TL1A相关疾病为纤维化。在另一实施方案中,所述方法进一步包括确定相对于正常个体的IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1的高水平表达的存在。
各种实施方案包括诊断受试者的TL1A相关疾病的方法,其包括从所述受试者获得样本,分析所述样本以确定是否存在与所述TL1A相关疾病有关的一种或多种危险变体和/或标志物,和根据与所述TL1A相关疾病有关的一种或多种危险变体和/或标志物的存在来诊断所述TL1A相关疾病。在另一实施方案中,所述一种或多种危险变体和/或标志物包括高表达的IL31RA。其它实施方案包括一种或多种危险变体和/或标志物,所述危险变体和/或标志物包括高表达的IFNγ、IL17、Ctgf、TgfB1和/或Igf1。在另一实施方案中,所述TL1A相关疾病为炎性肠病(IBD)。在另一实施方案中,所述TL1A相关疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述TL1A相关疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述TL1A相关疾病为纤维化。在另一实施方案中,所述方法进一步包括通过施用一种或多种TL1A抑制剂治疗所述TL1A相关疾病。在另一实施方案中,所述方法进一步包括通过施用TL1A抑制剂治疗所述TL1A相关疾病。在另一实施方案中,所述受试者为人。在另一实施方案中,所述方法进一步包括通过施用Dr3抑制剂治疗所述TL1A相关疾病。
其它实施方案包括治疗受试者的纤维化的方法,其包括提供包含TL1A抑制剂和DR3抑制剂的组合物,和向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述TL1A抑制剂为TL1A抗体。
其它实施方案包括逆转受试者的纤维化的方法,其包括提供包含TL1A抑制剂和DR3抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述组合物进一步包含IFNγ、IL17、Ctgf和/或IL31RA信号传导功能的抑制剂。
各种实施方案包括治疗炎症的方法,其包括提供包含TL1A抑制剂和/或DR3抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述组合物进一步包含IFNγ、IL17、Ctgf和/或IL31RA信号传导功能的抑制剂。
其它实施方案包括治疗受试者的疾病的方法,其包括抑制Ifnγ和Il-17表达,下调Tgfβ信号传导,和/或减少成纤维细胞/肌成纤维细胞,并治疗所述受试者。在另一实施方案中,所述疾病为炎性肠病。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述疾病为肠炎症。在另一实施方案中,所述疾病为与炎性肠病相关的并发症。
其它实施方案包括包含一种或多种TL1A、DR3和IL31RA信号传导功能的抑制剂和药学上可接受的载体的组合物。在另一实施方案中,所述一种或多种TL1A抑制剂为TL1A抗体。在另一实施方案中,所述一种或多种DR3抑制剂为DR3抗体。
本文的各种实施方案包括治疗与IBD相关的并发症的方法,其包括提供包含TL1A、DR3和IL31RA信号传导功能的抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,将所述组合物静脉内施用至所述受试者。
附图简述
示例性实施方案示于附图。预期本文公开的实施方案和附图被认为是说明性的而不是限制性的。
根据本文实施方案,图1描述Tl1a Ab减少结肠疾病特征。(A)用于过继转移模型的Tl1a Ab处理示意图;基线Rag-/-对照小鼠(Rag Co),基线野生型对照小鼠(WT Co),预处理组(Pre-Tx),同种型抗体组(Iso Ab),处理后组(Post-Tx)。(B)在Iso和Tl1aAb处理组之间比较DAI。(C)显示带有定量炎症评分(右图)的结肠代表性大体形态(左图)。将数据表示为平均值±SD。(D)将总数量的单核细胞从MLN和LPMC中分离。每一个实心圆代表一只独立的小鼠。将Tl1a Ab处理组与Pre-Tx和Iso Ab组比较。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图2描述Tl1a Ab处理逆转已形成的结肠炎症。(A)放大200倍的代表性H&E染色的中部结肠切片。(B)对过继转移模型的定量组织学评分。对至少20个独立视野进行评分并且将数据表示为平均值±SD。(C)测量髓过氧化物酶活性并表示为每克(g)结肠蛋白提取物的活性单位(u)。每一个实心圆代表一只独立的小鼠。将Tl1a Ab处理组与基线Rag Co、Pre-Tx和Iso Ab实验组相比较。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图3描述Tl1a Ab减少Th-1和-17免疫应答。(A)显示对于MLN(上图)和LPMC(下图)的染色用于细胞内Ifnγ和Il17表达的分类的CD4+细胞的代表性流式细胞术曲线。定量了对于MLN(B)和LPMC(C)的CD4+Il17+、CD4+Ifnγ+和CD4+Il17+Ifnγ+T-细胞的百分比。用抗-CD3和抗-CD28刺激从MLN和LPMC分离的单核细胞并通过ELISA(酶联免疫吸附测定)评估分泌的Il17(D)和Ifnγ(E)水平。每一个实心圆代表从一只独立的小鼠获得的值。将Tl1a Ab处理组与Pre-Tx和Iso Ab实验组相比较。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图4描述在过继转移模型中利用Tl1a Ab治疗对已形成的纤维化的逆转。(A)放大200倍下在中部结肠组织切片中胶原蛋白沉积的代表性天狼猩红染色。黑色箭头表示胶原蛋白沉积的厚度。(B)显示来自中部结肠切片的波形蛋白(绿色)和αSMA(红色)的代表性免疫荧光染色。橙色箭头表示共表达波形蛋白和αSMA的肌成纤维细胞。显示来自所述中部结肠切片的胶原蛋白厚度(C)的定量和激活的成纤维细胞(D)的百分比并表示为平均值±SD。每组至少对20个独立的视野进行评分。将Tl1a Ab处理组与基线RagCo、Pre-Tx和Iso Ab实验组相比较。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图5描述Dr3缺失的肠道成纤维细胞的增殖减少。(A)小鼠Dr3内源基因座和基因靶向策略的示意图。(B)显示Dr3基因型的代表性聚合酶链式反应,目标(Dr3 KO)带在506bp水平,且内源Dr3基因座在353bp水平。(C)表示从同窝WT和Dr3-/-结肠中重新获得的肠道成纤维细胞的6张照片(左图)以及绘制了每一结肠的个体总成纤维细胞(右图)。(D)显示自WT和Dr3-/-小鼠的增殖的成纤维细胞(上图)和正在经历细胞凋亡的成纤维细胞(下图)的定量的代表性细胞计数直方图。CellTrace Violet(细胞示踪紫色)荧光强度下降表明增殖。膜联蛋白V染色增强表明细胞凋亡。所示出的为具有相似结果的至少6个独立实验的代表性流式细胞计数直方图。***p<0.001。
根据本文实施方案,图6描述肠道成纤维细胞表达Dr3并响应Tl1a刺激。(A)在WT中检测到Dr3 mRNA而在Dr3-/-成纤维细胞中未检出(上)。ND=未检出。WT成纤维细胞的免疫荧光染色显示阳性Dr3染红色(下)。(B)原发肠道成纤维细胞用Dr3、αSMA和波形蛋白染色。如图所示将αSMA阳性和阴性成纤维细胞分类并在αSMA+WT中发现Dr3染色而在Dr3-/-和αSMA阴性细胞中未发现。显示的数据代表具有相似结果的至少3个独立实验。(C)Col1a2和Il31Ra mRNA在WT原发肠道成纤维细胞内的表达随Tl1a刺激(0-200ng/mL)增加并表示为平均值±SD。(D)Tl1a在WT和Dr3-/-肠道中对Col1a2和Il31Ra mRNA的相对诱导,并表示为平均值±SD。*p<0.05。
根据本文实施方案,图7描述由于长期的DSS施用Tl1a Ab降低炎性疾病活性。(A)在同种型Ab(n=14)和Tl1a Ab(n=9)处理组之间比较DAI。(B)显示带有定量的炎症评分(右图)的结肠的代表性大体形态(左图)。将数据表示为平均值+/-SD。(C)将总数量的单核细胞从MLN和LP中分离。每一个填充符号代表一只独立的小鼠。将Tl1a Ab处理组与Pre-Tx和Iso Ab组相比较。*P<0.05,**P<0.01,***P<0.001。
根据本文实施方案,图8描述Tl1a Ab逆转在长期DSS模型中已形成的结肠炎症。(A)显示代表性的H&E染色的放大200倍的中部结肠切片。(B)对来自至少20个独立的中部结肠视野的组织学炎症的定量进行评分并将数据表示为平均值+/-SD。(C)测量髓过氧化物酶活性并表示为每克(g)结肠蛋白提取物的活性单位(u)。将Tl1a Ab处理组与基线WT Co、Pre-Tx、和Iso Ab实验组相比较。每一个实心圆代表来自独立结肠的MPO活性。*P<0.05,**P<0.01,***P<0.001。
根据本文实施方案,图9描述Tl1a Ab减少在长期DSS结肠炎模型中的Th-1和-17免疫应答。(A)来自(上图)和LPMC(下图)的对于细胞内Ifnγ和Il17染色的分类的CD4+细胞的代表性流式细胞术曲线。定量了对于MLN(B)和LPMC(C)的CD4+Il17+、CD4+Ifnγ+和CD4+Il17+Ifnγ+T-细胞的百分比。(C)用抗-CD3ε和抗-CD28刺激来自MLN和LPMC的分离的单核细胞并通过ELISA评估分泌的Il17(D)和Ifnγ(E)的水平。每一个实心圆代表从一只独立的小鼠获得的值。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图10描述在长期DSS结肠炎模型中利用Tl1a Ab逆转已形成的纤维化。显示放大200倍下在中部结肠组织切片中胶原蛋白沉积的代表性天狼猩红染色。黑色箭头表示胶原蛋白沉积的厚度。(B)显示来自中部结肠切片的波形蛋白(绿色)和αSMA(红色)的代表性免疫荧光染色。橙色箭头表示共表达波形蛋白和αSMA的肌成纤维细胞。显示来自所述中部结肠切片的胶原蛋白厚度(C)的定量和激活的成纤维细胞(D)的百分比并表示为平均值±SD。每组至少对20个独立的视野进行评分。*p<0.05,**p<0.01,***p<0.001。
根据本文实施方案,图11描述Tl1a Ab减少肌成纤维细胞数量和Dr3和Tl1a的表达。显示了放大630倍的来自所述过继转移模型(a)和长期DSS模型(b)的中部结肠切片的波形蛋白(绿色)和αSMA(红色)的代表性免疫荧光染色。橙色箭头表示共表达波形蛋白和αSMA的肌成纤维细胞。对于过继转移模型(a,右图)和长期DSS模型(b,右图),定量来自所述中部结肠切片的肌成纤维细胞的百分比并表示为平均值±SD。对于(a)和(b),每组对至少10个独立的视野进行评分。显示来自所述过继转移模型(c)和长期DSS模型(d)的中部结肠切片的波形蛋白(绿色)和Dr3(红色)的代表性免疫荧光染色。(c)和(d)的插图为需要放大200倍的图像的较大视图。每组对至少8个独立的视野定量,且绘图为每个高倍视野(HPF)的Dr3+细胞。定量结肠Dr3(e)和Tl1a(f)mRNA并显示为平均值±SD(n=5-14)。将Tl1a Ab处理组与基线Rag Co、Wt Co、Pre-Tx和Iso Ab实验组相比较。*P<0.05,**P<0.01,***P<0.001。特别地,图11(c)和(d)显示,与Tl1a Ab处理组(与较低胶原蛋白沉积相关)相比,在预处理和同种型抗体组(两者都与较高胶原蛋白沉积相关)中成纤维细胞上的Dr3染色增加。此外,图11(e)和(f)通过RT-PCR表达分析显示,与同种型组(与较高胶原蛋白沉积相关)相比,Tl1a和Dr3在Tl1a Ab组(与较低胶原蛋白沉积相关)中的表达均被下调。
根据本文实施方案,图12描述Dr3缺失降低肠道成纤维细胞。(a)上图显示了放大100倍下带有炎症定量的代表性H&E染色的结肠。中间图显示了放大200倍下每个HPF带有成纤维细胞定量的代表性波形蛋白/αSMA染色的结肠(插图为放大200倍的较大视图)。显示了从同窝WT和Dr3-/-结肠中重新获得的肠道成纤维细胞和每个结肠各自总成纤维细胞的代表性照片(a,下图)。显示了来自WT和Dr3-/-小鼠的增殖的成纤维细胞(b)和正在经历细胞凋亡的成纤维细胞(c)的代表性细胞计数直方图。下降的CellTrace Violet荧光强度表明增殖。增强的膜联蛋白V染色表明细胞凋亡。显示至少6个独立实验的代表性细胞计数直方图具有相似结果。*P<0.05,**P<0.01,***P<0.001。特别地,关于12(a),上图显示组织学炎症在野生型和Dr3KO结肠之间没有差异,说明它不是引起Dr3KO结肠中成纤维细胞数量减少的根本炎症。12(a)中间显示,在结肠切片中直接染色时在Dr3缺失结肠中波形蛋白阳性细胞减少(图12a,中图),这对于说明在从所述结肠分离成纤维细胞之前成纤维细胞减少在所述结肠已经预先存在非常重要。
根据本文实施方案,图13描述肠道成纤维细胞表达Dr3并响应Tl1a刺激。(a)原发肠道成纤维细胞用Dr3、αSMA和波形蛋白染色并通过流式细胞术进行分析。如图所示,将αSMA高表达、αSMA中表达和αSMA低表达的成纤维细胞分类,并且Dr3染色以αSMA高>中>低的顺序优先被发现。进行三个独立实验。特别地,图13(a)显示在Dr3表达和αSMA表达之间有直接关联。这对于说明具有较高αSMA表达的成纤维细胞(更活跃的成纤维细胞)具有较高(Dr3表达)非常重要,表明这些更活跃的成纤维细胞更容易接受Tl1a信号转导。对于这个实验,本发明人将αSMA低、中和高表达的肌成纤维细胞分别分类然后展示表达Dr3的细胞的比例(图13a)。该图表明Dr3在成纤维细胞中的表达存在αSMA高>αSMA中>αSMA低的顺序。(b)数据代表放大200倍下3个独立分类的αSMA阳性肌成纤维细胞。在WT有Dr3的共染色,而在Dr3缺失αSMA阳性肌成纤维细胞中没有。特别地,图13(b)直接表明Dr3(Tl1a受体)在肌成纤维细胞上表达。这对于说明介导纤维化的肌成纤维细胞可以接收来自Tl1a的信号转导非常重要。为了进行这个实验,本发明人将用抗-αSMA和DR3抗体染色的αSMA阳性细胞分类。然后他们使用免疫荧光显微术表明Dr3在αSMA阳性WT上表达而不是在DR3 KO肌成纤维细胞上(图13b)。(c)显示Col1a2和Il31Ra mRNA在WT初生肠道成纤维细胞中的表达随Tl1a刺激(0-200ng/mL)增加而增加,并表示为平均值±SD(n=3)。(d)显示通过Tl1a、Tgfβ/Igf1和Tnfα在WT和Dr3-/-肠道中对Col1a2和Il31Ra mRNA的诱导并表示为平均值±SD(n=3)。*P<0.05,**P<0.01。特别地,图13(d)显示附加实验以增强所述体外实验(图13d)。本发明人使用Tgfβ和Igf1作为原型成纤维细胞生长因子并表明Col1a2和Il31Ra表达的诱导在WT和Dr3缺失原发肠道成纤维细胞之间没有差异(图13d)。他们使用Tnfα作为所述原型促炎刺激并表明,比较WT和Dr3缺失原发肠道成纤维细胞发现Col1a2和Il31Ra的诱导没有差异。这与使用Tl1a的刺激形成对照,在Tl1a刺激中,与在Dr3缺失原发肠道成纤维细胞中相比,在WT中有明显的Col1a2和Il31Ra表达的诱导。
发明描述
本文中引用的全部参考文献以引用的方式整体并入,如同全文引用一般。除非另外限定,否则本文所用的技术和科学术语都具有与本发明所属领域普通技术人员通常理解的含义相同的含义。下述文献向本领域技术人员提供了对本申请中使用的很多术语的一般指导:Singleton等人,微生物学与分子生物学词典第4版,约翰.威利出版社(纽约,NY2012)(Singleton et al.,Dictionary of Microbiology and Molecular Biology4th ed.,J.Wiley&Sons(New York,NY 2012));高等有机化学-反应、机理与结构第5版,约翰.威利出版社(纽约,NY 2001)(March,Advanced Organic Chemistry Reactions,Mechanisms andStructure 5th ed.,J.Wiley&Sons(New York,NY 2001));以及Sambrook和Russel,分子克隆实验指南第4版,冷泉港出版社(冷泉港,NY 2012)(Sambrook and Russel,MolecularCloning:A Laboratory Manual 4th ed.,Cold Spring Harbor Laboratory Press(ColdSpring Harbor,NY 2012))。本领域技术人员将会意识到与本文描述的方法和材料类似或等效的许多方法和材料,这些方法和材料可以用在本发明的实践中。事实上,本发明决不限于所述的方法和材料。
如本文所公开,肠道纤维狭窄是严重的克罗恩氏病的特征。具有某些TNFSF15变体的患者会过表达TL1A并具有较高在小肠中形成狭窄的风险。此外,具有持续Tl1a表达的小鼠在致结肠炎(colitogenic)条件下会导致小肠和大肠纤维狭窄。本发明人研究了中和Tl1a功能是否可以逆转已形成的鼠类结肠炎和结肠纤维化。
如本文进一步所公开,向已经患有慢性鼠类结肠炎和结肠纤维化的小鼠施用Tl1a阻断抗体(12F6A)或同型对照Ig(免疫球蛋白)。产生具有Dr3缺失(Dr3-/-)的小鼠。将原发(primary)鼠类肠道成纤维细胞分离。使用组织学和免疫荧光染色、流式细胞术、ELISA和mRNA水平比较炎症和纤维化的程度。使用CellTrace(细胞示踪)和膜联蛋白V(Annexin V)染色分别确定细胞增殖和细胞凋亡。本发明人发现使用Tl1a抗体的治疗减轻了鼠类结肠炎并使结肠纤维化恢复到最初的发炎前水平。这可能是由于降低的Ifnγ、Il17、Ctgf、Il31Ra表达和Tgfβ1和Igf1信号传导的下调。此外,阻断Tl1a功能会导致成纤维细胞和肌成纤维细胞数量减少。原发肠道肌成纤维细胞表达Dr3并且可以通过增加胶原蛋白和Il31Ra表达在功能上响应直接Tl1a信号传导。总之,TL1A信号传导的调节抑制肠炎症和纤维化。
在一个实施方案中,本发明提供治疗受试者的疾病的方法,其包括提供包含IL31信号传导抑制剂的组合物,并向所述受试者施用有效剂量的所述组合物。在另一实施方案中,所述疾病为TL1A相关疾病。在另一实施方案中,所述疾病为炎性肠病(IBD)。在另一实施方案中,所述疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述组合物包含一种或多种TL1A抗体。在另一实施方案中,所述组合物包含一种或多种IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1信号传导的抑制剂。
在另一实施方案中,本发明提供治疗受试者的疾病的方法,其包括提供包含IL31Ra信号传导抑制剂的组合物,并向所述受试者施用有效剂量的所述组合物。在另一实施方案中,所述疾病为TL1A相关疾病。在另一实施方案中,所述疾病为炎性肠病(IBD)。在另一实施方案中,所述疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述组合物包含一种或多种TL1A抗体。在另一实施方案中,所述组合物包含一种或多种IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1信号传导的抑制剂。在另一实施方案中,施用治疗有效剂量的所述组合物降低受试者的成纤维细胞和/或肌成纤维细胞的数量。
在一个实施方案中,本发明提供诊断受试者对TL1A相关疾病的易感性的方法,其包括从所述受试者获得样本,分析所述样本以确定相对于正常个体的高水平的IL31表达的存在或不存在,并根据所述相对于正常个体的高水平的IL31表达的存在来诊断对所述TL1A相关疾病的易感性。在另一实施方案中,所述TL1A相关疾病为炎性肠病(IBD)。在另一实施方案中,所述TL1A相关疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述TL1A相关疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述TL1A相关疾病为纤维化。在另一实施方案中,所述方法进一步包括确定相对于正常个体而言存在IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1的高水平表达。
一种诊断受试者对TL1A相关疾病的易感性的方法,其包括从所述受试者获得样本,分析所述样本以确定相对于正常个体的高水平的IL31Ra表达的存在或不存在,并根据所述相对于正常个体的高水平的IL31RA表达的存在诊断对所述TL1A相关疾病的易感性。在另一实施方案中,所述TL1A相关疾病为炎性肠病(IBD)。在另一实施方案中,所述TL1A相关疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述TL1A相关疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述TL1A相关疾病为纤维化。在另一实施方案中,本发明进一步包括确定相对于正常个体而言存在胶原蛋白、IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1的高水平表达。
在另一实施方案中,本发明提供诊断受试者的TL1A相关疾病的方法,其包括从所述受试者获得样本,分析所述样本以确定与所述TL1A相关疾病相关的一种或多种危险变体和/或标志物的存在或不存在,并根据所述一种或多种与所述TL1A相关疾病相关的危险变体和/或标志物的存在来诊断所述TL1A相关疾病。在另一实施方案中,所述一种或多种危险变体和/或标志物包括高表达的IL31RA。在另一实施方案中,所述一种或多种危险变体和/或标志物包括高表达的IFNγ、IL17、Ctgf、TgfB1和/或Igf1。在另一实施方案中,所述TL1A相关疾病为炎性肠病(IBD)。在另一实施方案中,所述TL1A相关疾病与在小肠形成的狭窄和/或肠炎症相关。在另一实施方案中,所述TL1A相关疾病为小肠和大肠纤维狭窄。在另一实施方案中,所述TL1A相关疾病为纤维化。在另一实施方案中,所述方法进一步包括通过施用一种或多种TL1A抑制剂治疗所述TL1A相关疾病。在另一实施方案中,所述方法进一步包括通过施用TL1A抑制剂治疗所述TL1A相关疾病。在另一实施方案中,所述受试者为人。在另一实施方案中,所述方法进一步包括通过施用Dr3抑制剂治疗所述TL1A相关疾病。
如本文所公开,在两种不同的慢性结肠炎模型中,已显示Tl1a Ab(Tl1a抗体)改善结肠炎疾病并且逆转肠道纤维化。TL1A信号传导的调节可通过治疗肠炎症和纤维化改变克罗恩氏病的自然发展过程(natural history)。阻断TL1A/DR3信号传导途径提供了治疗克罗恩氏病及其相关并发症的治疗方法,包括逆转已形成的纤维化。
在一个实施方案中,本发明提供一种治疗受试者炎性肠病(IBD)相关的纤维化的方法,诊断受试者的纤维化,然后施用一种或多种TL1A-DR3信号传导功能的抑制剂,诸如施用治疗有效的TL1A抗体,或者,使DR3表达缺失,或使编码TL1A表达(TNFSF15表达)的dsRNA或siRNA缺失。或者,在其它实施方案中,通过抑制一种或多种TL1A-DR3的下游分子。
在一个实施方案中,本发明提供通过向所述受试者施用包含治疗有效剂量的TL1A抑制剂和/或DR3抑制剂的组合物来治疗疾病的方法。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述疾病为炎性肠病。在另一实施方案中,所述疾病为克罗恩氏病。在另一实施方案中,所述疾病为结肠炎。在另一实施方案中,所述受试者为人。在另一实施方案中,所述TL1A抑制剂为TL1A抗体。在另一实施方案中,所述DR3抑制剂为DR3抗体。
在另一实施方案中,本发明提供通过向所述受试者施用包含治疗有效剂量的TL1A抑制剂和/或DR3抑制剂的组合物来逆转个体的纤维化的方法。
在另一实施方案中,本发明提供治疗受试者的纤维化的方法,其包括提供包含一种或多种TL1A-DR3信号传导功能的抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述组合物包含一种或多种TL1A阻断抗体。在另一实施方案中,所述组合物包含一种或多种Dr3阻断抗体。在另一实施方案中,所述组合物包含一种或多种通过直接与TL1A结合而抑制TL1A功能的化合物。在另一实施方案中,所述组合物包含一种或多种Ifnγ、IL17、Ctgf和IL31Ra的抑制剂。在另一实施方案中,所述组合物包含一种或多种Tgfβ和Igf1的抑制剂。在另一实施方案中,所述组合物包含一种或多种IL31信号传导抑制剂。在另一实施方案中,施用治疗有效剂量的所述组合物使得纤维化恢复到发炎前水平。在另一实施方案中,所述纤维化为结肠纤维化。在另一实施方案中,施用治疗有效剂量的所述组合物进一步导致对所述受试者的肠炎症的抑制。在另一实施方案中,施用治疗有效剂量的所述组合物减少所述受试者的成纤维细胞和/或肌成纤维细胞的数量。在另一实施方案中,施用治疗有效剂量的所述组合物减少所述受试者的原发肠道肌成纤维细胞的数量。
在一个实施方案中,本发明提供治疗受试者的纤维化的方法,其包括提供包含TL1A抑制剂和DR3抑制剂的组合物;和向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述TL1A抑制剂为TL1A抗体。在另一实施方案中,所述DR3抑制剂使DR3的表达缺失。在另一实施方案中,所述纤维化减少。在另一实施方案中,所述组合物抑制TL1A-DR3信号传导功能。
在一个实施方案中,本发明提供逆转受试者的纤维化的方法,其包括提供包含TL1A抑制剂和DR3抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述组合物进一步包含IFNγ、IL17、Tgfβ、Ctgf和/或IL31RA信号传导功能的抑制剂。在另一实施方案中,所述组合物抑制TL1A-DR3信号传导功能。
在一个实施方案中,本发明提供治疗炎症的方法,其包括提供包含TL1A抑制剂和/或DR3抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,所述组合物进一步包含IFNγ、IL17、Ctgf和/或IL31RA信号传导功能的抑制剂。在另一实施方案中,所述组合物抑制TL1A-DR3信号传导功能。
在一个实施方案中,本发明提供治疗受试者的疾病的方法,其包括抑制Ifnγ和Il-17表达,下调Tgfβ信号转导,和/或减少成纤维细胞/肌成纤维细胞,并治疗所述受试者。在另一实施方案中,所述疾病为炎性肠病。在另一实施方案中,所述疾病为纤维化。在另一实施方案中,所述疾病为肠炎症。在另一实施方案中,所述疾病为与炎性肠病相关的并发症。
在一个实施方案中,本发明提供治疗与IBD相关的并发症的方法,其包括提供包含TL1A、DR3和IL31RA信号传导功能的抑制剂的组合物,并向所述受试者施用治疗有效剂量的所述组合物。在另一实施方案中,通过静脉注射将所述组合物施用至所述受试者。
在一个实施方案中,本发明提供包含一种或多种TL1A抑制剂和/或一种或多种DR3抑制剂和药学上可接受的载体的组合物。在另一实施方案中,所述一种或多种TL1A抑制剂为TL1A抗体。在另一实施方案中,所述一种或多种DR3抑制剂为DR3抗体。
在另一实施方案中,本发明提供通过向受试者施用包含治疗有效剂量的TL1A抑制剂和/或DR3抑制剂的组合物来降低所述受试者的炎症的方法。
在另一实施方案中,本发明提供通过抑制Ifnγ和Il-17表达,下调Tgfβ信号传导,和/或减少成纤维细胞/肌成纤维细胞来抑制与纤维化相关的病症的方法。
在一个实施方案中,本发明提供包含一种或多种TL1A、DR3和IL31RA信号传导功能的抑制剂和药学上可接受的载体的组合物。在另一实施方案中,所述一种或多种TL1A抑制剂为TL1A抗体。在另一实施方案中,所述一种或多种DR3抑制剂为DR3抗体。
在本领域中有很多现有技术,用于检测是否存在多肽或其它标志物/生物标志物,包括蛋白质微阵列。例如,为此目的可采用的一些检测范式包括光学方法、电化学方法(伏安法和电流分析技术)、原子力显微技术和射频方法,例如,多极共振光谱法。除显微镜检查(共焦和非共焦)外,示例性的光学方法还有荧光、冷光、化学发光、吸光度、反射率、透光率和双折射或折射率的检测(例如,表面等离子体共振、椭圆偏振、共振成像方法、光栅耦合器波导方法或干涉法)。
类似地,有很多用来分离(isolate)和/或分级(fractionate)生物标志物的技术。例如,可使用生物特异性捕捉剂(capture reagent)来捕获生物标志物,所述生物特异性捕捉剂例如是抗体、适体(aptamer)或识别该生物标志物及其修饰形式的抗体。这种方法也可导致蛋白质交互子(interactor)的捕获,该交互子与蛋白质结合或者另外被抗体识别,并且其本身可为生物标志物。所述生物特异性捕捉剂也可与固相结合。然后,被捕获的蛋白质可通过SELDI质谱法检测或通过将蛋白质从所述捕捉剂中洗脱并通过传统MALDI或通过SELDI检测洗脱的蛋白质来检测。SELDI的一个实例称为"亲和捕获质谱法",或"表面增强亲和捕获(Surface-Enhanced Affinity Capture)"或"SEAC”,其涉及探针的使用,所述探针表面具有能够捕获分析物的材料,通过所述材料和所述分析物之间的非共价亲和作用(吸附)来捕获所述分析物。质谱仪的一些实施例为飞行时间法、扇形磁场、四极滤质器、离子捕集器、离子回旋共振、静电扇形分析器及这些的混合。
或者,例如,可使用传统的免疫测定技术检测诸如多肽的生物标志物的存在。免疫测定需要生物特异性捕捉剂,诸如抗体,来捕获所述分析物。所述测定还可设计用于特异性辨别蛋白质及蛋白质的修饰形式,其可通过采用夹心(sandwich)测定完成,在所述夹心测定中一种抗体捕获不止一种形式,并且其次明显标记的抗体,特异性结合,并提供对各种形式的不同检测。可通过使用生物分子免疫动物来产生抗体。传统的免疫测定可包括夹心免疫测定(包括ELISA),或者基于荧光的免疫测定,以及其它酶免疫测定。
在检测之前,可将生物标志物分级以将其与溶液或血液中的其它可能干扰检测的组分分离。分离可包括将血小板与其它血液成分分离、血小板组分的亚细胞分离和/或将所期望的生物标志物与血小板中发现的其它生物分子分离,所采用的技术诸如是色谱法、亲和纯化、1D和2D映射技术,和本领域技术人员已知的其它用于纯化的方法。在一个实施方案中,通过生物芯片分析样本。生物芯片通常包括固体基质并具有通常是平滑的表面,捕捉剂(也称为吸附剂或亲和试剂)粘着与所述表面上。常常,生物芯片的表面包含多个可访问的位点,其中每个位点都结合有捕捉剂。
上述各种方法和技术提供实现本发明的多种方式。当然,应理解,未必所有描述的目的和优点都根据本文描述的任何特定实施方案实现。因此,例如,本领域技术人员将认识到,所述方法可以通过一种方式进行,这种方式实现或最优化如本文中所教导的一个优点或一组优点而未必实现如本文中可能教导或提出的其它优点。本文提及多种有利或不利的可选方案。应理解一些优选实施方案明确包括一种、另一种或几种有利特征,而其它实施方案明确排除一种、另一种或几种不利特征,然而仍有其它实施方案通过包含一种、另一种或几种有利特征明确减少了目前不利特征。
此外,本领域技术人员将认识到不同实施方案的各种特征的适用性。类似地,以上讨论的各种元素、特征和步骤,以及其它已知的每一种此类元素、特征和步骤的等效物,可由本领域普通技术人员混合或匹配以进行根据本文描述的原理的方法。在所述各种元素、特征和步骤中,一些明确包括在不同实施方案中而其它被明确排除。
尽管本发明已在某些实施方案和实施例的上下文中公开,本领域技术人员将理解本发明的实施方案从明确公开的实施方案延伸到其它可选实施方案和/或用途以及其修改及等效物。
许多变化和可选元素已在本发明的实施方案公开。再进一步变化和可选元素对本领域技术人员将是显而易见的。这些变化包括但不限于所述发明组合物的组成分子的选择,以及用其可诊断、预测和治疗的所述疾病和其它临床症状。本发明的各种实施方案可明确包括或排除任何这些变化或元素。
在一些实施方案中,表达用于描述和要求保护本发明某些实施方案的成分、性质(诸如浓度、反应条件等等)的量的数字应理解为在一些实例中被术语“约”修饰。因此,在一些实施方案中,在书面描述和所附权利要求中阐述的数值参数为近似值,其可根据特定实施方案要寻求获得的所需性质而变化。在一些实施方案中,应当根据报道的有效数字个数并通过应用普通舍入技术解释所述数值参数。尽管阐明本发明的一些实施方案的广泛范围的数字范围和参数是近似值,但具体实施例中阐述的数值应尽可能予以精确报道。在本发明的一些实施方案中提出的所述数值可包含由发现于它们各自的测试测量中的标准偏差必然导致的某些误差。
在一些实施方案中,描述本发明特定实施方案(特别是某些下列权利要求的上下文)的上下文中使用的术语“一个/一种(a)”和“一个/一种(an)”和“该(the)”以及类似的提及可被解释为涵盖单数和复数两者。本文中值范围的引用仅仅意图充当单独涉及落在范围内的每个不同值的简易方法。除非本文另外指出,将每个单个值并入说明书,如同其在本文中被单独引用一样。本文描述的所有方法可以以任何合适的顺序进行,除非本文另外指出或与上下文明显矛盾。本文相对于某些实施方案提供的任何和所有的实施例或示例性语言(例如,“诸如”)的使用仅仅意图更好地阐明本发明,而并不是对另外要求保护的本发明的范围构成限制。说明书中的语言不应解释为指出对实施本发明必需的任何未要求保护的要素。
本文所公开的本发明的替代要素或实施方案的群组不应解释为限制。每一群组成员可单独地或以与组的其它成员或本文中存在的其它要素进行任何组合的方式被提及和被要求保护。为方便性和/或专利性原因,组的一个或多个成员可包括于组中或从组中删除。当发生任何这种包括或删除时,说明书被视为包含改变的组,因而符合所附权利要求中使用的马库什(Markush)组的书面描述。
在本文中描述了本发明的优选实施方案,包括发明人已知的实施本发明的最佳方式。本领域普通技术人员在阅读上述说明时,这些所述优选实施方案的变化将变得显而易见。预期熟练技术人员在适当情况下可以采用这些变化,并且本发明可以以不同于本文具体描述的方式实施。因此,此发明的许多实施方案包括如适用法律所许可的所附的权利要求所列举的对象的所有修改和等效物。而且,在其所有可能的变化中,上述要素的任何组合均由本发明涵盖,除非本文另外指出或另外与上下文明显矛盾。
此外,本说明书通篇参考了大量的专利和印刷的出版物。每个上述引用的参考文献和印刷的出版物各自以引用的方式整体并入本文。
最后,应理解本文公开的本发明的实施方案阐明了本发明的原则。其它可被采用的修改可处于本发明的范围内。因此,通过实例但不是限制的方式,可根据本文的教导使用本发明的替代性构造。因此,本发明的实施方案不限于本文所精确显示和描述的。
本发明提供了包括但不限于以下实施方案:
1.一种治疗受试者的纤维化的方法,其包括:
提供包含一种或多种TL1A-DR3信号传导功能的抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
2.如实施方案1所述的方法,其中所述组合物包含一种或多种TL1A阻断抗体。
3.如实施方案1所述的方法,其中所述组合物包含一种或多种Dr3阻断抗体。
4.如实施方案1所述的方法,其中所述组合物包含一种或多种通过直接与TL1A结合而抑制TL1A功能的化合物。
5.如实施方案1所述的方法,其中所述组合物包含一种或多种Ifnγ、IL17、Ctgf和IL31Ra的抑制剂。
6.如实施方案1所述的方法,其中所述组合物包含一种或多种Tgfβ和Igf1的抑制剂。
7.如实施方案1所述的方法,其中所述组合物包含一种或多种IL31信号传导的抑制剂。
8.如实施方案1所述的方法,其中施用治疗有效剂量的所述组合物使得所述纤维化逆转到发炎前水平。
9.如实施方案1所述的方法,其中所述纤维化为结肠纤维化。
10.如实施方案1所述的方法,其中施用治疗有效剂量的所述组合物进一步导致对受试者的肠炎症的抑制。
11.如实施方案1所述的方法,其中施用治疗有效剂量的所述组合物减少所述受试者的成纤维细胞和/或肌成纤维细胞的数量。
12.如实施方案1所述的方法,其中施用治疗有效剂量的所述组合物减少所述受试者的原发肠道肌成纤维细胞的数量。
13.一种治疗受试者的疾病的方法,其包括:
提供包含IL31Ra信号传导的抑制剂的组合物;和
向所述受试者施用有效剂量的所述组合物。
14.如实施方案13所述的方法,其中所述疾病为TL1A相关疾病。
15.如实施方案13所述的方法,其中所述疾病为炎性肠病(IBD)。
16.如实施方案13所述的方法,其中所述疾病与在所述小肠形成的狭窄和/或肠炎症相关。
17.如实施方案13所述的方法,其中所述疾病为小肠和大肠纤维狭窄。
18.如实施方案13所述的方法,其中所述疾病为纤维化。
19.如实施方案13所述的方法,其中所述组合物包含一种或多种TL1A抗体。
20.如实施方案13所述的方法,其中所述组合物包含一种或多种IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1信号传导的抑制剂。
21.如实施方案13所述的方法,其中施用治疗有效剂量的所述组合物减少所述受试者的成纤维细胞和/或肌成纤维细胞的数量。
22.一种诊断受试者对TL1A相关疾病的易感性的方法,其包括:
从所述受试者获得样本;
分析所述样本以确定相对于正常个体的高水平的IL31Ra表达的存在或不存在;和
根据所述相对于正常个体的高水平的IL31RA表达的存在来诊断对所述TL1A相关疾病的易感性。
23.如实施方案22所述的方法,其中所述TL1A相关疾病为炎性肠病(IBD)。
24.如实施方案22所述的方法,其中所述TL1A相关疾病与在所述小肠形成的狭窄和/或肠炎症相关。
25.如实施方案22所述的方法,其中所述TL1A相关疾病为小肠和大肠纤维狭窄。
26.如实施方案22所述的方法,其中所述TL1A相关疾病为纤维化。
27.如实施方案22所述的方法,其进一步包括确定相对于正常个体的胶原蛋白、IL31RA、IFNγ、IL17、Ctgf、TgfB1和/或Igf1的高水平表达的存在。
28.一种诊断受试者的TL1A相关疾病的方法,其包括:
从所述受试者获得样本;
分析所述样本以确定一种或多种与所述TL1A相关疾病相关的危险变体和/或标志物的存在或不存在;和
根据与所述TL1A相关疾病相关的一种或多种危险变体和/或标志物的存在诊断所述TL1A相关疾病。
29.如实施方案28所述的方法,其中所述一种或多种危险变体和/或标志物包括高表达的IL31RA。
30.如实施方案28所述的方法,其中所述一种或多种危险变体和/或标志物包括高表达的IFNγ、IL17、Ctgf、TgfB1和/或Igf1。
31.如实施方案28所述的方法,其中所述TL1A相关疾病为炎性肠病(IBD)。
32.如实施方案28所述的方法,其中所述TL1A相关疾病与在所述小肠形成的狭窄和/或肠炎症相关。
33.如实施方案28所述的方法,其中所述TL1A相关疾病为小肠和大肠纤维狭窄。
34.如实施方案28所述的方法,其中所述TL1A相关疾病为纤维化。
35.如实施方案28所述的方法,其进一步包括通过施用一种或多种TL1A抑制剂治疗所述TL1A相关疾病。
36.如实施方案28所述的方法,其进一步包括通过施用TL1A抑制剂治疗所述TL1A相关疾病。
37.如实施方案28所述的方法,其中所述受试者为人。
38.如实施方案28所述的方法,其进一步包括通过施用Dr3抑制剂治疗所述TL1A相关疾病。
39.一种治疗受试者的纤维化的方法,其包括:
提供包含TL1A抑制剂和DR3抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
40.如实施方案39所述的方法,其中所述TL1A抑制剂为TL1A抗体。
41.如实施方案39所述的方法,其中所述DR3抑制剂使DR3的表达缺失。
42.如实施方案39所述的方法,其中所述纤维化减少。
43.如实施方案39所述的方法,其中所述组合物抑制TL1A-DR3信号传导功能。
44.一种逆转受试者的纤维化的方法,其包括:
提供包含TL1A抑制剂和DR3抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
45.如实施方案44所述的方法,其中所述组合物进一步包含IFNγ、IL17、Tgfβ、Ctgf和/或IL31RA信号传导功能的抑制剂。
46.如实施方案44所述的方法,其中所述组合物抑制TL1A-DR3信号传导功能。
47.一种治疗炎症的方法,其包括:
提供包含TL1A抑制剂和/或DR3抑制剂的组合物;并且
向所述受试者施用治疗有效剂量的所述组合物。
48.如实施方案47所述的方法,其中所述组合物进一步包含IFNγ、IL17、Ctgf和/或IL31RA信号传导功能的抑制剂。
49.如实施方案47所述的方法,其中所述组合物抑制TL1A-DR3信号传导功能。
50.一种治疗受试者的疾病的方法,其包括:
抑制Ifnγ和Il-17表达,下调Tgfβ信号传导,和/或减少成纤维细胞/肌成纤维细胞;并且
治疗所述受试者。
51.如实施方案50所述的方法,其中所述疾病为炎性肠病。
52.如实施方案50所述的方法,其中所述疾病为纤维化。
53.如实施方案50所述的方法,其中所述疾病为肠炎症。
54.如实施方案50所述的方法,其中所述疾病为与炎性肠病相关的并发症。
55.一种组合物,其包含:
一种或多种TL1A、DR3和IL31RA信号传导功能的抑制剂;以及
药学上可接受的载体。
56.如实施方案55所述的组合物,其中所述一种或多种TL1A抑制剂为TL1A抗体。
57.如实施方案55所述的组合物,其中所述一种或多种DR3抑制剂为DR3抗体。
58.一种治疗与IBD相关的并发症的方法,其包括:
提供包含TL1A、DR3和IL31RA信号传导功能的抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
59.如实施方案58所述的方法,其中将所述组合物通过静脉施用至所述受试者。
实施例
提供下面的实施例以更好地示出要求保护的本发明,而不应解释为限制本发明的范围。就提到的特定材料来说,这仅是为了说明的目的并且不打算限制本发明。本领域的技术人员在无需具有创造性能力且不脱离本发明的范围的情况下可开发等效方法或反应物。
实施例1
慢性结肠炎的诱导及治疗
C57BL/6J小鼠购自杰克逊实验室。如前所述进行长期葡聚糖硫酸钠(DSS)结肠炎诱导。在所述过继转移模型中,通过将从WT小鼠分离的500,000个CD4+CD45RBhi初始T-细胞腹腔内注射到Rag1-/-小鼠诱导结肠炎。仓鼠抗-小鼠Tl1a Ab(12F6A,梯瓦制药工业有限公司,北威尔士,宾夕法尼亚)(12F6A,TEVA,North Wales,Pennsylvania)阻断Tl1a的功能并按20-或80-mg/kg施用,或者对照免疫球蛋白(Ig)G(Leinco技术公司,圣路易斯,密苏里州)(Leinco Technologies,St.Louis,Missouri)按80-mg/kg的剂量一周两次腹腔内注射到小鼠中,对于长期DSS模型在第15天开始注射,并且对于过继转移模型注射在第29天开始注射(图1A)。基线对照(Rag Co或WT Co)为在DSS治疗或过继转移初始T-细胞之前进行分析的小鼠。预治疗(Pre-Tx)对照为在对于长期DSS模型第14天和对于过继转移模型第28天进行分析的小鼠。治疗组为在对于长期DSS模型第28天和对于过继转移模型第56天进行分析的小鼠(图1A)。所有小鼠在雪松-西奈医学中心(Cedars-Sinai Medical Center,CSMC)的动物设施(Animal Facility)中的无特异病原体条件下进行饲养。该研究严格按照美国国家卫生研究院的实验动物管理与使用指南(Guide for the Care and Use of LaboratoryAnimals of the National Institutes of Health)进行。动物研究由CSMC动物管理与使用委员会批准(Animal Care and Use Committee)(方案3813)。
实施例2
疾病活动指数、髓过氧化物酶、宏观及组织病理学分析
如前所述,对于DSS模型每隔一天确定一次疾病活动指数(DAI)分数,对于过继转移模型每周确定两次DAI分数。使用髓过氧化物酶荧光检测试剂盒(MyeloperoxidaseFluorometric Detecton Kit)根据制造商的方案(恩佐生命科学,普利茅斯密亭,宾夕法尼亚州)(Enzo Life Sciences,PlymouthMeeting,PA)评估髓过氧化物酶活性。使用已确立的分类对炎症的宏观证据盲打分。处理组织样本并由CSMC组织学中心(CSMC Histology-Core)利用苏木精和伊红(H&E)染色。使用诺瓦超级金天狼猩红染色试剂盒(NovaUltraSirius Stain Kit)根据制造商的方案(IHC World公司,伍德斯托克,马里兰州)(IHCWorld,Woodstock,MD)进行天狼猩红染色。使用驴α-兔IgG和羊α-鸡IgY(艾博抗,剑桥,马萨诸塞州)(Abcam,Cambridge,MA)二抗对用10%福尔马林固定并用稀释100倍的α-SMA Ab(Abcam)和稀释2000倍的α-波形蛋白Ab(科文斯,圣地亚哥,加利福尼亚州)(Covance,SanDiego,CA)染色的4μM的冷冻切片进行免疫荧光染色。如前所述,组织病理学分数由两位受训动物病理学家(DQS和JC)以盲模式给出。使用莱卡(Leica)TCS SP光谱共聚焦显微镜对每只小鼠的每段肠区域在放大200倍下观察≥5个不同的视野来确定组织学分数和胶原蛋白沉积,并在放大630倍下计算成纤维细胞/肌成纤维细胞数量。
实施例3
Dr3-/-小鼠的产生
与genOway公司(genOway公司,里昂,法国)(genOway,Lyon,France)合作进行Dr3目标载体的克隆和Dr3+/-创始者小鼠的产生。简单来讲,使用来自C57BL/6J小鼠的基因组DNA通过PCR扩增产生包含1.5kb上游外显子1和3kb下游外显子8的Dr3内源基因座并克隆到pCR4-TOPO载体(英俊公司,卡尔斯巴德,加利福尼亚州)(Invitrogen,Carlsbad,CA)。随后,将两个loxP位点插入Dr3外显子2至5侧翼(图5A)。将侧接有FRT位点的阳性选择新霉素基因插入到外显子1和2之间的内含子来产生目标载体(图5A)。通过限制性分析和测序确认该克隆方法的每个步骤。使所述Dr3基因目标构建体线性化,并通过电穿孔将其转染至具有C57BL/6J背景的genOway专用胚胎干(ES)细胞。通过G418选择同源重组体并通过DNA印迹分析确认。将具有正确5’和3’重组的ES克隆显微注射到C57BL/6J囊胚并引入假孕C57BL/6J小鼠。繁殖雄性嵌合后代以得到种系突变小鼠,然后将其与Flpe缺失小鼠品系繁殖以去除新霉素盒,然后与Cre缺失小鼠繁殖以切除loxP侧翼序列(图5A),通过DNA印迹确认,并维持在C57BL/6J遗传背景上。
实施例4
表达分析
使用RNeasy微阵列组织微型试剂盒(RNeasy Microarray Tissue Mini Kit)(凯杰公司,巴伦西亚,加利福尼亚州)(Qiagen,Valencia,CA)分离总RNA,并且使用RT2 HT第一链(RT2 HT First Strand)进行逆转录聚合酶链式反应(RT-PCR)并按照制造商方案使用RT2定制纤维化阵列CAPM11248(RT2 Custom Fibrosis Array CAPM11248)(Qiagen,Valencia,CA)试剂盒测量基因表达。按照制造商方案使用多重免疫测定,小鼠Th1/Th2/Th17/Th22 13丛流式细胞混合试剂盒(Mouse Th1/Th2/Th17/Th22 13plex KitFlowCytomix)(eBioscience公司,圣地亚哥,加利福尼亚州)(eBioscience,San Diego,CA)测定细胞因子浓度。确认的Dr3 qPCR测定Mm.PT.51.17321439、Il31Ra qPCR测定Mm.PT.56a.32787326和β-肌动蛋白qPCR测定Mm.PT.39a.22214843购自IDT Technologies公司(斯科基,伊利诺州)(Skokie,IL)。
实施例5
细胞分离,培养,细胞内细胞因子表达和流式细胞术
进行固有层单核细胞(LPMC)、肠系膜淋巴结(MLN)和脾细胞的分离和培养以及由抗-CD28和抗-CD3ε对它们进行随后刺激。对于LPMC分离,本发明人使用整个结肠和回肠的10cm末梢。从在1mM DTT(飞世尔科技,塔斯廷,加利福尼亚州)(Fisher Scientific,Tustin,CA)中于37℃孵育15min,然后在含有5mM EDTA的1mM DTT(普洛麦格,麦迪逊,威斯康星州)(Promega,Madison,WI)中于37℃孵育30min的结肠分离小鼠原发结肠成纤维细胞。剩余的结肠组织用1x HBSS(康宁公司的品牌为Cellgro的产品,斯韦兹伯勒,新泽西州)(Corning Cellgro,Swedesboro,NJ)冲洗,切碎,然后用1.5mg/mL胶原酶II(沃辛顿,莱克伍德,新泽西州)(Worthington,Lakewood,NJ)、0.3mg/mL DNA酶I和3mg/mL透明质酸酶(西格玛,圣路易斯,密苏里州)(Sigma,St.Louis,MO)在DMEM(康宁公司的品牌为Cellgro的产品,斯韦兹伯勒,新泽西州)(Corning Cellgro,Swedesboro,NJ)中于37℃消化30min。所分离的细胞在补充有10%FCS、青霉素/链霉素(100IU/mL)、两性霉素(0.5μg/mL)的DMEM中培养。原发肠道成纤维细胞在第二代使用。在LSR II流式细胞仪(BD生物科学公司,圣何塞,加利福尼亚州)(BD Biosciences,San Jose,CA)上获取细胞并使用FlowJo分析软件分析。
实施例6
离体肠道成纤维细胞增殖和细胞凋亡测定
按照制造商说明书分离原发肠道成纤维细胞并用CellTrace Violet(英俊公司,卡尔斯巴德,加利福尼亚州)(Invitrogen,Carlsbad,CA)染色。之后用100ng/mL的Tl1a将染色的细胞在补充有10%FCS、青霉素/链霉素(100IU/mL)和两性霉素(0.5μg/mL)的DMEM中孵育。48小时后,按照制造商说明书使用膜联蛋白V细胞凋亡检测试剂盒(Annexin VApoptosis Detection Kit)(eBioscience公司,圣地亚哥,加利福尼亚州)(eBioscience,San Diego,CA)将培养的肠道成纤维细胞染色。膜联蛋白V染色后,收获成纤维细胞,洗涤并用2%多聚甲醛固定,用BD LSR II流式细胞仪进行流式细胞术分析并通过FlowJo软件分析。
实施例7
统计分析
将数据表示为平均值±标准偏差(SD)。在两组间通过双尾费舍尔精确检验(two-tailed Fisher’s Exact Test)比较分类变量以及通过学生t-检验比较连续变量。根据检验假设的实行使用参数检验和非参数检验。使用方差分析(ANOVA)在三组间进行比较,随后通过使用图凯HSD(Turkey’s HSD)和贝伦斯-费舍尔-检验(Behrens-fisher-Test)修正的成对事后分析进行多重比较。p<0.05认为是显著的。
实施例8
Tl1a Ab施用减弱疾病活性和已形成的慢性结肠炎的总炎症
使用Tl1a Ab在用初始CD4+CD45RBhi T-细胞过继转移的免疫缺陷Rag1-/-小鼠中评估中和Tl1a功能对慢性鼠类结肠炎的影响。转移后第29天当结肠炎形成时开始按20-和80-mg/kg、每周两次施用Tl1a Ab或按80-mg/kg、每周两次施用同种型对照Ab(IsoAb)(图1A)。到第6周以及持续至第8周研究结束,用Tl1aAb处理的小鼠的疾病活动指数(DAI)明显低于接受Iso Ab的小鼠(图1B)。与Iso Ab组相比,在两种剂量下接受Tl1a Ab的小鼠的总结肠炎症明显减少(图1C)。与Iso Ab组相比,在Tl1aAb处理的情况下,从肠系膜淋巴结(MLN)和固有层(LP)重新获得的单核细胞的数量也减少(图1D)。在Tl1a 80-mg/kg Ab处理的小鼠中,比Pre-Tx组较轻的总结肠炎症和明显减少的LP单核细胞(LPMC)的数量显示了已形成的结肠炎及细胞浸润的改善(图1C和D)。
使用长期DSS结肠炎模型得出类似发现。在这个模型中,在第15天当结肠炎形成时开始按一周两次施用Tl1a Ab(20-mg/kg)(图1A)。与Iso Ab组相比,我们观察到较低的DAI(图7A),减少的总炎症(图7B),和从MLN和LP中重新获得的较少的单核细胞(图7C)。DAI和单核细胞的减少同样小于Pre-Tx组。这些数据表明用Tl1a Ab处理会导致肠内炎症总指标减少以及炎性细胞积累减少。
实施例9
Tl1a Ab施用减轻已形成的鼠类结肠炎的组织病理学特征
在过继转移模型中,结肠的组织学检查显示,与Iso Ab组相比,通过Tl1a Ab治疗的以细胞浸润减少、粘蛋白损耗、隐窝脓肿和结构变化为特征的炎症的减少(图2A和B)。与4周Pre-Tx组相比,组织学炎症的减少也明显降低(图2A和B),表明炎症部分解决。一致地,与Iso Ab组相比,通过两种剂量的Tl1a Ab施用,以及与Pre-Tx组相比,通过80-mg/kg的Tl1aAb施用,结肠髓过氧化物酶(MPO)活性明显降低(图2C)。随着Tl1aAb剂量当结肠MPO活性降低到与Rag基线对照(RagCo)组没有明显差异的水平时提出结肠炎的黏膜分辨率(图2C)。
类似地,在长期DSS模型中,与Iso Ab和Pre-Tx组相比,使用Tl1a Ab结肠的组织病理学会有改善(图8A和B)。尽管通过Tl1a Ab处理使组织学炎症减少,但与基线WT Co组相比,结肠炎症仍明显较高(图8B)。此外,与Iso Ab和Pre-Tx组相比,通过Tl1a Ab处理结肠MPO活性明显较低(图8C)。这些结果表明施用Tl1a Ab导致结肠组织病理学正常化。
实施例10
Tl1a Ab抑制Th-1和-17免疫应答
为了评估在两种致结肠炎模型中降低的已形成的鼠类结肠炎的可能免疫机理,测量Ifnγ、Il13和Il17的表达。在过继转移模型中,与Iso Ab组和Pre-Tx组相比,Tl1a Ab降低在MLN和LPMC中的CD4+Il17+T-细胞的频率(图3A和B)。通过两种剂量的Tl1a Ab处理CD4+Ifnγ+ T-细胞同样减少,在LPMC中(按20-mg/kg施用Tl1a Ab并没有导致与Pre-Tx组相比明显的CD4+Ifnγ+ T-细胞减少)除外(图3A和C)。此外,本发明人还发现在MLN和LPMC中,与Pre-Tx和Iso Ab组相比,通过Tl1a Ab处理Ifnγ+和Il17+双阳性CD4+ T-细胞明显减少(图3B和C,右图)。使用CD3/CD28刺激的MLN和LPMC细胞,在Tl1a Ab处理的小鼠中看到与接受Iso Ab的小鼠和预治疗组相比更低的Il17产生(图3D)。除了在MLN以外,两种剂量下的Tl1aAb处理导致与Iso Ab和Pre-Tx组相比较低的Ifnγ分泌(图3E)。各组之间的CD4+Il13+ T-细胞的百分比和Il13产生并无明显差异。在长期DSS结肠炎模型中,通过Tl1a Ab处理在MLN和LPMC中同样观察到CD4+Il17+、CD4+Ifnγ+和CD4+Il17+Ifnγ+T-细胞的减少(图9A-C)。一致地,Tl1a Ab处理导致Il17和Ifnγ在分离的用CD3/CD28刺激的MLN和LPMC细胞中的较低产生(图9D和E)。在长期DSS结肠炎模型中各组之间的CD4+Il13+ T-细胞的百分比和Il13产生没有不同。这些数据表明Tl1a Ab降低Th-1和-17促炎免疫应答。
实施例11
Tl1a Ab逆转已形成的结肠纤维化
先前显示具有组成型Tl1a表达的小鼠形成了增强的肠纤维化。为了评估阻断Tl1a信号传导是否可以减少结肠纤维化,我们进行天狼猩红染色以测量胶原蛋白沉积的程度。本发明人发现,在初始T细胞转移的第4周之前,与基线Rag Co组相比,在Pre-Tx组中胶原蛋白沉积增强(图4A和C)。在接受对照Iso Ab的小鼠中在第8周之前胶原蛋白沉积的程度越来越大。然而,与接受Iso Ab的小鼠或Pre-Tx组相比时,Tl1a Ab处理导致胶原蛋白沉积的明显减少(图4A和C)。值得注意的是,当80mg/kg的Tl1a处理与正常Rag Co小鼠相比时胶原蛋白沉积并没有明显不同(图4C)。在长期DSS模型中,与Iso Ab或Pre-Tx组相比,通过Tl1a Ab处理观察到类似的胶原蛋白沉积减少(图4A和C)。此外,Tl1a处理导致胶原蛋白沉积减少到与WT基线对照没有统计学差异的水平(图4A和C)。总之,这些数据表明阻断Tl1a信号传导将胶原蛋白沉积逆转到炎症发作前的相似水平。
实施例12
阻断Tl1a-Dr3信号转导减少肠道成纤维细胞和肌成纤维细胞数量
为了开始研究使用Tl1a Ab减少胶原蛋白沉积的机理,测量肠道成纤维细胞和肌成纤维细胞的频率。肠道肌成纤维细胞是涉及肠纤维发生的细胞群。波形蛋白阳性细胞为成纤维细胞,其在α平滑肌肌动蛋白(αSMA)共表达的情况下,代表肌成纤维细胞。所述数据表明初始T-细胞转移4周后(Pre-Tx组),成纤维细胞和肌成纤维细胞的数量增加(图4B和D)。在接受Iso Ab的小鼠中成纤维细胞和肌成纤维细胞的数量在第8周之前进一步增加。然而,Tl1a Ab处理导致成纤维细胞和肌成纤维细胞的数量减少到与正常Rag Co相似的水平(图4B和D)。有趣的是,在接受80-mg/kg的Tl1a Ab的小鼠中肌成纤维细胞的减少达到与RagCo小鼠无统计学差异的水平(图4B和D),表明纤维发生的逆转。
在长期DSS模型中,当与同种型或Pre-Tx组相比时,通过Ab处理观察到类似的成纤维细胞和肌成纤维细胞的数量的减少(补充图4B和D)。与过继转移模型一致,通过Tl1a Ab处理肠成纤维细胞和肌成纤维细胞的数量的减少达到与WT基线对照无统计学差异的水平(图10B和D)。
本发明人生成Dr3缺失(Dr3-/-)的小鼠(图5A和B)来描述肠道成纤维细胞和肌成纤维细胞的数量的减少是否起因于直接Tl1a-Dr3信号传导。与野生型同窝基线(非结肠炎)小鼠相比在Dr3-/-内肠道成纤维细胞明显较少(图5C)。然后,本发明人进行离体CellTraceViolet测定和膜联蛋白V染色以确定肠道成纤维细胞在WT和Dr3-/-小鼠之间的差异是否分别起因于增殖和/或细胞凋亡。流式细胞术分析通过在WT和Dr3-/-肠道成纤维细胞之间的重叠的CellTrace Violet强度证实显示相似的增殖速率(图5D,上图)。在野生型和Dr3-/-肠道成纤维细胞之间没有观察到细胞凋亡速率差异(图5D,下图)。
实施例13
通过Tl1a Ab治疗逆转纤维发生
为了研究使用Tl1a Ab逆转已形成的肠道纤维化的分子机理,测量胶原蛋白、纤维发生程序介体(mediator)(Tgfβ1、Ctgf、Igf1、Pten和Il31Ra)和涉及细胞外基质(ECM)重构的因素(Mmp和Timp)的表达。在过继转移模型和长期DSS模型中都发现较低水平的胶原蛋白表达(本文表1和表2)。观察到使用Tl1a Ab的具有前-纤维化介体(包括在过继转移模型和长期DSS模型中的Tgfβ1和Il31Ra以及在过继转移模型中的Igf1)的较低表达的纤维发生程序的正常化(表1和表2)。在过继转移模型中,通过Tl1a Ab施用结缔组织生长因子(Ctgf),Tgfβ信号转导的下游介体的表达与Pre-Tx和Iso Ab组相比减少。通过测量金属蛋白酶(Mmp)和金属蛋白酶的组织抑制剂(Timp)的表达评估ECM重构。与同种型Ab组相比,在过继转移模型(Mmp2、Mmp3;表1)和长期DSS模型(Mmp2、Mmp3、Mmp13;表2)中的Tl1a Ab处理的小鼠中涉及ECM降解的基因的表达减少。值得注意的是,在过继转移模型(Timp2,表1)和在长期DSS模型(Timp1,Timp2;表2)中,通过Tl1a治疗Timp的表达较低。这些结果表明使用Tl1aAb纤维发生程序减少,其导致胶原蛋白合成减少。Mmp和Timp的较低表达可能有助于已形成的ECM组分的强化去除而不是诱导组织损伤。因此,所述数据表明通过Tl1a Ab的已形成的纤维化的逆转可能是纤维发生程序减少和可能Mmp和Timp的减少的净结果。
实施例14
肠道成纤维细胞表达Dr3并响应Tl1a刺激
本发明人研究了肠道成纤维细胞是否可以在功能上响应直接Tl1a信号传导。测量了Dr3(唯一已知的Tl1a受体)的mRNA水平,并发现其在WT中以低水平表达而在Dr3缺失初生肠道成纤维细胞中却没有(图6A,上图)。一致地,免疫荧光染色表明Dr3在WT初生肠道成纤维细胞上表达(图6A,下图)。使用流式细胞术,本发明人发现,与无αSMA表达的成纤维细胞相比,Dr3优先在共表达αSMA的成纤维细胞上表达(图6B)。本发明人接着检查肠道成纤维细胞是否可以响应Tl1a刺激并用胶原蛋白(Col1a2)和Il31受体(Il31Ra)作为成纤维细胞激活的标志物。本发明人表明Tl1a可剂量依赖性地增加Col1a2和Il31Ra在鼠类初生肠道成纤维细胞中的离体表达(图6C)。在离体Dr3-/-鼠类肠道成纤维细胞中Col1a2和Il31Ra的迟钝诱导显示Tl1a刺激的特异性(图6D)。这些数据表明肠道成纤维细胞表达Dr3并可以在功能上响应直接Tl1a信号转导。
实施例15
纤维化介体的表达分析的结果
表1.纤维化介体在过继转移结肠炎模型中的表达分析。
ns=不显著
表2.纤维化介体在DSS模型中的表达分析。
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实施例16
阻断TL1A-Dr3信号传导降低肠道成纤维细胞和肌成纤维细胞的数量–附加结果
结肠肌成纤维细胞为涉及肠纤维发生的细胞群。为了研究使用Tl1a Ab的胶原蛋白沉积减少的分子机理,测量了波形蛋白的成纤维细胞的表达以及波形蛋白和α平滑肌肌动蛋白(αSMA)的肌成纤维细胞共表达,以评估这些细胞类型的数量。将初始T-细胞转移到Pre-Tx和Iso Ab组后,结肠成纤维细胞和肌成纤维细胞的数量增加(图11a)。然而,Tl1a Ab治疗导致成纤维细胞和肌成纤维细胞的数量减少到与正常Rag Co相似的水平(图11a)。
在长期DSS模型中,与Iso或Pre-Tx组相比,用Tl1a Ab处理的小鼠显示出结肠成纤维细胞和肌成纤维细胞数量的相似的减少(图11b)。与在过继转移模型中观察到的一致,通过Tl1a Ab处理肠成纤维细胞和肌成纤维细胞的数量减少至与WT基线对照无统计学差异的水平(图11b)。由于在长期DSS结肠炎模型中通过Tl1a Ab处理与WT Co组相比仍然有明显恶化的结肠炎,肌成纤维细胞和成纤维细胞减少的数量与,至少部分,中和Tl1a的直接结果一致,而不仅仅是通过炎症减少的二次效应。
接下来评估在这些慢性结肠炎的鼠类模型中是否有与纤维化变化相关联的Dr3表达变化。免疫荧光染色显示,在过继转移和长期DSS结肠炎模型中与基线对照组(Rag Co和WT Co)和Tl1a Ab处理组相比,Dr3在Pre-Tx和Iso Ab组中的表达增加(图11c,d)。值得注意的是,在Pre-Tx和同种型Ab组中存在Dr3按成纤维细胞的百分比表达(图11c,d)。实时定量逆转录酶-PCR分析表明,在两种模型中,Dr3在Iso Ab组中的表达与在基线对照(Rag Co和WT Co)和Tl1a Ab治疗组中的小鼠相比明显较高(图11e)。此外,在过继转移和长期DSS结肠炎模型中,Tl1a mRNA在Iso Ab组中的表达与未发炎对照(Rag Co和WT Co)和Tl1a Ab处理组相比明显增加(图11f)。这些结果与Dr3-Tl1a表达和肠道纤维化的增加之间的直接关系一致。
为了确定肠道成纤维细胞和肌成纤维细胞的数量的减少是否可以起因于直接Tl1a-Dr3信号传导,生成Dr3缺失(Dr3-/-)小鼠。尽管在高达8周龄的WT或Dr3-/-小鼠中没有自发结肠炎(图12a,上图),但如通过波形蛋白的免疫荧光染色(图12a,中图)和每个结肠的总的重新获得的成纤维细胞的定量(图12a,下图)所显示,与WT同窝小鼠相比,在Dr3-/-中的肠道成纤维细胞明显较少。通过使用波形蛋白和αSMA的免疫荧光染色(图12a,中图)或使用光学显微镜检查(图12a,下图),在WT和Dr3-/-成纤维细胞之间没有形态学差异。使用离体CellTrace Violet测定和膜联蛋白V染色确定WT和Dr3-/-小鼠之间的肠道成纤维细胞的数量差异是否分别起因于增殖和/或细胞凋亡。流式细胞术分析显示相似的增殖速率,如用WT和Dr3-/-肠道成纤维细胞之间的重叠的CellTrace Violet强度(图12b)所证明。在WT和Dr3-/-肠道成纤维细胞之间未观察到细胞凋亡速率的差异(图12c)。
实施例17
肠道成纤维细胞表达Dr3和响应TL1A刺激–附加结果
为了确定肠道成纤维细胞是否在功能上响应直接Tl1a信号传导,测量了Dr3的mRNA水平并发现其在WT中(0.0018±0.001%β-肌动蛋白)以低水平表达,但在Dr3缺失初生肠道成纤维细胞中检测不到。进行流式细胞术分析确定Dr3是否在波形蛋白+αSMA-成纤维细胞或波形蛋白+αSMA+肌成纤维细胞上表达。所述结果表明,与波形蛋白+αSMA-成纤维细胞相比,Dr3优先在波形蛋白+αSMA+肌成纤维细胞上表达。此外,Dr3表达与肌成纤维细胞上的αSMA水平有直接关联;在肌成纤维细胞上有较高比例的Dr3表达,有最高的αSMA表达(图13a)。此外,用αSMA和Dr3免疫染色的分类的αSMA阳性原发肠道成纤维细胞在WT中显示Dr3的共染色而在Dr3缺陷肌成纤维细胞中无显示,表明Dr3在αSMA阳性初生肠道成纤维细胞上表达(图13b)。
为了确定肠道成纤维细胞是否可以响应直接Tl1a刺激,通过加入外源Tl1a蛋白质测量了胶原蛋白(Col1a2,成纤维细胞功能标志物)和Il31Ra(Il31Ra在成纤维细胞上表达)的表达的变化。结果显示在离体鼠类原发肠道成纤维细胞中Col1a2和Il31Ra表达的Tl1a剂量依赖性增加(图13c)。在离体Dr3-/-鼠类肠道成纤维细胞中通过Col1a2和Il31Ra的迟钝Tl1a诱导显示了Tl1a刺激的特异性(图13d)。相反,使用已知的成纤维细胞生长因子(Tgfβ和Igf1)或促炎刺激(Tnfα)没有看到Col1a2或Il31Ra的差异诱导(图13d)。这些数据表明肠道成纤维细胞表达Dr3并且可在功能上响应直接Tl1a信号传导。
实施例18
通常
肠道纤维狭窄是严重克罗恩氏病的特征。具有特定TNFSF15(基因名称为TL1A)变体的患者过度表达TL1A并具有较高在小肠中形成狭窄的风险。此外,小鼠中的持续Tl1a表达在致结肠炎情况下导致小肠和大肠纤维狭窄。本发明人确定了是否可以用Tl1a抗体逆转已形成的鼠类结肠纤维化。由于结缔组织生长因子(Ctgf)、Il31Ra、转化生长因子(Tgf)β1和胰岛素样生长因子-1(Igf1)的较低表达,通过中和Tl1a抗体的治疗将结肠纤维化逆转回原始的发炎前水平。此外,通过中和Tl1a抗体或缺失死亡结构域受体3(Dr3)来阻断Tl1a功能减少了成纤维细胞和肌成纤维细胞(介导组织纤维化的原发细胞类型)的数量。初生肠道肌成纤维细胞表达Dr3并且通过增加胶原蛋白和Il31Ra表达在功能上响应直接Tl1a信号传导。这些数据表明TL1A-DR3信号传导在组织纤维化中的直接作用以及TL1A-DR3信号传导的调节抑制肠纤维化。
本发明的各种实施方案在以上详细说明中描述。尽管这些描述直接描述上述实施方案,但应当理解,本领域技术人员可设想本文显示和描述的具体实施方案的修改和/或变化。任何落在本说明范围内的此类修改和变化也旨在包括在其中。除非具体说明,发明人的意图是,为可应用领域的普通技术人员给出说明书和权利要求中的词和短语的普通和习惯含义。
在申请本申请的同时,本申请人已知的本发明的各种实施方案的上述说明已被提出并旨在用于说明和描述的目的。本描述不旨在穷尽或将本发明限制到所公开的精确形式,并且鉴于上面的教导许多修改和变化是可能的。所描述的实施方案用于解释本发明的原理及其实际应用,以使本领域其他技术人员利用本发明的不同实施方案和不同的修改以适于预期的特定用途。因此,希望本发明不限于公开的用于实施本发明的特定实施方案。
尽管本发明的特定实施方案已经示出和描述,对本领域技术人员将是显而易见的是,基于本文的教导,再不背离本发明及其更广泛的方面的情况下可以进行变化和修改,并且因此,所附权利要求将涵盖其范围内所有此类改变和修改如在本发明的真正精神和范围内。本领域人员将理解的是,一般地,本文使用的术语通常意指“开放的”术语(例如,术语“包括”应该被解释为“包括但不限于”,术语“具有”应该被解释为“具有至少”,术语“包括”应该被解释为“包括但不限于”等)。
Claims (10)
1.一种治疗受试者的纤维化的方法,其包括:
提供包含一种或多种TL1A-DR3信号传导功能的抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
2.一种治疗受试者的疾病的方法,其包括:
提供包含IL31Ra信号传导的抑制剂的组合物;和
向所述受试者施用有效剂量的所述组合物。
3.一种诊断受试者对TL1A相关疾病的易感性的方法,其包括:
从所述受试者获得样本;
分析所述样本以确定相对于正常个体的高水平的IL31Ra表达的存在或不存在;和
根据所述相对于正常个体的高水平的IL31RA表达的存在来诊断对所述TL1A相关疾病的易感性。
4.一种诊断受试者的TL1A相关疾病的方法,其包括:
从所述受试者获得样本;
分析所述样本以确定一种或多种与所述TL1A相关疾病相关的危险变体和/或标志物的存在或不存在;和
根据与所述TL1A相关疾病相关的一种或多种危险变体和/或标志物的存在诊断所述TL1A相关疾病。
5.一种治疗受试者的纤维化的方法,其包括:
提供包含TL1A抑制剂和DR3抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
6.一种逆转受试者的纤维化的方法,其包括:
提供包含TL1A抑制剂和DR3抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
7.一种治疗炎症的方法,其包括:
提供包含TL1A抑制剂和/或DR3抑制剂的组合物;并且
向所述受试者施用治疗有效剂量的所述组合物。
8.一种治疗受试者的疾病的方法,其包括:
抑制Ifnγ和Il-17表达,下调Tgfβ信号传导,和/或减少成纤维细胞/肌成纤维细胞;并且
治疗所述受试者。
9.一种组合物,其包含:
一种或多种TL1A、DR3和IL31RA信号传导功能的抑制剂;以及
药学上可接受的载体。
10.一种治疗与IBD相关的并发症的方法,其包括:
提供包含TL1A、DR3和IL31RA信号传导功能的抑制剂的组合物;和
向所述受试者施用治疗有效剂量的所述组合物。
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