CN107106014A - 5‑甲氧基色胺酸作为发炎疾病诊断试剂的用途 - Google Patents

5‑甲氧基色胺酸作为发炎疾病诊断试剂的用途 Download PDF

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CN107106014A
CN107106014A CN201580051141.9A CN201580051141A CN107106014A CN 107106014 A CN107106014 A CN 107106014A CN 201580051141 A CN201580051141 A CN 201580051141A CN 107106014 A CN107106014 A CN 107106014A
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郭呈钦
伍焜玉
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Abstract

本发明关于一种发炎疾病的诊断方法，及用于该方法的诊断套组。本发明的诊断方法包含使用一种新颖色胺酸代谢物，5‑甲氧基色胺酸(5‑methoxytryptophan，5‑MTP)，作为炎症反应的诊断标记物。本发明特别提供一种高度特异性竞争式免疫酵素法，借由测量人类血清中5‑MTP浓度以诊断包括败血病及全身性红斑性狼疮等发炎疾病的发生与严重程度。

Description

5-甲氧基色胺酸作为发炎疾病诊断试剂的用途
技术领域
本发明关于一种发炎疾病的诊断方法及其诊断套组。特别地，本发明关于一种利用5-甲氧基色胺酸(5-MTP)作为诊断生物标记物作为发炎疾病的诊断方法。本发明更涉及一种测量人类血清中5-MTP含量程度的高特异性竞争式酵素免疫法，用以检测发炎疾病，例如败血病及全身性红斑性狼疮(SLE)的发生与严重程度。
背景技术
发炎反应是一种具有新定义的旧概念。其分子与细胞机制的快速进展已彻底改变其对于生物医学的意义及应用。发炎是由于过度及不当的先天免疫系统活化所导致，例如COX-2-和类铎受体(TLRs)-信号的过度活化；该过程现今被认为是许多重要的人类疾病和健康问题的一个基本过程，例如脓毒病、全身性红斑性狼疮（SLE）、心血管疾病、代谢症候群、癌症、败血症与多样炎性关节、胃肠道和肾脏疾病。这些疾病影响世界超过千百万人的健康医疗保健负担、高成本高花费且造成社会经济影响。以2010年为例，败血病一年需要花费约50亿美金。在各种不同的健康问题与疾病，细胞与分子因子对于炎症的反应是既复杂又并非相同的。细胞因子、趋化因子以及小分子介质如落花生酸类、一氧化氮与其他脂质媒介等正逐渐成为各种炎症疾病控制的重要目标。另一方面，生物标记已被广泛应用于协助多种病况的诊断、预测或治疗(Ridker, Nutrition reviews 65:S253-259, 2007)。其对于促进病患治疗与新药发展亦相当重要。
包括TNF、IL-1β和IL-6等细胞因子可调控先天免疫系统对于受伤或感染的初步反应。该等细胞因子可以活化表皮细胞，吸引循环中的多型核白血球(PMNs)至该位置。彼等细胞因子亦可进入血液循环中，而引起发烧和其他全身性的症状。此外，某些细胞因子如IL-6可促进肝脏生成所谓的急性期反应物质(包含CRP)，其亦可刺激骨随中大量生产细胞，造成更多的PMNs被制造出来。因此，包含TNF、IL-1β和IL-6等细胞因子主要负责全身性发炎与发炎状态的病征，而可能具有作为败血症、红斑性狼疮以及炎症相关疾病生物标记物的潜力。仅管细胞因子已被作为有力的生物标记物，致力于使得提供全身性发炎或炎症疾病的病理生理学更具理解并确定更精确和灵敏的诊断、预测或治疗是相当重要的。我们假设，将细胞因子与和全身性发炎的进展或发展相关的特殊具潜力的代谢物组合，将有可能成功达到高灵敏度诊断。
Deng等人自人类纤维母细胞条件培养液中分离出水溶性小分子因子(称细胞护卫因子)，该等小分子因子可抑制纤维母细胞、巨噬细胞和表皮细胞内由LPS、促炎性细胞因子和有丝分裂因子所诱导的COX-2表现 (Deng et al., FASEB J 16:1286-1288, 2002)。本发明近期已借由比较代谢方法(comparative metabolomics)，鉴定出一种具新颖的色胺酸代谢产物，5-甲氧基色胺酸(5-MTP)，作为一细胞护卫因子(Cheng et al., Proc NatlAcad Sci U S A 109:13231-13236, 2012)。L-色胺酸系一种必需胺基酸，其不仅是蛋白质合成的构成单元，也可作为制造不同代谢产物的受体，其中有些如血清素、褪黑激素和犬尿胺酸等是公认扮演具有重要生理作用的角色。5-MTP是由L-色胺酸经过一新的途径所产生的(Cheng et al., 2012)。5-MTP可抑制在纤维母细胞和癌细胞内由前发炎因子所诱导的COX-2表现，并在异种移植模型中减少了癌细胞移转与侵犯和癌症转移(Cheng et al.,2012)。
5-MTP的生理功能与临床意义仍有待阐明。由于COX-2为多种发炎疾病包含败血病的发炎和过度表现主要调控者(Bitto et al., Crit Care 16:R32, 2012; Ejima etal., FASEB J 17:1325-1327, 2003; Wu et al., Arterioscler Thromb Vasc Biol 25:679-685, 2005)，我们推测5-MTP在发炎疾病如败血病和全身性红斑性狼疮中扮演重要一角。为了进一步研究5-MTP在全身性炎症中的角色，于本发明中，我们在败血症患者与全身性红斑性狼疮病患身上确定了5-MTP的临床意义。
发明内容
因此，在一方面，本发明提供一种发炎疾病的诊断套组，其包含：一检测试剂用于检测受试者血清中的5-MTP浓度。
于本发明的一些实施例，该发炎疾病包含败血病与全身性红斑性狼疮。
于本发明的一实施例，该检测试剂包含一抗-5-MTP抗体以及一5-MTP-结合的HRP化合物。
在另一方面，本发明亦关于一种发炎疾病的诊断方法，其包含检测受试者血清中5-MTP浓度的减少。
较佳的是，本发明所述的诊断方法包含一种竞争式免疫酵素法，用以测量血清中5-MTP的浓度。
于本发明的一些实施例，该诊断方法包含将一抗-5-MTP抗体与一含有5-MTP-结合的HRP化合物及受试者血清检体的混合物接触。
附图说明
图1A显示败血病患者与健康捐赠者的血清5-MTP浓度，该浓度是借由竞争式5-MTP免疫酵素法测定。图1B显示借由ROC曲线辨别5-MTP、hs-CRP和IL-β的分析结果。
图2显示于败血病小鼠模型中，5-MTP因脂多醣而减少。血清中5-MTP浓度是借由竞争式5-MTP免疫酵素法测量LPS感染前与感染24小时后的小鼠血清。该黑色实线为平均值。
图3A与3B表示源自于内皮细胞的5-MTP抑制由LPS引起的COX-2表现(图3A)，以及抑制巨噬细胞内细胞因子的产生。图3C表示5-MTP中和抗体剂量相关性地消除HUVEC-CM的抑制效果，而控制组IgG 1则无影响。
图4显示使用竞争式5-MTP免疫酵素法测量全身性红斑性狼疮患者与健康捐赠者血清中5-MTP浓度。
具体实施方式
本发明的其他特点与优势将在以下实施例中作进一步地说明。以下实施例系用于协助图式的说明描述，而非用于限制本发明。
特异性竞争式酵素免疫法的研发
尚未知晓循环血液中是否含有5-MTP。在本实例中，我们研发出一种高特异性竞争式酵素免疫法，用以量测病人、健康对照组和小鼠血清中的5-MTP 浓度。执行5-MTP特异性竞争式ELISA其关键步骤在于，产生一种5-MTP-结合的HRP化合物。5-MTP-结合的HRP (5-MTP-conjugated HRP)的制造步骤如下所述：
(1) 将0.8~1.0 mg的5-MTP完全溶解于100 μl含有30% DMSO 的1M碳酸氢钠缓冲液(pH=8.3) 中。将该溶液加入NH2-Reactive过氧化酶试管中，并将其轻吸放混匀至NH2-Reactiv过氧化酶完全溶解；
(2) 将该试管置于37 ℃混合反应1小时，而后移置4℃反应过夜；
(3) 将200 μl PBS加至该反应溶液中，并将该溶液转移至一过滤管中；
(4) 于8,000 xg离心10分钟后，去除上清液，将200 μl PBS加至该试管中；
(5) 于8,000 xg离心10分钟后，去除上清液，再次将200 μl PBS加至该试管中；
(6) 加入400 μl 保存缓冲液(含30%DMOSO的PBS)，并吸放约10分钟以溶解该结合物(conjugate)；
(7) 将该溶液移至微量离心管中，并于-20或-80°C进行储存。
血清5-MTP是在96孔微量滴定盘中以改良后竞争式ELISA量测如下所述：
(1) 于4°C下，以溶解于0.05 M碳酸盐-碳酸氢盐(pH9.6)涂覆缓冲液的多株兔抗-5-MTP抗体进行96孔微量滴定盘的涂覆反应的过夜；
(2) 经PBST进行润洗并用封闭缓冲液处理后，将含有5-MTP-结合的HRP化合物及5-MTP标准液或血清检体的混合液加入各孔中，并于4°C反应过夜；
(3) 将各孔以PBST进行润洗，并以受质四甲基联苯胺(tetramethylbeuzidine)于室温反应20~30分钟；
(4) 反应后，将0.1N H2SO4停止液加入各孔中；及
(5) 于30分钟内，以波长450 nm进行产物分析。以浓度0.1-500 μM的纯5-MTP制定校准曲线。
以竞争式酵素免疫法检测败血病患者的血清5-MTP浓度
为评估5-MTP的临床意义，遂进一步检测经临床证实已罹患败血病的患者与一般健康控制组的血清5-MTP浓度。血清5-MTP的检测系借由改良式竞争型酵素免疫分析法，于已使用溶解于涂覆缓冲液(0.05M碳酸盐-碳酸氢盐, pH9.6)的多株兔抗-5-MTP抗体(Abcam)于4°C放置隔夜进行涂覆的96孔盘中进行。经PBST进行润洗并用封闭缓冲液处理后，将含有经由使用NH2过氧化酶标定套组 (Abnova)所产生的5-MTP-结合的HRP化合物，及5-MTP标准液或血清检体的混合液加入各孔中，并于4°C反应过夜。将各孔进行润洗，并以受质四甲基联苯胺于室温反应20~30分钟。反应完毕后，将0.1N H2SO4停止液加入各孔中。于30分钟内，以波长450 nm进行分析产物。以浓度0.1-500 μM的纯5-MTP制定校准曲线。
有55位败血病患者进行登记(29位男性及21位女性，平均年龄为64.0±19.6岁)。取自30位健康控制组的平均正常血清5-MTP浓度为1.05 μM(表一)。败血病患者的血清5-MTP浓度平均值显著减少为0.37 μM(图1A及表一)。败血病患者相较于健康者，其高敏感度-C反应蛋白( high-sensitivity-C reactive protein, hs-CRP) (98.2 ± 74.3 mg/L 相对于对照组0.5 ± 0.5 mg/L, P < 0.001)和IL-1β (1327 ± 2445 pg/ml相对于对照组526 ± 175 pg/ml, P = 0.025)浓度显著增加(表一)。
表一　败血病患者及健康捐赠者血清中5-MTP、hs-CRP与IL-1β浓度
当已确认血清hs-CRP与IL-1β浓度可作为败血病严重程度的诊断标记时，我们利用ROC曲线下面积(area under the receiver operating characteristic curve, AUROC)以检测5-MTP、hs-CRP与IL-1β浓度于上述该组败血病患者的识别力(图1B及表二)。
表二　5-MTP、hs-CRP与IL-1β于败血病最佳诊断临界值的敏感度及特异度
5-MTP的AUROC值(0.958, 95% CI 0.919-0.997)与hc-CRP的AUROC值(0.995, 95% CI0.987-1.000)差异不大，而且显著大于IL-1β的AUROC值。由AUROC曲线演算出，hs-CRP及IL-1β最佳诊断效率的临界水平分别为2.73 mg/L(敏感度100%，特异度93.9%)及467.29 pg/ml(敏感度53.3%，特异度78%)。以浓度0.63 μM血清5-MTP作为临界值，其敏感度为83%以及其特异度为94% (图1B)。以上结果显示5-MTP为败血病严重程度的预测生物标记物。更重要的是，于败血病患者的血清5-MTP与炎症标记物如hs-CRP及IL-1β呈现正相关。此外，由前述结果推论，比起单独检测hs-CRP或IL-1β，同时检测hs-CRP与5-MTP可提供更好的败血病严重度预测。
于异种败血病鼠模型中LPS抑制5-MTP
我们推论，败血病患者血清5-MTP的降低是由于内毒血症所导致。为进一步左证，遂分析败血病小鼠的血清5-MTP，该败血病小鼠是经由LPS感染所产生。C57BL/6小鼠(6-8周龄)在进行腹腔注射LPS的前30分钟，先以腹腔注射生理食盐水或不同浓度的5-MTP进行处理。监测小鼠存活及其他临床症状，包含竖毛、嗜睡、腹泻及体重减轻。一些小鼠在LPS注射后，于不同时间进行牺牲，收集其血液检体、腹腔体液、肺脏及脾脏。所有老鼠实验皆经过动物护理机构与使用委员会、国卫院批准。
小鼠在使用LPS处理之前的血清5-MTP平均浓度为0.187 μM，约为人类血清5-MTP平均浓度的1/6。在LPS感染后，血清5-MTP显著减少为0.036 μM (图2)。8只小鼠于LPS感染后，其中6只的血清5-MTP浓度变为无法检测或极端减少，其他1只为稍减弱，1只则保持不变。以上结论推测，内毒血症会抑制5-MTP，而导致临床严重度。
源自内皮细胞的5-MTP抑制巨噬细胞内由LPS所诱导的COX-2表现及细胞因子的产生
内皮细胞对于败血病被认为在发炎组织伤害的控制系统机制中扮演重要角色。我们假设内皮细胞会制造水溶性因子如5-MTP以调控发炎反应。为验证此假设，我们以含有或不含LPS的HUVEC条件培养液培养小鼠RAW264.7巨噬细胞24小时，而后测量COX-2表现量以及IL-6产生量。在RAW264.7细胞内，由LPS所诱发的COX-2表现量以及IL-6产生量，会因加入HUVEC条件培养液而衰减(图3A, B)。
由于5-MTP已被认为是一种在抑制前发炎调节剂所诱发的COX-2表现上扮演重要一角的纤维母细胞释放因子 (Cheng et al., 2012)，我们利用5-MTP中和抗体，判别5-MTP是否在负责抑制由LPS所诱发COX-2表现与细胞因子产生的HUVEC-CM反应中作为可溶性因子。图3C的结果显示，5-MTP中和抗体以剂量依赖的方式，消除HUVEC-CM对于的抑制效果，而IgG控制组则不受影响。
SLE患者具较低的5-MTP浓度
血清5-MTP浓度与SLE生理学是否有关并未知。因此，我们利用如上所述的高特异性免疫酵素法测量SLE患者中的血清5-MTP浓度。共135名受试者。值得注意的是可以观察到SLE患者血清5-MTP浓度显著减少致平均约为0.45μM，其意味5-MTP降低可能影响SLE患者对于过度发炎反应的预防。
综合上述，观察到于败血病患者以及SLE患者中的血清5-MTP浓度，显著减少至健康受试者的30%。更重要地，败血病患者的血清5-MTP浓度与发炎标记物如hs-CRP与IL-1β呈现正相关。另外，血清5-MTP对于败血病的严重度具有高度辨识力。本发明的结果显示，比起单独检测hs-CRP或IL-1β，同时检测hs-CRP与5-MTP可提供更好的败血病严重度预测。另外，本发明亦请求5-MTP为一种用于预测败血病、SLE与发炎疾病的新颖诊断生物标记物。更进一步地，请求高特异性5-MTP竞争型酵素免疫分析作为一种判断发炎疾病发生及严重度的诊断套组。

Claims (8)

1.一种发炎疾病的诊断套组，其特征在于，包含：一检测试剂用于检测受试者血清中的5-甲氧基色胺酸(5-methoxytryptophan，5-MTP)浓度。
2.如权利要求1所述的诊断套组，其特征在于，该发炎疾病为败血病。
3.如权利要求1所述的诊断套组，其特征在于，该发炎疾病为全身性红斑性狼疮(SLE)。
4.如权利要求1所述的诊断套组，其特征在于，该检测试剂包含一抗-5-MTP抗体以及一5-MTP-结合的HRP化合物。
5.如权利要求1所述的诊断套组，其特征在于，进一步包含一检测试剂用于侦测受试者血清中hs-CRP浓度。
6.如权利要求1所述的诊断套组，其特征在于，炎症患者血清中5-MTP浓度降低至约为健康受试者的30-50%。
7.如权利要求2或6所述的诊断套组，其特征在于，败血症患者血清中5-MTP浓度降低至约为健康受试者的30%。
8.如权利要求3或6所述的诊断套组，其特征在于，全身红斑性狼疮患者血清中5-MTP浓度降低至约为健康受试者的30%。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050214859A1 (en) * 2003-03-03 2005-09-29 Dyax Corp. Peptides that specifically bind HGF receptor (cMet) and uses thereof
WO2007054348A1 (de) * 2005-11-11 2007-05-18 Ernst-Moritz-Arndt-Universität Greifswald Neue arzneimittel
US20070167474A1 (en) * 2004-05-12 2007-07-19 Helmut Schmidhammer Use of opioid receptor antagonist compounds for the prevention and/or treatment of diseases associated with the target calcineurin
WO2009151967A1 (en) * 2008-05-28 2009-12-17 Georgia Tech Research Corporation Metabolic biomarkers for ovarian cancer and methods of use thereof
WO2011106635A1 (en) * 2010-02-25 2011-09-01 The Trustees Of The University Of Pennsylvania Treatment of sepsis using complement inhibitors
US20140113833A1 (en) * 2012-10-18 2014-04-24 The Cleveland Clinic Foundation Use of multiple risk predictors for diagnosis of cardiovascular disease

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2557458B1 (fr) * 1983-12-30 1987-09-04 Centre Nat Rech Scient Nouveaux anticorps capables de reconnaitre specifiquement des groupements hapteniques, leur preparation et leur application, et nouveaux antigenes permettant de les preparer

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050214859A1 (en) * 2003-03-03 2005-09-29 Dyax Corp. Peptides that specifically bind HGF receptor (cMet) and uses thereof
US20070167474A1 (en) * 2004-05-12 2007-07-19 Helmut Schmidhammer Use of opioid receptor antagonist compounds for the prevention and/or treatment of diseases associated with the target calcineurin
WO2007054348A1 (de) * 2005-11-11 2007-05-18 Ernst-Moritz-Arndt-Universität Greifswald Neue arzneimittel
WO2009151967A1 (en) * 2008-05-28 2009-12-17 Georgia Tech Research Corporation Metabolic biomarkers for ovarian cancer and methods of use thereof
US20120004854A1 (en) * 2008-05-28 2012-01-05 Georgia Tech Research Corporation Metabolic biomarkers for ovarian cancer and methods of use thereof
WO2011106635A1 (en) * 2010-02-25 2011-09-01 The Trustees Of The University Of Pennsylvania Treatment of sepsis using complement inhibitors
US20140113833A1 (en) * 2012-10-18 2014-04-24 The Cleveland Clinic Foundation Use of multiple risk predictors for diagnosis of cardiovascular disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUEI-HSUAN CHENG ET AL: "Quiescent and Proliferative Fibroblasts Exhibit Differential p300 HAT Activation through Control of 5-Methoxytryptophan Production", 《PLOS ONE》 *
杨惠聪等: "超敏C-反应蛋白(hs-CRP)检测在儿科细菌感染性疾病中的应用价值", 《现代诊断与治疗》 *

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