CN1228705A - 寡糖作为免疫调节剂在皮肤美容组合物中的用途 - Google Patents
寡糖作为免疫调节剂在皮肤美容组合物中的用途 Download PDFInfo
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Abstract
本发明涉及至少一种含有2—6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖的衍生物在制备免疫调节药物中的用途。还涉及一种皮肤美容组合物和一种过度反应性皮肤的美容疗法。
Description
本发明涉及可用于免疫学领域,尤其是用于治疗导致变态反应和各种无耐受力现象的过敏性反应的化合物。
通过识别抗原(或变应原)的外源特性和活化用于消除外来抗原的细胞或激素介质来完成针对传染性物质、毒素或肿瘤的免疫防御。然而,当它太强或在遇到非内在有害的外界抗原时,有时这种机理可能是不希望有的;在器官移植或组织移植中情况同样如此。
作为变态反应基础的免疫反应被分成四类:-类型Ⅰ;肥大细胞通过其Fc受体与IgE抗体结合;抗原的固定引发肥大细胞的脱粒和介质(组胺、SRS-A、ECF-A)的释放。-类型Ⅱ:特异性抗体(IgG或IgM)与靶细胞表面的抗原反应;这通过K细胞的直接作用或通过补体的活化导致细胞溶解。-类型Ⅲ:抗体(IgG或IgM)与抗原和补体形成沉积在组织中并导致多核嗜中性粒细胞趋化因子产生的免疫复合物;并产生局部炎症。-类型Ⅳ:对抗原敏感的T淋巴细胞与其反应并释放淋巴因子。淋巴因子诱导炎症反应并导致巨噬细胞汇集。
因此,在细胞或激素介导的,尤其是抗体分泌介导的免疫中,淋巴细胞是关键细胞。
变应性疾病可以是一种或多种类型的免疫反应的体现。
这些反应同样可以是在被称为“反应过度的”皮肤中观察到的对卫生和护理产品无耐受力反应的基础。
这些现象是由于内在的遗传因子和由环境导致的后天过敏性。
出乎意料的是,申请人现已发现这些过敏现象可通过含有2-6个糖苷残基并且在非还原末端位置具有半乳糖残基的寡糖或被疏水残基取代的该寡糖的衍生物而得以控制。
本发明涉及含有2-6个糖苷残基并且在非还原末端位置具有半乳糖残基的寡糖或其衍生物在制备免疫调节组合物,尤其是用于治疗或预防过敏性反应的组合物中的用途。
尤其适宜的寡糖可选自蜜二糖、乳糖和其能通过加入疏水残基而获得的衍生物。
疏水性取代基主要被理解为指直链或支链C1-C18烷基、C1-C18烷基胺、任选取代的直链或支链C1-C18羧酸、直链或支链伯、仲或叔C1-C18酰胺和C1-C18芳基烷基。
适于本发明的寡糖衍生物可尤其属于下述类别的一类,其中寡糖对应于下面通式:
半乳糖-n(α或β)-(Hex)p其中n代表位置1,2,3,4或6,Hex代表α-或β-连接的己糖或戊糖,p为1-5的整数;a)-对应于下式的糖苷;.(Ⅰ)寡糖1-O-R,其中R为1-18个碳原子的直链或支链烷基残基,.(Ⅱ)寡糖1-O-R-O-1-寡糖,其中R=(CH2)m,m为2-10,b)-根据下式之一的酰化的糖胺,其中寡糖优选为乳糖、蜜二糖或水苏糖:-对应于下式之一的酰化的糖胺:.(Ⅲ)寡糖1-NH-CO-R,其中R为包含0、1或2个双键的含有2-18个碳原子的烷基残基,.(Ⅳ)寡糖1-NH-CO-R-CO-NH-1-寡糖,其中R=(CH2)m,m为2-8,c)-被由寡糖氧化获得的醛糖酸酰化的烷基胺.(Ⅴ)寡糖-CO-NH-R,其中R具有与式(Ⅲ)中相同的含义,.(Ⅵ)寡糖-CO-NH-R-NH-CO-寡糖,其中R具有与式(Ⅲ)中相同的含义,d)-或通过寡糖与脂族单或二胺形成的对应于下式之一的希夫碱的还原产物:.(Ⅶ)Gal-(Hex)n-X-HN-R,.(Ⅷ)Gal-(Hex)n-X-HN-R-NH-X-(Hex)n-Gal,其中:Hex为己糖或戊糖,n=0,1或2,X=1-NH2-己糖醇,和R具有如(Ⅲ)中的相同含义。
根据一个特别有利的方法,如上定义的寡糖或其衍生物将被用来制备还包含适宜于外部局部途径给药的药物可接受的赋形剂的组合物。
事实上,本申请人发现参与过敏性相关疾病的反应可能与来自弹性蛋白,尤其是由卡巴-弹性蛋白降解的肽在特异性淋巴细胞受体上的固定相关。
这些受体的活化引发裂解酶、β-葡糖醛酸糖苷酶、弹性蛋白酶和自由基如超氧化物离子或产生羟基自由基的过氧化氢的释放。这些产物可参与细胞外基质的大分子、纤连蛋白、胶原蛋白和透明质酸的降解。弹性蛋白肽的固定同样刺激淋巴细胞的增殖。
这些现象在特异反应性来源的免疫变态反应,尤其是特异反应性皮炎或过敏反应、寻麻疹和变态反应性接触性皮炎中起着重要的作用。
拥有被称为“敏感”或反应过度的皮肤的个体在人群中越来越普遍。这种皮肤发红或感到刺痛,且相对于其它皮肤,其反应性阈值降低。
个体遭受与红斑有关的皮肤不适并且可发生轻微的脱皮。
通过使用包含本发明的寡糖的组合物将改善或甚至抑制所有这些症状;蜜二糖、乳酸或其衍生物部分或完全抑制细胞增殖,尤其是被在先刺激过的淋巴细胞的增殖;它们同样可抑制裂解酶产生的潜能和其释放。
该组合物优选被配制在不含有任何香料或变态原性物质的赋形剂中。该组合物可为溶液、凝胶、洗剂、乳膏、W/O或O/W乳剂或多重乳剂的形式或脂质体形式。本领域技术人员优选用润肤剂或温和的表面活性剂来配制它们。
该组合物尤其适宜于治疗或预防皮肤和/或粘膜的无耐受力和/或变态反应。
尤其是,根据本发明的组合物被用来防止或降低自由基的形成。
寡糖或其衍生物可与能使皮肤被保护和/或被水合的其它物质混合,如透明质酸、维生素E、银杏(G.biloba)的乙二醇提取物、山梨糖醇、葡糖胺基聚糖、藻酸盐等;同样它们可与植物油混合以营养皮肤和/或与活性润肤剂和油膏混合,如猫眼葡萄、蜀葵、燕麦、菩提树、春黄菊、甜三叶草、假叶树(Ruscus)的提取物、矢车菊醇、α-没药醇、椰子油和18-β-甘草亭酸。
根据本发明的另一方面,如上定义的寡糖和其衍生物被用来制备另外还含有适宜于经胃肠外或肠内途径给药的药物可接受的赋形剂的组合物。
本发明的寡糖的功效是基于其对细胞介导的免疫反应的意想不到的活性。
根据本发明制备的组合物尤其可用于治疗或预防淋巴细胞介导的过敏性反应。
它们尤其被用来治疗或预防选自特异反应性疾病、多形式红斑、干皮病、红斑狼疮、天疱疮、皮炎、牛皮癣和湿疹的疾病症状。
在非还原末端位置具有半乳糖残基的寡糖和其被疏水残基取代的衍生物可被用作限制能被其它有效成分激发的过敏性反应的佐剂。
本发明也涉及一种反应过度皮肤的美容治疗方法,特征在于通过局部途径施用含在美容可接受的赋形剂中的包含至少一种含有2-6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖衍生物的组合物。
用于实施该方法的特别优选的化合物为蜜二糖、乳糖和其能通过加入疏水残基而获得的衍生物。下面的实施例旨在说明本发明。
在这些实施例中,将参考下面附图:
图1:乳糖和蜜二糖对κ-弹性蛋白刺激淋巴细胞增殖的活性的抑制。乳糖和蜜二糖的浓度为1μg/ml,10μg/ml,100μg/ml,1mg/ml和2mg/ml。图2:乳糖和蜜二糖对用2μg/mlκ-弹性蛋白刺激的淋巴细胞弹性蛋白活性表达的抑制。活性存在于培养基中。图3:乳糖和蜜二糖对用2μg/mlκ-弹性蛋白刺激的淋巴细胞组织蛋白酶G活性表达的抑制。活性存在于培养基中。
实施例11-方法淋巴细胞的分离
从循环人血和从扁桃体摘除术后的人扁桃体获得用于这些实验的淋巴细胞。如下进行外周淋巴细胞的分离:在分离两相之前,在Ficoll-paqueplus(Pharmacia)中小心地使5ml血沉积(于15ml离心管中),接着室温(20℃)下,以3000 rpm(即600g)离心40分钟。回收含有淋巴细胞和单核细胞的层并与10ml RPMI培养基混合,20℃下,以2200rpm(即400g)离心10分钟。将沉淀重新悬浮在0.5ml RPMI中,然后再加入4.5ml RPMI,20℃下,以1500rpm(即400g)再次离心10分钟。将最终沉淀回收在10mlRPMI中并对细胞计数。通过粘附在塑料表面(在CO2/O2培养箱中培养2小时)清除单核细胞和巨嗜细胞。多核细胞(PMN)的分离
在以3000rpm(即600g)首次离心后,将含有红细胞和多核细胞的残留物重新悬浮在1%聚乙烯醇(PVA)的DPBS溶液中(Dulbecco氏改进的磷酸缓冲盐溶液)(2体积DPBS/体积沉淀),接着在室温下让其沉积20分钟。4℃下,以400g将上清离心5分钟,通过轻微搅拌将沉淀用DPBS洗涤以除去聚乙烯醇而不活化多核细胞,接着4℃下,以400g离心。除去上清。通过渗压震扰使红细胞溶解,然后加入过量的DPBS以重建渗透平衡。4℃下,以400g离心5分钟后,将含有多核细胞的沉淀溶解在少量体积的RPMI中。进行细胞计数,并可通过0℃下加入0.1%Triton X-100的1M NaCl溶液达20分钟溶解细胞以释放裂解酶(弹性蛋白酶、组织蛋白酶),接着0℃下离心20分钟。上清含有这些酶。从人扁桃体开始的淋巴细胞的制备
无菌条件下,在10ml RPMI中将新摘除的扁桃体切成小片。在粗过滤器中过滤组织悬液以去除最大体积的碎片。将悬液放置在试管中,室温下,让其沉积15分钟。将上清置于Ficoll-paque plus中,并如对来自血液的淋巴细胞所描述地将其离心。如对来自血液的淋巴细胞所描述地除去单核细胞。将含有淋巴细胞的沉淀重新悬浮,在两次如所描述的离心后进行细胞计数。从扁桃体获得的淋巴细胞为大约50%T型和50%B型。血液来源的淋巴细胞为大约80%T型和20%B型。淋巴细胞的培养
以500μl细胞悬液/孔(5×105细胞/ml或2.5×105细胞)将如上所述分离的淋巴细胞培养在24孔Costar平板中的由10%胎牛血清(ATGC)、2mM谷氨酰胺(Gibco)、青霉素和链霉素(500U/ml,0.25mg/ml)和植物凝集素(SIGMA)5μg/ml组成的RPMI1640培养基(Eurobio)中。在细胞培养条件下(37℃,CO2/O2培养箱)培养4天后,用移液管回收细胞悬液,20℃下以400g离心10分钟,将细胞沉淀溶解在0.5ml RPMI(不含FCS)中,搅拌分散,接着在加入10ml不含FCS的RPMI后,20℃下,以1500rmp(即400g)再离心10分钟。再进行两次如上所述的洗涤后,将沉淀溶解在10ml不含FCS的RPMI中,将细胞再次培养在24孔Costar平板中。弹性蛋白肽的作用
以所示浓度(例如2μg/ml)将κ-弹性蛋白(75KD,Solabia)的无菌溶液加入到被放回到不含FCS的培养基中的细胞中,在37℃下培养2.5小时。培养后,轻轻振荡平板,通过移液管吸取来回收细胞并计数。4℃下,以1500rpm(即400g)将悬液离心10分钟,以50μl/管的比例将上清分配在1ml Eppendorf管中,如果不立即用于酶测定则贮存在-40℃下。将细胞沉淀重新悬浮在提取缓冲液(0.1%Triton X-100,1M NaCl,0.02%NaN3,0.01%Brij35,PH8)中。0℃下,以1600g将1ml/106细胞振荡15分钟,并将如上所述通过离心获得的上清重新分配在Eppendorf管中,贮存在-40℃下以用于酶测定。白细胞弹性蛋白酶类型的酶活性的测定
用于测定弹性蛋白酶类型的酶活性的合成底物为Me-O-Suc-Ala-Ala-Pro-Val-pNA。将50μl培养基或20μl细胞溶胞产物与缓冲液(100mMtris-HCl,0.05%CaCl2,0.02%NaN3,0.01%Brij35,pH8)混合至190μl,接着与10μl 85mM底物(N-甲基吡咯烷酮)溶液混合至总体积为200μl。立即以及在37℃下温育4,24,48和72小时后读取410nm处的光密度。以每106细胞每小时水解的底物的nM表示弹性蛋白酶活性。组织蛋白酶G的酶活性的测定
在如上的相同条件下使用25mg底物MeO-Suc-Ala-Ala-Pro-Met-pNA的1ml N-甲基吡咯烷酮溶液(40nM)。2-结果A)弹性蛋白肽对淋巴细胞增殖的影响
通过将弹性蛋白肽加入到血液白细胞中所产生的钙通道可被认为是引发一系列细胞功能的胞内信号的指征。其中之一为细胞进入增殖状态。已表明在弹性蛋白肽存在时人皮肤成纤维细胞即为这种情况(Ghuysen-Itard等C.R.Acad.Sci.,1992,315:473-478)。报导在表1的结果表明观察到了类似于淋巴细胞增殖的刺激。表1
κ弹性蛋白的浓度 实验次数 刺激百分数,平均值±SD |
2μg/ml 6 62.67±37.9010μg/ml 13 35.76±29.50 |
在2μg/ml弹性蛋白肽时观察到最大刺激,在10μg/ml弹性蛋白肽时观察到稍微弱一些的刺激。B)弹性蛋白肽导致的蛋白水解活性的释放
当在存在2μg/mlκ-弹性蛋白的培养条件下培养多核细胞或淋巴细胞时,在细胞提取物和细胞溶胞产物中可测得弹性蛋白酶和组织蛋白酶活性的逐渐增加。在来自老年动脉粥样硬化个体的细胞中这种增加更为显著。在不存在κ-弹性蛋白时未观察到这种增加。虽然这种作用对于培养物上清中的酶活性的释放更为显著,但弹性蛋白肽的加入同时增加培养基(被盐析的酶)和细胞提取物(与细胞结合的酶)中的弹性蛋白酶以及组织蛋白酶G的蛋白水解活性。C)弹性蛋白肽对细胞存活的影响
在如上所述的培养条件下,在存在植物凝集素(PHA)时进行本实验。
将5ml从人扁桃体获得的淋巴细胞悬液的等分试样(5ml中有2.5×106个细胞)分配在试管中,加入递增浓度的κ-弹性蛋白(BPM,PM<10kDa):0.1μg/ml,2μg/ml,10μg/ml,500μg/ml,1mg/ml和2mg/ml。在培养条件下保温4天后,回收细胞并计数。表2给出了作为加入的弹性蛋白肽浓度的函数的细胞损失。表2弹性蛋白肽的浓度,μg/ml通过锥虫蓝排阻法确定的细胞损失的百分数0 5.31 5.02 2.510 17.4100 19.6500 28.91000 39.32000 39.1
看来在高浓度时(比刺激细胞增殖和盐析裂解酶的浓度高数千倍)弹性蛋白肽产生细胞毒性活性。实施例2:乳糖和蜜二糖对通过淋巴细胞弹性蛋白受体介导的反应的影响1)细胞增殖的抑制
如图1所示,递增浓度的乳糖和蜜二糖逐渐抑制弹性蛋白肽的生长刺激作用,接着的是在等于5.84×10-3mM的最大试验浓度(1和2mg/ml)时完全抑制增殖。增殖的最强抑制对于乳糖为16-30%,对于蜜二糖为26-58%。2)乳糖和蜜二糖对通过弹性蛋白受体引发的蛋白水解酶的盐析的影响
如上所示,在存在2μg/mlκ-弹性蛋白时在培养基以及培养的人淋巴细胞的细胞溶胞产物中观察到蛋白水解酶活性增加40-120%。从1μg/ml开始的蜜二糖有效地抑制裂解酶活性释放的刺激作用。这可证实对弹性蛋白酶活性以及组织蛋白酶G的抑制。乳糖同样具有功效,但它不如蜜二糖功效强(图2和3)。实施例3:人淋巴细胞亚群中的弹性蛋白受体的定量测定方法使用的抗体:-一抗:在小鼠中产生的67kD弹性蛋白/层纤连蛋白抗受体抗体(牛)(类型:IgM)(Elastin Products Company)。-二抗:用罗丹明(TRITC)标记的在山羊中产生的小鼠抗IgG+IgM(H+L)抗体(Jackson免疫研究实验室)(用于荧光显微镜)。-二抗:抗IgM抗体(用r-藻红素(Chemicon)标记的在山羊中产生的小鼠(F(ab’)2)(用于流式细胞计数法)。方法:a)荧光显微镜
从扁桃体分离人淋巴细胞(如实施例1中所描述),在存在5μg/ml植物凝集素(以活化它们)以及对于某些培养存在2μg/ml高分子量的(75kD)卡巴弹性蛋白的条件下,将其培养在含有10%胎牛血清(FCS)的RPMI1640培养基中。37℃下,培养48-120小时后,将淋巴细胞用含2%FCS的RPMI培养基洗涤3次,接着离心(400g,4℃,10分钟)。然后,进行细胞计数,用含2%FCS的RPMI培养基将细胞密度调至107细胞/ml。
接着,冰浴中将1体积(100μl)的人淋巴细胞的细胞悬液(约106细胞)与10μl一抗溶液(稀释至1∶100)一起温育30分钟。将1.5ml冷RPMI加入到2%FCS中,接着,4℃下,将细胞在冷冻离心机中进行洗涤(400g,10分钟)。
将二抗溶液(与TRITC结合)(在冷RPMI中稀释至1∶200)加入到沉淀层中。轻微搅拌悬液后,4℃下,将其温育30分钟。接着将1.5ml冷RPMI加入到2%FCS中,4℃下,以400g将悬液离心10分钟。
在最后洗涤结束时,在己通过倾析除去上清后,将淋巴细胞重新悬浮在剩余的培养基中。在载玻片上制作涂片并风干。在用无水乙醇固定5分钟后,通过浸没在几份PBS中使载玻片重新水合并在缓冲甘油(9体积甘油加1体积PBS)中封固。这种固定后处理增加免疫荧光的亮度。
为了鉴定被标记的细胞,交替地在紫外照射和可见光下检查显微镜视野。b)荧光测定法
在最后洗涤结束时,将淋巴细胞悬浮在1ml PBS中,将细胞用细胞荧光光度术分析。
被鉴定的细胞群如下:-全T淋巴细胞(CD3+)-“辅助”T淋巴细胞(CD4+)-抑制性T淋巴细胞(CD8+)-B淋巴细胞(CD20+)-T活化的淋巴细胞(CD25+)-记忆T淋巴细胞(CDA+/CD45RO+)-粒细胞(CD15+)所采用标记的描述CD3
所有成熟的人T细胞都表达CD3复合物。它具有16-28kD的分子量,且由5条以非共价方式与T细胞受体结合的链(γ,σ,ε,ζ,η)组成。它参与活化信号的传递。CD4
在CD4+细胞与抗原呈递细胞或靶细胞的细胞相互作用期间,CD4(T4)识别Ⅱ型MHC分子。它为属于免疫球蛋白超家族的59kD的糖蛋白。它存在于T淋巴细胞的“辅助细胞/诱导物”亚群(45%的外周血淋巴细胞)。CD8
CD8分子(T8,30/32KD)是由两条肽链组成的糖蛋白。它存在于T淋巴细胞的细胞毒性/抑制因子亚群(20-35%的外周血淋巴细胞)。它还出现在NK细胞和30%的外周血“裸”细胞中。CD15
CD15抗原(3FAL,X-半抗原,SSEA)为乳糖-N-岩藻戊糖Ⅲ(200-185kD)。CD15的至少5种主要抗原存在于多核细胞(循环人粒细胞的约90%)的表面和部分循环单核细胞(30-60%)上。该抗原不存在于正常淋巴细胞的表面。CD20
CD20抗原为35/37kD的磷蛋白。它存在于外周血、扁桃体以及骨髓的所有正常的B细胞上。CD25
CD25分子相当于白细胞介素-2的低亲和性受体。它为由活化的淋巴细胞(T和B)且也为由活化的巨噬细胞表达的55kD糖蛋白。CD45RO
这是一种180kD的跨膜糖蛋白(白细胞共同抗原(LCA)的低分子量的同种型)。它存在于T淋巴细胞、胸腺细胞、粒细胞、单核细胞的表面(但不存在于巨噬细胞的表面)和少量B淋巴细胞上。表达CD 45RO的T淋巴细胞为记忆T淋巴细胞(或接触过抗原的T淋巴细胞)(外周血T淋巴细胞的45%)
CD4+/CD45RO+细胞产生“辅助细胞”信号。这些为IL-2和IFN-γ的早期生产者。
为了用抗CDx抗体(来自Serotec的Sigma产品,抗CD25抗体除外)进行标记,以107细胞/ml的细胞密度将100μl淋巴细胞悬液(已标记或未标记)用弹性蛋白的67kD抗受体抗体处理。
加入10ml抗CDx抗体,20℃下,将悬浮液温育30分钟(对于抗CD25抗体:0℃下进行保温)。接着加入2ml PBS。两次洗涤后(两次20℃下以400g进行10分钟的离心),取细胞层,向其中加入0.5ml的PBS,将悬液用细胞荧光光度术进行分析。
同样通过同种型类似的小鼠免疫球蛋白(非特异性骨髓瘤蛋白)进行细胞的标记(用于对照)。结果a)荧光显微镜活化淋巴细胞中的弹性蛋白受体的证实
在上述实验条件下,表达67kD弹性蛋白/层纤连蛋白受体的部分被分析的淋巴细胞显示出特异性免疫荧光(阳性细胞)。通过荧光显微镜评价培养第4天时的阳性细胞的百分数:-在存在2μg/ml卡巴弹性蛋白时培养的细胞:28.52±12.60%-不存在卡巴弹性蛋白时培养的细胞;28.09±10.91%。
在两组之间没有显著性差异,PHA的活化是足以使弹性蛋白受体达的刺激。培养第5天时的阳性细胞的百分数:-在存在2μg/ml卡巴弹性蛋白时培养的细胞:77.2%±6.7%。用乳糖或蜜二糖洗涤细胞的作用:-在存在2μg/ml卡巴弹性蛋白时培养的+在细胞培养结束时用1mg/ml乳糖溶液洗涤的细胞:26.6%±6.7%(p<0.001)。
洗涤前,77.2%的细胞为阳性。-在存在2μg/ml卡巴弹性蛋白时培养5天的+在细胞培养结束时用1mg/ml蜜二糖溶液洗涤的细胞:18.3%±9.7%(p<0.001)。
仅与二抗而不与一抗一起保温的荧光细胞(阴性对照)未显示任何荧光。因此,看来蜜二糖对于解吸淋巴细胞弹性蛋白受体的67kD亚基比乳糖更有效:在所采用的实验条件下,乳糖解吸66%的受体,蜜二糖解吸76%的受体。b)细胞荧光光度术表3在不同的培养天数表达弹性蛋白受体的人淋巴细胞的百分数D0:分离淋巴细胞的当天;D2,D3,D5:分离淋巴细胞后的第二;三;五天。
阳性细胞的百分数 | ||||
天 | 不存在卡巴弹性蛋白 | 实验次数 | 存在2μg/ml卡巴弹性蛋白 | P |
D0 | 1.12±0.2% | 6 | 1.15±0.1% | - |
D2 | 22.33±5.2% | 5 | 23.02±3.2% | - |
D3 | 29.70±0.8% | 7 | 32.40±3.5% | 0.178 |
D5 | 59.91±4.9% | 10 | 66.42±1.9% | 0.006 |
从本实验可以看出将细胞与作为刺激物的PHA一起保温逐渐诱导弹性蛋白受体的表达。在存在弹性蛋白肽时也刺激了这种诱导。然而,直至培养的第五天开始,这种刺激才变得明显。在这种条件下,约三分之二的淋巴细胞(≥66%)在其表面表达弹性蛋白受体。-双标记的结果表4确定表达弹性蛋白受体亚群的淋巴细胞双标记实验
CDx+R67kD=同时用抗CDx抗体和67kD弹性蛋白受体的抗亚基抗体标记细胞。注意:由于细胞可同时表达几种受体,因此百分数之和不等于100%。
表达弹性蛋白受体(67kD)和标记CDx的细胞的百分数 | ||
不存在卡巴弹性蛋白 | 存在卡巴弹性蛋白 | |
R67kD+ | 59.9 | 66.4 |
CD4+R67kD+ | 26.5 | 45.7 |
CD8+R67kD+ | 11.9 | 16.1 |
CD15+R67kD+ | 0.0 | 0.0 |
CD20+R67kD+ | 36.7 | 36.3 |
CD25+R67kD+ | 39.6 | 46.9 |
CD45RO+R67kD+ | 26.6 | 41.1 |
在本实验中,通过双标记确定在存在和不存在弹性蛋白肽时表达弹性蛋白受体的淋巴细胞亚群的特性。
看来检测的大多数淋巴细胞亚群表达弹性蛋白受体,除开仍为阴性的CD15+细胞。然而,该CD15标记对应于PMN和部分单核细胞。
在CD4+和CD45RO+淋巴细胞中,这种表达仅在存在弹性蛋白肽时才被显著刺激,其中在存在弹性蛋白肽时所述淋巴细胞强烈地增加弹性蛋白受体的表达。在被认为是辅助细胞和记忆细胞的细胞亚群的情况时即是如此。因此,在活化后通过对自身合成的正反馈作用偶联弹性蛋白受体应是这些细胞特有的。实施例4:针对低分子量的卡巴弹性蛋白对淋巴细胞的细胞毒性作用的保护1)淋巴细胞的分离
根据实施例1中描述的方法分离淋巴细胞。
将细胞悬液用含有5mM谷氨酰胺和10%FCS的RPMI稀释以使浓度为106细胞/2ml。2)细胞培养(D0)
将淋巴细胞培养在24孔Costar平板中(500μl细胞悬液/孔,浓度为106细胞/2ml)的补充RPMI1640培养基中。细胞的分配如下:-10ml不含κ-弹性蛋白的细胞悬液;-10ml含有2μg/mlκ-弹性蛋白的细胞悬液,和10ml含有2mg/mlκ-弹性蛋白的细胞悬液(对照含有κ-弹性蛋白而不含有乳糖和蜜二糖);-10ml含有2mg/mlκ-弹性蛋白+1mg/ml蜜二糖的细胞悬液;-10ml含有2mg/mlκ-弹性蛋白+1mg/ml乳糖的细胞悬液;-10ml含有1mg/ml蜜二糖的细胞悬液;-10ml含有1mg/ml乳糖的细胞悬液;3)在存在锥虫蓝时计数细胞以确定死亡细胞的百分数。
在培养的第5天(D4),回收细胞悬液,在存在0.1%锥虫蓝(Sigma)时在Malassez室中进行细胞计数(仅死亡细胞被锥虫蓝染成蓝色)。鉴于锥虫蓝的毒性,在加入染色剂后立即进行计数。结果
处理 | 细胞数目/ml | 死亡细胞的百分数(锥虫蓝) |
不存在卡巴弹性蛋白 | 5.8±0.6 | 9.2±0.4 |
存在2μg/ml卡巴弹性蛋白(对照) | 10.23±3.5 | 6.6±1.3 |
存在2mg/ml卡巴弹性蛋白 | 3.6+1.0 | 41.3+3.1 |
存在1mg/ml乳糖 | 7.7±1.5 | 14.5±1.9 |
存在1mg/ml蜜二糖 | 7.26±1.3 | 15.4±1.6 |
存在2mg/ml卡巴弹性蛋白和1mg/ml乳糖 | 8.8+0.7 | 10.6+2.3 |
存在2mg/ml卡巴弹性蛋白和1mg/ml蜜二糖 | 8.8+1.6 | 10.5+0.9 |
本表显示在存在弹性蛋白肽时死亡细胞的百分数以及乳糖和蜜二糖抗细胞死亡的保护。这种保护接近于100%:使用2mg/ml弹性蛋白肽的过度死亡率(与无κ-弹性蛋白的对照比较)为32.1%。在存在乳糖或蜜乳糖时,这种过度死亡率为1.3%(96%保护)。
Claims (13)
1.至少一种含有2-6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖的衍生物在制备免疫调节药物中的用途。
2.至少一种含有2-6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖的衍生物在制备用于治疗或预防过敏性反应的组合物中的用途。
3.根据权利要求1和2任一项的寡糖的用途,其特征在于寡糖选自蜜二糖、乳糖和其能通过加入疏水残基而获得的衍生物。
4.根据权利要求1-3任一项的寡糖的用途,其特征在于使用被选自下面的疏水残基取代的衍生物:直链或支链C1-C18烷基、C1-C18烷基胺、任意取代的直链或支链C1-C18羧酸、直链或支链伯、仲或叔C1-C18酰胺和C1-C18芳基烷基。
5.根据权利要求1-4任一项的寡糖的用途,其特征在于该组合物另外还含有适宜于经外部局部途径给药的药物可接受的赋形剂。
6.根据权利要求1-4任一项的用途,其特征在于该组合物另外还含有适宜于经胃肠外或肠道途径给药的药物可接受的赋形剂。
7.根据权利要求1-6任一项的寡糖的用途,其用于制备用于治疗或预防由淋巴细胞介导的过敏性反应的组合物。
8.根据权利要求1-7任一项的寡糖的用途,其特征在于该组合物用于治疗或预防皮肤和/或粘膜的无耐受力和/或变态反应。
9.根据权利要求1-8任一项的用途,其特征在于该组合物用来防止或降低自由基的形成。
10.根据权利要求1-8任一项的用途,其特征在于该组合物用来治疗或预防选自特异反应性疾病、牛皮癣、多形式红斑、干皮病、红斑狼疮、天疱疮、皮炎和湿疹的疾病症状。
11.皮肤美容组合物,其特征在于它含有至少一种活性成分以及一种限制对活性成产生过敏性反应的佐剂,其中该佐剂为含有2-6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖的衍生物。
12.美容治疗过度反应性皮肤的方法,其特征在于通过局部途径施用含在美容可接受的载体中的包含至少一种含有2-6个糖苷残基并在非还原末端具有半乳糖残基的寡糖或被疏水残基取代的该寡糖衍生物的组合物。
13.根据权利要求12的美容治疗方法,其特征在于寡糖选自蜜二糖和其能通过加入疏水残基而获得的衍生物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR96/09649 | 1996-07-31 | ||
FR9609649A FR2751876B1 (fr) | 1996-07-31 | 1996-07-31 | Utilisation d'un oligosaccharide comme immunomodulateur, composition dermato-cosmetique et methode de traitement cosmetique |
Publications (1)
Publication Number | Publication Date |
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CN1228705A true CN1228705A (zh) | 1999-09-15 |
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CN97197506A Pending CN1228705A (zh) | 1996-07-31 | 1997-07-30 | 寡糖作为免疫调节剂在皮肤美容组合物中的用途 |
Country Status (15)
Country | Link |
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EP (1) | EP0954322A1 (zh) |
JP (1) | JP2000516591A (zh) |
KR (1) | KR20000029754A (zh) |
CN (1) | CN1228705A (zh) |
AU (1) | AU3457697A (zh) |
BR (1) | BR9710630A (zh) |
CA (1) | CA2262564A1 (zh) |
CZ (1) | CZ29599A3 (zh) |
FR (1) | FR2751876B1 (zh) |
HU (1) | HUP9903904A3 (zh) |
NZ (1) | NZ333985A (zh) |
PL (1) | PL331478A1 (zh) |
RU (1) | RU99104398A (zh) |
SK (1) | SK12199A3 (zh) |
WO (1) | WO1998004270A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015059561A1 (en) * | 2013-10-25 | 2015-04-30 | Red Pinnace Limited | Dietary regime for treatment of acne and other inflammatory skin conditions |
US11328621B2 (en) | 2013-10-25 | 2022-05-10 | Red Pinnace Limited | Dietary regime for treatment of acne and other inflammatory skin conditions |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19836339B4 (de) | 1998-08-11 | 2011-12-22 | N.V. Nutricia | Kohlenhydratmischung |
WO2003101464A1 (fr) * | 2002-05-31 | 2003-12-11 | Amano Enzyme Inc. | Anti-inflammatoire, agent de lutte contre des affections allergiques, et aliment fonctionnel |
EP2123282A3 (en) * | 2003-10-24 | 2010-01-20 | N.V. Nutricia | Immunemodulating oligosaccharides |
JP2005281298A (ja) * | 2004-03-04 | 2005-10-13 | Fancl Corp | メリビオースを有効成分とするt細胞免疫調節剤 |
EP1597978A1 (en) | 2004-05-17 | 2005-11-23 | Nutricia N.V. | Synergism of GOS and polyfructose |
EP2012807A4 (en) * | 2006-04-10 | 2009-07-08 | Dikovskiy Aleksander Vladimiro | PHARMACEUTICAL COMPOSITION FROM AN ENTEROSORBEN AND PREBIOTIKA, DOSAGE FORMS AND METHOD FOR THE PREVENTION AND TREATMENT OF GASTROINTESTINAL DISEASES |
GB0915315D0 (en) | 2009-09-03 | 2009-10-07 | Univ Manchester | Use of non-digestible oligosaccharides |
GB2500585A (en) | 2012-03-23 | 2013-10-02 | Univ Manchester | Use of oligosaccharides to reduce skin pigmentation |
KR101689877B1 (ko) | 2014-08-28 | 2016-12-26 | (주)셀아이콘랩 | 아토피 개선용 화장료 조성물 |
KR101689875B1 (ko) | 2014-08-28 | 2016-12-26 | (주)셀아이콘랩 | 펩타이드와 아미노산의 혼합물을 함유하는 아토피 개선용 화장료 조성물 |
KR102046566B1 (ko) | 2018-08-09 | 2019-11-19 | 박정혜 | 피부 가려움 개선용 화장료 조성물 |
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FR2545087B1 (fr) * | 1983-04-29 | 1985-12-27 | Malte Oeuvres Hospit Fses Ordr | Nouveaux derives glucidiques du 5-hydroxytryptophane, obtention et application comme medicaments |
GR860379B (en) * | 1985-02-22 | 1986-06-11 | Akzo Nv | Novel disaccharide and trisaccharide derivatives of the lipid a type |
CA2118405A1 (en) * | 1992-05-26 | 1993-09-12 | Robert Maurice Ippolito | Immunosuppressive and tolerogenic modified lewisc and lacnac compounds |
-
1996
- 1996-07-31 FR FR9609649A patent/FR2751876B1/fr not_active Expired - Fee Related
-
1997
- 1997-07-30 NZ NZ333985A patent/NZ333985A/xx unknown
- 1997-07-30 CA CA002262564A patent/CA2262564A1/en not_active Abandoned
- 1997-07-30 KR KR1019997000867A patent/KR20000029754A/ko not_active Application Discontinuation
- 1997-07-30 HU HU9903904A patent/HUP9903904A3/hu unknown
- 1997-07-30 BR BR9710630-5A patent/BR9710630A/pt unknown
- 1997-07-30 EP EP97930717A patent/EP0954322A1/en not_active Withdrawn
- 1997-07-30 PL PL97331478A patent/PL331478A1/xx unknown
- 1997-07-30 SK SK121-99A patent/SK12199A3/sk unknown
- 1997-07-30 CZ CZ99295A patent/CZ29599A3/cs unknown
- 1997-07-30 JP JP10508650A patent/JP2000516591A/ja active Pending
- 1997-07-30 RU RU99104398A patent/RU99104398A/ru unknown
- 1997-07-30 WO PCT/IB1997/000951 patent/WO1998004270A1/en not_active Application Discontinuation
- 1997-07-30 CN CN97197506A patent/CN1228705A/zh active Pending
- 1997-07-30 AU AU34576/97A patent/AU3457697A/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015059561A1 (en) * | 2013-10-25 | 2015-04-30 | Red Pinnace Limited | Dietary regime for treatment of acne and other inflammatory skin conditions |
US10650064B2 (en) | 2013-10-25 | 2020-05-12 | Red Pinnace Limited | Dietary regime for treatment of acne |
US11328621B2 (en) | 2013-10-25 | 2022-05-10 | Red Pinnace Limited | Dietary regime for treatment of acne and other inflammatory skin conditions |
Also Published As
Publication number | Publication date |
---|---|
FR2751876A1 (fr) | 1998-02-06 |
KR20000029754A (ko) | 2000-05-25 |
SK12199A3 (en) | 2000-01-18 |
PL331478A1 (en) | 1999-07-19 |
NZ333985A (en) | 2000-09-29 |
EP0954322A1 (en) | 1999-11-10 |
RU99104398A (ru) | 2001-02-20 |
WO1998004270A1 (en) | 1998-02-05 |
JP2000516591A (ja) | 2000-12-12 |
BR9710630A (pt) | 2000-01-11 |
HUP9903904A2 (hu) | 2000-04-28 |
FR2751876B1 (fr) | 1998-12-31 |
HUP9903904A3 (en) | 2000-05-29 |
AU3457697A (en) | 1998-02-20 |
CA2262564A1 (en) | 1998-02-05 |
CZ29599A3 (cs) | 1999-06-16 |
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