CN1310724A - 用于自身免疫疾病的免疫疗法中的新型肽 - Google Patents
用于自身免疫疾病的免疫疗法中的新型肽 Download PDFInfo
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Abstract
本发明涉及新型肽在肽诱导耐性疗法以预防自身免疫疾病中的用途,并且特别是其在治疗关节软骨慢性破坏中的用途。本发明还涉及含有所述肽的药物组合物和检测试样中自体反应性T细胞的诊断方法。
Description
本发明涉及新型肽、其在治疗自身免疫疾病中关节软骨慢性损伤中的用途、含有所述肽的药物组合物、以及检测试样中自体反应性T细胞的诊断方法。
免疫系统是建立在外来抗原(非自身抗原)和自身抗原(来自个体自己身体的自体抗原)之间通过抗自身抗原的固定耐性实现辨别的原理上的。
免疫系统保护个体抵抗外来抗原，并通过激活特异细胞如T-和B淋巴细胞和产生可溶性因子类白介素、抗体和补体因子响应外来抗原的接触。免疫系统响应的抗原通过抗原呈递细胞(APC)降解，并且该抗原的片段在伴有主要组织相容性复合物(MHC)Ⅱ型糖蛋白的细胞表面上表达。凭借其T细胞受体识别与结合其上的MHCⅡ型蛋白质相连的抗原片段，将该MHC-糖蛋白-抗原-片段复合物呈递到T细胞上。该T细胞被激活，即繁殖和/或产生白介素，使得介导到受到攻击的抗原上的活化淋巴细胞扩展(Grey等人，Sci.,Am.,261:38-46,1989)。
自身抗原也被连续加工并通过MHC糖蛋白以抗原片段呈递到T细胞上(Jardetsky等人，自然353:326-329,1991)。因此自身识别是免疫系统所固有的。在正常情况下，免疫系统耐自身抗原，并且避免了通过这些自身抗原激活免疫反应。
当自身抗原耐性丧失时，免疫系统可能被一种或多种自身抗原激活，这使得激活自体反应性T细胞并产生自体抗体。这种现象被称之为自身免疫。由于免疫反应通常是破坏性的，即意味着破坏侵袭性外来抗原，自身免疫反应可能造成身体自身组织的破坏。
T细胞对自身免疫疾病的贡献建立在几个研究中。在小鼠中，试验自身免疫脑脊髓炎(EAE)通过T细胞的高度限制性基团介导，通过对复合到MHCⅡ型分子上的髓鞘碱性蛋白(MBP)的单个表位的特异性相连。在Lewis大鼠中，对各种自身免疫疾病的敏感性高的种，已显示疾病是通过T细胞介导的。在人自身免疫疾病中，还认为与自侵T细胞的发育有关。
破坏性自身免疫反应已涉及到如类风湿性关节炎(RA)的各种疾病，在类风湿性关节炎中关节软骨的整体性被慢性炎性过程破坏，这导致出现大量激活的淋巴细胞和表达MHCⅡ型的细胞。软骨中存在的节看起来必需承受局部炎症反应：它已暗示软骨降解与软骨反应的自身反应性T细胞在RA中的活性有关(Sigall等人的Clin.Exp.Rheumat.6:59,1988；Glant等人的Biochem.Soc.Trans.18:796,1990；Burmester等人的Rheumatoid arthritis Smolen,Kalden,Maini(编辑)Springer-VerlagBerlin Heidelberg,1992)。而且，通过手术将软骨从RA患者中除去显示减轻了炎性过程(R.S.Laskin,J.Bone Joint Surgery(Am)72:529,1990)。因此软骨蛋白被认为是胜任刺激T细胞的靶自身抗原。这些自身反应性T细胞的活化导致自身免疫疾病形成。但是，起类风湿性关节炎发作作用的自身抗原性组分的鉴定至今为止仍然难以捉摸。
导致软骨破坏的炎症反应可以通过几种药物治疗，例如类固醇药。但是，这些药物经常为免疫抑制性药物，它为非特异性且具有毒性副作用。非特异性免疫抑制的缺陷使其对治疗非常不利。
抗原特异性、非毒性免疫抑制疗法提供了一种非常吸引人的非特异性免疫抑制的替代。该抗原特异性疗法包括用靶自身抗原或者用来自该自身抗原的合成-T细胞反应性肽治疗患者。这些合成肽相应于该自身抗原的T细胞肽。尽管用引起激活免疫系统的非常相同的抗原脱敏该免疫系统看起来是矛盾的，但是在免疫系统脱敏时控制地给药该靶(自身)抗原可能是非常有效的。免疫系统的脱敏或免疫耐性是基于长期观察的现象，当通过全身途径导入所述抗原或肽时，被饲养或吸入抗原或肽的动物很少能向所述抗原或表位产生全身性免疫反应。
以前在类风湿性关节炎(RA)中以靶自身抗原鉴定了人软骨糖蛋白-39(HC gp-39)(Verheijden等人，Arthitis Rheum.40:1115-1125,1997)。用于鉴定HC gp-39中相关自身表位所遵循的策略是基于以下假设：DR4或DR1分子以两种水平易患RA(Gao等人，Arthitis Rheum.33:939-946,1990；Nelson等人的《类风湿性关节炎》，在第7届国际组织相容性研讨和协商会的会议录中，第1卷，Tsuji等人编辑，牛津大学出版社，1991)：首先，通过形成T细胞所有组成部分，其次，通过决定簇选择。在伴有RA的DR分子中发现的共享表位可能涉及到用于呈递T细胞的肽的相似组的选择(Gregerson等人，Arthitis Rheum.30:1205-1213,1987)。通过使用DR4(B1*0401)肽结合基序鉴定在HC gp-39的一级结构中的推定的结合序列(Verheijden等人，类风湿性关节炎40:1115-1125,1997)。HCgp-39，一种具有362个氨基酸的蛋白质，不包括信号序列(Hakala等人，生物学化学杂志268:25803-25810,1993)，含有6个调节该基序的区域。合成这样选择的4个肽，并测定其结合伴有RA的DR1和DR4(B1*0401和0404)变异体。发现所有以基序为基础的肽、跨越HC gp-39的残基103-116、259-275、263-275和326-338、以相当高的亲和性结合到DRB1*0401分子上。之后测定这些肽通过来自RA患者和健康供体的周围血液T细胞的识别。所有以基序为基础的肽易于在RA患者中识别，由此暗示HC gp-39-特异性T细胞在RA中的频率高。对263-275的反应最显著；18个RA患者中有8个对该肽有响应(Verheijden等人，类风湿性关节炎40:1115-1125,1997)。因此，HC gp-39为在关节中免疫识别的靶子。
通过Balb/c小鼠中的关节炎遗传性还证实了该蛋白质对关节炎疾病的重要性。在胸部区一次注射混合在IFA中的μg量的蛋白质，诱导RA的慢性关节炎症回忆(Verheijden等人，类风湿性关节炎40:1115-1125,1997)。
最近，分离并描述了新型人软骨细胞蛋白，YKL-39(Hu等人，J.Biol.Chem.271:19415-19420,1996)。该蛋白质与HC gp-39(YKL-40)具有明显的序列相同性。HC gp-39的另一同源物通过人巨噬细胞分泌并被称为壳三糖苷酶(Boot等人，J.Biol.Chem.270:26252-26256,1995)。相应于HC gp-39(263-275)肽RSFTLASSETGVG的序列(SEQ ID NO:3)被鉴定分别为YKL-39蛋白质(266-278)中的HSFTLASAETTVG(SEQ IDNO:2)和巨噬细胞壳三糖苷酶(269-282)中的RSFTLASSSDTRVG(SEQID NO:4)(表1)。
壳三糖苷酶肽Chi(269-282)含有以前用于选择蛋白质中T-细胞表位的DRB1*0401肽结合基序。与之相反，YKL-39(266-278)不含该0401基序。
很显然，HC gp-39(263-275)-反应性T-细胞的耐性可能是对RA患者有益的。同样地，HC gp-39(263-275)的模拟表位可能具有相似功能并且可以用于诱导耐性。优选这些模拟表位具有至少相同的耐受能力。
为了有效地使用耐性诱导疗法治疗T细胞介导的软骨破坏，大量需要鉴定可以使抗正激活引起该炎症过程的T细胞的自身抗原的患者脱敏的T细胞-反应性肽。
尽管YKL-39肽不含该0401基序，但是出人意料地发现，该YKL-39(266-278)肽为HC gp-39(263-275)的模拟表位。因此该表位对耐受在类风湿性关节炎患者中对HC gp-39(263-275)、YKL-39(266-278)或其模拟表位具有反应性的自身反应性T-细胞有用。
本发明的目的是提供能够诱导全身性免疫耐性，更具体地说特异性T细胞耐性的肽，优选对遭受T细胞介导的软骨破坏的患者中的响应性软骨抗原。本发明的肽的特征在于脱敏含有一个或多个氨基酸序列FTLASAETT(SEQ ID NO:1)。更具体地说，根据本发明的肽含有HSFTLASAETTVG(SEQ ID NO:2)。
根据本发明的肽的多聚体如根据本发明的肽的二聚体或三聚体也在本发明的范围内。根据本发明的多聚体或者可以为由多个相同肽组成的均聚物，或者可以为由不同肽组成的杂聚物。
根据本发明的肽的特征氨基酸序列两侧可以是随机氨基酸序列。优选为侧翼序列，它们对这些肽具有稳定作用，因此增加了其生物可利用率。
人软骨糖蛋白39为RA患者中的靶自身抗原，它激活特异性T细胞，因此造成或介导炎症过程。来自HC gp-39的肽主要被来自RA患者的自身反应性T细胞识别，但很少被来自健康供体的T细胞识别，这说明HCgp-39为RA中的自身抗原。HC gp-39的关节炎遗传性质还在Balb/c小鼠中得到证实。在Balb/c小鼠中单独、皮下注射所述蛋白质能够启动动物中的关节炎信号。HC gp-39诱导的疾病过程通过在前爪和/或后爪中周期性地出现复发来鉴定并渐渐由轻微关节炎发展成较严重的形式。而且，观察给人痛苦的关节的对称分布，同时观察关节炎，特别是RA的疾病进程的复发、回忆。
出人意料地发现，YKL-39 266-278肽起耐受原的效果。对本领域技术人员来说，很显然，这些肽可以在肽的任一边或在两边延伸并且仍然挥发相同的免疫功能。延伸部分可以是与蛋白质YKL-39的天然序列相似的氨基酸序列。
本发明的肽可以通过肽合成的熟知的有机化学方法制备，如在美国化学家协会杂志85:2149(1963)和国际肽蛋白质研究杂志35:161-214(1990)中所述的固相肽合成。本发明的肽还可以通过重组DNA技术制备。可以将编码本发明肽或所述肽的多聚物的核酸序列插入表达载体中。适宜表达载体包括复制和表达的必需控制区。可以使该表达载体在宿主细胞中表达。适宜的宿主细胞例如有细菌、酵母细胞和哺乳动物细胞。这些技术在本领域中为公知，参见例如Sambrooke等人的《分子克隆：试验手则》，冷泉港实验室出版社，冷泉港，1989。
这些肽可以通过C-和/或N-端修饰稳定，这将降低外肽酶催化水解。这些修饰可以包括：C-端酰化(例如乙酰化=Ac-肽)、N-端酰胺导入(例如肽-NH2)、酰化和酰胺导入的组合(例如Ac-肽-NH2)和导入D-氨基酸替代L-氨基酸(Powell等人，药物科学杂志，81:731-735,1992)。
其它修饰集中在通过内肽酶防止水解。这些修饰的例子有：导入D-氨基酸替换L-氨基酸、修饰的氨基酸、在肽中环化、引入修饰的肽键如经过还原的肽键φ[CH2NH]以及例如肽(N-烷基化甘氨酸衍生物)(Adang等人，Recl.Trav.Chim.Pays-Bas,113:63-78,1994和Simon等人，美国国家科学院院报，89:9367-9371,1992)。
根据本发明的肽为T-细胞表位，它通过自身反应性T-细胞识别并能够刺激自身反应性T-细胞。这些自身反应性T细胞例如可以在遭受自身免疫疾病的患者血液中发现。
因此，根据本发明，这些肽、与在含有SEQ ID NO:1或SEQ ID NO:2的肽的靶自身抗原上出现的MHCⅡ型限制性T-细胞表位相似的所述肽，非常适宜用于一治疗中，从而诱导特异性T-细胞对遭受T-细胞介导的软骨破坏如关节炎，尤其是类风湿性关节炎的哺乳动物，尤其是人中的所述自身抗原的耐受性。任选地这些治疗可以与施用其它药物相结合，这些药物例如有DMARD(缓和疾病的抗风湿性药物如柳氮磺胺吡啶、可注射或口服金的抗疟药(氯喹、羟氯喹)、甲氨蝶呤、D-青霉胺、硫唑嘌呤、环孢菌素、霉酚酸盐)NSAID(非甾族消炎药)、皮质类固醇或已知影响自身免疫患者中疾病过程的其它药物。
还可以使用本发明的肽调节淋巴细胞，该淋巴细胞与除所述自身抗原之外的抗原反应但存在于与该自身抗原即含有根据SEQ ID NO∶1或SEQID NO∶2的肽的蛋白质或其部分相同的组织中。通过诱导抗原-特异性T-细胞耐性，可以通过旁观者抑制治疗自身免疫疾病。更一般的说，待调节的细胞为造血细胞。一般来说，为了起一耐受原的作用，该肽必需达到至少两种条件，即它必需具有免疫调节能力并且它必需通常以较大蛋白质部分局部地表达。
因此，本发明提供了一种通过给药含有本发明的肽的药物制剂治疗遭受炎症性自身免疫疾病的患者的方法。这些患者可能遭受如下疾病：格雷夫斯氏病、青年期关节炎、原发性肾小球性肾炎、骨关节炎、斯耶格伦氏病、重症肌无力、类风湿性关节炎、阿狄森氏病、原发性胆汁硬化症、眼色素层炎、全身性红斑狼疮、炎性肠病、多发性硬化或糖尿病。可以使用本发明的肽制备诱导遭受这些疾病的患者中的耐性的药物。
使用本发明的肽对自身免疫疾病的治疗利用了如下事实：对不相关但共定位的抗原诱导旁观者抑制。调节细胞以抗原特异性形式分泌多向性蛋白质，例如可以负调节免疫反应的细胞因子。
根据本发明，可以使用含有本发明的一种或多种肽和药用上可接受的载体的药物组合物治疗自身关节软骨的T-细胞介导的破坏的患者。给药根据本发明的药物组合物将诱导对在攻击下关节软骨中的自身抗原蛋白质和其它自身抗原的全身性免疫耐性，特别是这些患者的特异性自身反应性T细胞的耐性，这些其它自身抗原呈递通过本发明的一个或多个肽的氨基酸序列表征或模拟的经过鉴定的MHCⅡ型结合T细胞表位。因此该诱导耐性将导致攻击下关节软骨中局部炎症性反应降低。
用于本发明药物组合物的非常适宜的肽为含有由总长高达55个氨基酸的序列侧翼的YKL-39(268-276)或YKL-39(266-278)肽的肽。更优选这些肽具有25个氨基酸的长度。甚至更优选这些肽的氨基酸序列为FTLASAETT或HSFTLASAETTVG。
当与免疫抑制性药物的非特异性抑制效果比较时，本发明的肽的优点是它们具有对自身反应性T细胞的特异性效果，因此它们使免疫系统的其它组分完整。用本发明的肽治疗安全且无毒副作用产生。
通过给药高或低剂量的本发明的肽抗原获得全身性免疫耐性。肽的量取决于给药途径、给药时间、患者年龄以及总的健康状况和饮食。
一般来说，可以使用每kg体重0.01-10000μg肽的剂量，优选0.05-500μg、更优选0.1-100μg肽。
药用上可接受的载体对本领域技术人员来说为公知，包括例如无菌盐水、乳糖、蔗糖、磷酸钙、明胶、糊精、琼脂、果胶、花生油、橄榄油、芝麻油和水。如果希望包埋在脂质体中的话，其它载体可以是例如MHCⅡ型分子。
此外本发明的药物组合物可以含有一种或多种佐剂。适宜的佐剂包括，尤其是，氢氧化铝、磷酸铝、白榴石、生育酚、单膦苯基脂A、胞壁酰基二肽和例如Quill A的皂甙。优选，用于本发明的耐性疗法的佐剂为与粘膜上皮结合的例如霍乱毒素B-亚基或carbomers的粘膜佐剂。佐剂的量取决于佐剂自身的性质。
而且，根据本发明的药物组合物可以含有一种或多种稳定剂，例如包括山梨糖醇、甘露糖醇、淀粉、蔗糖糊精和葡萄糖的碳水化合物、例如白蛋白或酪蛋白的蛋白质、以及类似碱性磷酸盐的缓冲液。
适宜的给药路径有例如肌肉注射、皮下注射、静脉注射或腹膜内注射、例如喷雾的口服和鼻内投药。
本发明的另一目的是提供一种测定在关节软骨的破坏中涉及的自身反应性T细胞的方法和用于所述方法的测定试剂盒。因此，本发明的肽还非常适宜用于测定在慢性炎症和关节软骨的破坏中涉及的激活的自身反应性T细胞的存在的诊断方法。
本发明的诊断方法包括以下步骤：
a)从个体血样中分离周围血液单核细胞(PBMC)，
b)在适宜条件下培养所述PBMC，
c)在有本发明的一种或多种肽的情况下培养所述PBMC培养物，和
d)测定T细胞的反应，例如表示在个体中存在被激活的T细胞的繁殖反应。
可以通过例如掺入3H-胸腺嘧啶核苷测定T细胞的繁殖反应的测定。
含有一种或多种本发明的肽的测定试剂盒也在本发明的范围内。这些测定试剂盒适宜用于根据本发明的诊断方法中。
以下实施例是对本发明的例证说明，无论如何不应作为限制本发明范围的解释。
附图说明
图1
图1a、b、c为三个不同HC gp-39-特异性杂交瘤(8B12、14G11、20H5)与YKL-39(266-278)的交叉反应性
(CVR0271B=HC gp-39(263-275),KV0432B=YKL-39(266-278),CC0332B=Chi(269-282),KV0431A=YKL-39(262-274)。HCDA.8B12.1D8,14G11.1H7和20H5.4F6.2F6为对HC gp-39(263-275)特异性的HLA-DRB1*0401-限制性杂交瘤。T-细胞杂交瘤的活化被表示为IL-2的生产。
图2为体内对HC gp-39(263-275)或YKL-39(266-278)的耐受性
通过鼻内施加50、10或2微克HC gp-39(263-275)或YKL-39(266-278)之后用HC gp-39(263-275)免疫，使Balb/c小鼠产生耐性。用生理盐水预处理或未经处理的小鼠作为对照。
实施例
实施例1 序列对比
人软骨细胞蛋白，YKL-39与HC gp-39(YKL-40)具有明显的序列相同性。HC gp-39的另一同源物是通过人巨噬细胞分泌的并被称为壳三糖苷酶(Boot等人，1995)。相应于RSFTLASSETGVG的序列(HC gp-39(263-275),SEQ ID NO:3)分别在YKL-39蛋白质(266-278)中被鉴定为HSFTLASAETTVG，在巨噬细胞壳三糖苷酶(269-282)中被鉴定为RSFTLASSSDTRVG(SEQ ID NO:4)(表1)。Chi(269-282)含有HLA-DRB1*0401肽结合基序，该基序以前被用于选择蛋白质中的T-细胞肽。与此相反，YKL-39(266-278)肽不含该基序。所有肽都是合成的。
表1．HC gp-39(263-275)序列与YKL-39和巨噬细胞壳三糖苷酶中的相应区域的序列对比
| HC gp-39 263-275 R S F T L A S S - E T G V GYKL-39 266-278 H S F T L A S A - E T T V GChi(269-282) R S F T L A S S S D T R V G |
实施例2 肽与HLA-DRB1*0401的结合
测定来自实施例1的肽与DAR1*0401-编码分子结合。从纯合EBV-转化的人B成淋巴细胞样细胞系Huly138IC2中提纯HLA-DR4(DRB1*0401)分子，并基本上以Verheijden等人在1997年所述的进行该竞争肽HLA-DR结合试验。给定肽结合DRB1*0401-编码分子的亲和力与和标记肽的竞争有关。该相关的结合亲和力以信号降低到50％(IC50)时肽的浓度来定义。该HA-F肽为正对照(Hemagglutinin 307-319；PKFVKQNTLKLAT；在第309位置的Y被F替换；SEQ ID NO:5)。已知该肽对DRB1*0401分子具有高的亲和力。
正如所预料的，发现Chi(269-282)肽高度亲和地结合到DRB1*0401上(参见表2)。该YKL-39(266-278)肽，没有提供有效的DRB1*0401肽结合基序，非常高亲和力地结合到DR4(B1*0401)上。
表2．肽与HLA-DRB1*0401-编码分子结合
| IC50值 | ||||
| 肽 | 批次 | 实验A | 实验B | 实验C |
| YKL-39(262-274) | KV0431AKV432BCVR271B | 0.0060.035ND | 0.0050.0320.008 | ND0.120.038 |
| YKL-39(266-278) | ||||
| HC gp-39(263-275) | ||||
| Chi(269-282) | CC0332BAE0690A | 0.0530.20 | 0.110.14 | 0.160.20 |
| HA-F | ||||
ND=未测定
实施例3 刺激T-细胞杂交瘤
测定对HC gp-39(263-275)特异性的杂交瘤对其相应序列的识别。
为了测定3个不同的HC gp-39-特异性杂交瘤细胞系与YKL-39或壳三糖苷酶肽的交叉反应性，将带有DRB1*0401特异性的5×104个杂交瘤细胞和2×105个经辐照(12000RAD)、EBV-转化的B细胞以150μl体积在圆底微量滴定平皿的孔中培养。向一式两份孔中添加50μl体积的肽抗原(HC gp-39(263-275)、YKL-39(266-278)、壳三糖苷酶(269-282)或对照肽)。使用具有对小鼠IL-2特异的Pharmingen抗体的夹心式ELISA测定48小时后100μl培养物上清液的IL-2生产。
发现，合成肽YKL-39(266-278)产生与HC gp-39(263-275)相似的反应，然而Chi(269-282)不产生反应。这些数据暗示，当HC gp-39(263-275)或YKL-39(268-278)通过DRB1*0401-编码分子呈递时被3个不同杂交瘤利用的3个不同TCR不能在HC gp-39(263-275)或者YKL-39(268-278)之间区别(图1a、b、c)，但是能在HC gp-39(263-275)和Chi(269-282)之间区别(图1a、b、c)。这些数据说明，YKL-39(266-278)为HC gp-39(263-275)的模拟肽。(图1a、b、c)
实施例4 通过PBMC的YKL-39(266-278)的识别
在Ficoll-Paque(Pharmacia,Uppsala,Sweden)上通过标准离心分离将外周血单核细胞(PBMC)从肝素化外周血液中分离。将这些细胞以5×105个细胞/ml的浓度悬浮在24孔平皿的孔中。将这些细胞在仅有培养基或在有10-50μg/ml肽抗原(YKL-39(266-278))下培养。将培养物在37℃、5％CO2的潮湿环境下培养6天。然后将细胞悬浮并以4倍将100或150μl体积的培养基分布到96孔圆底平皿的孔中。然后用0.5μCi(1.85×104Bq)[3H]胸腺嘧啶核苷([3H]TdR)将细胞脉冲，18小时后测定掺入的放射性。表3中所示的结果解释了刺激指数(SI)(抗原特异性计数/背景计数)。
从表3a中可以得出，YKL-39(266-278)表位易于在RA患者中被识别。表3b说明，通过PBMC的YKL-39(266-278)的识别与HC gp-39(263-275)和HC gp-39的识别一致，而且YKL-39(266-278)的识别通常比HC gp-39(263-275)的识别更显著。
表3a．通过从RA患者的PBMC识别YKL-39(266-278)
| 供体 分类 SI SI10μg/ml 50μg/ml |
| 242-0.2 NR 0404/15 3 ＜2337-0.2 R 0401/02 19 58338-0.1 NR 03/14 ＜2 ＜2454-0 R 0401/ 9 9456-0 R ND 15 4457-0 NR ND ＜2 ＜2458-0 R ND 4 27459-0 R ND ＜2 25460-0 NR ND 3 ＜2 |
SI=抗原特异性计数/背景计数。SI≥5被认为阳性，R=效应器，NR=非效应器。
表3b．YKL-39(266-278)的识别与HC gp-39(263-275)和HC gp-39蛋白质的识别一致
| 供体 R/N YKL-39(266-278) HC gp-39(263-275) HC gp-39SI SI SI SI SI SIμg/ml 10 50 10 50 10 50 |
| 169 R 27 32 10 27 24 44455 R 20 35 1 15 45 95447 NR 1 2 1 1 1 1327 R 6 5 3 5 12 19 |
SI=抗原特异性计数/背景计数。SI≥5被认为阳性，R=效应器，NR=非效应器。NT=未测出。供体447相应于破伤风类毒素和白色念珠菌。
实施例5 耐性诱导
进行适宜用肽抗原监控耐性诱导的HC gp-39(263-275)-特异性DTH试验。用在不完全弗氏佐剂(IFA)中的HC gp-39(263-275)的Balb/c小鼠的免疫发现，在用HC gp-39(263-275)肽攻击之后，DTH反应的诱导是有效的。使用以该肽为基础的DTH体系检测通过鼻施加HC gp-39(263-275)肽的DTH反应的调节。发现，以剂量依赖型方式鼻施加HC gp-39(263-275)，负调节了HC gp-39(263-275)-诱导的DTH反应。但是，鼻施加YKL-39(266-278)，导致DTH反应的负调节进一步加强，这说明YKL-39(266-278)可以有效地耐受用HC gp-39(263-275)诱导的肽特异性反应(表4，图2a、b、c)。
表4．实验性设置耐受性实验
| 预处理 致敏 攻击 耐性无 HC gp-39(263-275) HC gp-39(263-275) 无生理盐水 HC gp-39(263-275) HC gp-39(263-275) 无HC gp-39(263-275) HC gp-39(263-275) HC gp-39(263-275) 有YKL-39(266-278) HC gp-39(263-275) HC gp-39(263-275) 有 |
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Claims (8)
1．一种具有9-55个氨基酸残基的氨基酸序列的肽，含有氨基酸序列FTLASAETT(SEQ ID NO:1)。
2．如权利要求1的肽，含有氨基酸序列HSFTLASAETTVG(SEQ IDNO:2)。
3．如权利要求1或2的肽，具有高达25个氨基酸的氨基酸序列。
4．如权利要求1或2的肽，具有氨基酸序列FTLASAETT(SEQ IDNO:1)或HSFTLASAETTVG(SEQ ID NO:2)。
5．如权利要求1-4任一项的肽，用作治疗物质。
6．含有权利要求1-4的一种或多种肽和药用上可接受的载体的药物组合物。
7．权利要求1-4的一种或多种肽用于生产诱导对患有自身免疫疾病，更具体地说患有关节炎的患者中的自身抗原的特异性T-细胞耐性的药物制品的用途。
8．含有权利要求1-4中任一项的一种或多种肽和一测定剂的诊断组合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98202470 | 1998-07-23 | ||
| EP98202470.5 | 1998-07-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1310724A true CN1310724A (zh) | 2001-08-29 |
Family
ID=8233961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99808862A Pending CN1310724A (zh) | 1998-07-23 | 1999-07-16 | 用于自身免疫疾病的免疫疗法中的新型肽 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6964766B1 (zh) |
| EP (1) | EP1100823A2 (zh) |
| JP (1) | JP2002521388A (zh) |
| KR (1) | KR20010071020A (zh) |
| CN (1) | CN1310724A (zh) |
| AU (1) | AU758310B2 (zh) |
| BR (1) | BR9912378A (zh) |
| CA (1) | CA2334947A1 (zh) |
| CO (1) | CO5090903A1 (zh) |
| CZ (1) | CZ2001286A3 (zh) |
| HU (1) | HUP0103384A3 (zh) |
| ID (1) | ID27998A (zh) |
| IL (1) | IL140825A0 (zh) |
| NO (1) | NO20010355L (zh) |
| NZ (1) | NZ509417A (zh) |
| PE (1) | PE20000931A1 (zh) |
| PL (1) | PL345958A1 (zh) |
| RU (1) | RU2233290C2 (zh) |
| SK (1) | SK1042001A3 (zh) |
| TR (1) | TR200100175T2 (zh) |
| WO (1) | WO2000005254A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004003007A1 (fr) * | 2002-06-27 | 2004-01-08 | People's Hospital, Peking University | Peptides se liant a des cellules non lymphocytaires, et utilisations correspondantes |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7265208B2 (en) | 2001-05-01 | 2007-09-04 | The Regents Of The University Of California | Fusion molecules and treatment of IgE-mediated allergic diseases |
| JP2006508014A (ja) | 2001-07-24 | 2006-03-09 | イエール・ユニバーシテイ | キチナーゼおよびキチナーゼ様分子、ならびに炎症性疾患に関する方法、組成物およびキット |
| RU2667423C1 (ru) * | 2017-06-28 | 2018-09-19 | ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "ПраймБиоМед" | Мышиная гибридома ykl-39, клон 1b2 g4 - продуцент моноклонального антитела, обладающего специфичностью к цитоплазматическому антигену ykl-39 человека |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL115744A (en) | 1994-10-27 | 2000-07-16 | Akzo Nobel Nv | Peptides comprising a subsequence of human cartilage glycoprotein - 39 |
| IL120561A0 (en) | 1996-04-24 | 1997-07-13 | Akzo Nobel Nv | Peptides suitable for use in immunosuppressive therapy |
| EP0805206A3 (en) * | 1996-05-03 | 1999-09-15 | Smithkline Beecham Corporation | Human cartilage glycoprotein |
| AU6693996A (en) * | 1996-08-09 | 1998-03-06 | Human Genome Sciences, Inc. | Human chitinase alpha and chitinase alpha-2 |
-
1999
- 1999-07-16 PL PL99345958A patent/PL345958A1/xx not_active Application Discontinuation
- 1999-07-16 EP EP99940012A patent/EP1100823A2/en not_active Withdrawn
- 1999-07-16 KR KR1020017000992A patent/KR20010071020A/ko not_active Application Discontinuation
- 1999-07-16 NZ NZ509417A patent/NZ509417A/xx unknown
- 1999-07-16 HU HU0103384A patent/HUP0103384A3/hu unknown
- 1999-07-16 IL IL14082599A patent/IL140825A0/xx unknown
- 1999-07-16 US US09/744,170 patent/US6964766B1/en not_active Expired - Fee Related
- 1999-07-16 CN CN99808862A patent/CN1310724A/zh active Pending
- 1999-07-16 ID IDW20010192A patent/ID27998A/id unknown
- 1999-07-16 SK SK104-2001A patent/SK1042001A3/sk unknown
- 1999-07-16 CA CA002334947A patent/CA2334947A1/en not_active Abandoned
- 1999-07-16 BR BR9912378-9A patent/BR9912378A/pt not_active IP Right Cessation
- 1999-07-16 WO PCT/EP1999/005050 patent/WO2000005254A2/en not_active Application Discontinuation
- 1999-07-16 RU RU2001105086/04A patent/RU2233290C2/ru not_active IP Right Cessation
- 1999-07-16 TR TR2001/00175T patent/TR200100175T2/xx unknown
- 1999-07-16 AU AU54112/99A patent/AU758310B2/en not_active Ceased
- 1999-07-16 JP JP2000561210A patent/JP2002521388A/ja not_active Withdrawn
- 1999-07-16 CZ CZ2001286A patent/CZ2001286A3/cs unknown
- 1999-07-21 PE PE1999000730A patent/PE20000931A1/es not_active Application Discontinuation
- 1999-07-22 CO CO99046229A patent/CO5090903A1/es unknown
-
2001
- 2001-01-22 NO NO20010355A patent/NO20010355L/no not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004003007A1 (fr) * | 2002-06-27 | 2004-01-08 | People's Hospital, Peking University | Peptides se liant a des cellules non lymphocytaires, et utilisations correspondantes |
| US7291600B2 (en) | 2002-06-27 | 2007-11-06 | Zhanguo Li | Non-T cell binding peptides and their uses |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9912378A (pt) | 2001-04-17 |
| EP1100823A2 (en) | 2001-05-23 |
| ID27998A (id) | 2001-05-03 |
| CA2334947A1 (en) | 2000-02-03 |
| RU2001105086A (ru) | 2004-01-20 |
| NZ509417A (en) | 2003-03-28 |
| CZ2001286A3 (en) | 2001-08-15 |
| HUP0103384A3 (en) | 2004-06-28 |
| HUP0103384A2 (hu) | 2001-12-28 |
| AU758310B2 (en) | 2003-03-20 |
| NO20010355L (no) | 2001-03-20 |
| KR20010071020A (ko) | 2001-07-28 |
| JP2002521388A (ja) | 2002-07-16 |
| US6964766B1 (en) | 2005-11-15 |
| AU5411299A (en) | 2000-02-14 |
| NO20010355D0 (no) | 2001-01-22 |
| PE20000931A1 (es) | 2000-09-16 |
| PL345958A1 (en) | 2002-01-14 |
| IL140825A0 (en) | 2002-02-10 |
| CO5090903A1 (es) | 2001-10-30 |
| WO2000005254A3 (en) | 2000-06-15 |
| WO2000005254A2 (en) | 2000-02-03 |
| TR200100175T2 (tr) | 2001-09-21 |
| RU2233290C2 (ru) | 2004-07-27 |
| SK1042001A3 (en) | 2001-09-11 |
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