CN1146156A - 自身免疫疾病的治疗剂及其治疗方法 - Google Patents
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Abstract
将滋养性β-I-糖蛋白(TBG)用作治疗显示抑制基因免疫缺损的自身免疫疾病的试剂。治疗自身免疫疾病的方法包括给予免疫校正制剂，所述制剂是滋养性β-I-糖蛋白(TBG)，所述制剂的指征是通过试验单核细胞(MNCs)的TBG敏感性来决定的。
Description
本发明涉及医学，特别是涉及用免疫校正制剂来治疗自身免疫疾病。
本发明可被用作诊断人免疫状态的抑制基因成分的药物和评价治疗自身免疫疾病(特别是多发性硬化，风湿性关节炎等)可能性的药物。
来源于胎盘的β-I-糖蛋白是已知的，它是用作造血细胞的生成和增殖刺激因子的滋养性β-I-糖蛋白(TBG)的类似物(US专利5169835，cl.A61K 35/50，1989)。
然而，该已知的化合物未被用于治疗自身免疫疾病的试剂。
将TBG用于诊断和预示怀孕过程是已知的(见L.G.Sotniko-va，I.N.Golovistikov等，The Role of β-I-glycoprotein Trophoblastin Diagnosing and Prognosticating Pregnancy，Metodicheskije Re-comendatsii，Moscow，1984)。
然而，所述研究未公开将TBG用于诊断抑制基因成分和治疗自身免疫疾病的可能性。
通过给予来源于胎盘的药物来治疗脓疱性牛皮癣的方法是已知的(见USSR Inventor′s Certificate No.1061818，cl.A61K35/50，19.07.82)。
然而，按所述方法使用该药物不能防止因杂质而可能引起的副作用。
已知治疗自身免疫疾病的方法，包括给予一定剂量的来源于胎盘的免疫校正制剂(见USSR Inventor′s Certificate No.1657190，clA61K35/50，1989)。
然而，所述方法使用含有可引起过敏反应的杂质的制剂，而且，所述制剂仅在术后期有效而且局限于自身免疫睾丸炎。
本发明的主要目的是提供一种通过给予显示免疫校正活性且不引起副作用的制剂来治疗自身免疫疾病的有效方法，并扩大可用其治疗的自身免疫疾病的范围。
通过将滋养性β-I-糖蛋白(TBG)用作治疗自身免疫疾病的试剂这一新用途来实现所述目的，并且治疗自身免疫疾病的方法包括给予本发明的免疫校正制剂，另外包括预先研究免疫状态，在测定了抑制基因的缺失情况下，再把滋养性β-I-糖蛋白(TBG)用作免疫校正制剂。
预先研究免疫状态可包括收集外周血样，获得单核细胞(MNCs)，将样品分成两部分，在不含TBG下培养第一份，且在TBG存在下培养第二份，从培养基中洗出MNCs，阻断增殖，将从正常供体新鲜分离的MNCs(已用植物血凝素刺激)按等比例加到各个所述MNC部分中来产生试验培养物，培养所述培养物，更进一步评价所述培养物的增殖情况并基于各试验培养物增殖水平之比来计算抑制值。
实验和临床试验已显示TBG作为治疗不同自身免疫疾病的免疫校正制剂的新特性。
对154名患有自身免疫疾病(多发性硬化，风湿性关节炎等)的病人的免疫值研究显示T-抑制基因缺损，它是自身免疫化(即自身耐受缺失)机制的开始。
TBG的治疗效果取决于TBG在患有多发性硬化、风湿性关节炎等疾病的患者中诱导淋巴细胞抑制基因活性的能力。
对患有上述疾病的病人和对照组(105名供体)所进行的临床免疫学研究包括评价T-抑制基因的功能活性。通过在phycoll-urotrust Single-stage density gradient(Boyum，1968)中离心来从外周血中分离单核细胞(MNCs)。
已经表明，在患有多发性硬化的病人中，疾病急性期T-细胞的相对数量(41.3±2％)比正常值(63.2±2％)低1.5倍。
基于初步的试验数据，可以作出一个结论：TBG可用于治疗所有处于该疾病急性期的病人，40％的病人被缓解，而剩余的60％的病人应暂时避免给予TBG。
可将给药的制剂制成与任何可药用溶剂相组合的可注射溶液形式。
剂量和给药方法取决于疾病的性质和阶段。TBG的剂量范围为3～120μg/ml病人的血。
TBG具有高的效果并且甚至在一次给予最小剂量后就达到显著的效果。
优选地，将TBG以60μg/ml的浓度与来自外周血的自身MNC一起预培养之后，将TBG非肠道或静脉内给药。
本发明的进一步详细描述公开在特定实施方案的实施例中以及附图中，其中图1公开了在急性期(1)、缓解开始期(2)和缓解期(3)时的刺激(反抑制基因)和抑制基因活性，以患有多发性硬化的病人的外周血中TBG诱导的淋巴细胞的百分数表示。
通过以下列步骤来试验单核细胞(MNC)对TBG的敏感性而进行免疫状态的预先研究。
用静脉穿刺术从病人体中取出外周血，放入含肝素溶液的管中，然后，通过在phycoll-urotrust single-step gradient中的细胞沉降而获得单核细胞(MNCs)的悬浮液，并分为两部分。在不含抑制基因激活剂(TBG)下将第一份培养48小时，并在TBG存在下培养第二份。接着从培养基中洗出MNCs并用丝裂霉素C处理MNC来阻断增殖。
下一步是将从正常供体中新鲜分离的淋巴细胞(该淋巴细胞已用植物血凝素(PHA)刺激以便用作响应的试验细胞)以等比例加到各个上文所述的对照和TBG刺激的淋巴细胞中来获得试验培养物。培养72小时。然后用N3-胸苷评价试验培养物的增殖情况，并通过增殖减小的程度来评价抑制情况。
用下式计算抑制指数(SI)：
抑制指数表示人免疫状态的抑制基因成分。根据病人免疫状态研究结果所获得的数据，更进一步确定了自身免疫疾病的治疗方法。
本发明通过下列实施例进行更进一步的说明。
实施例1
病人C.，29，诊断：多发性硬化(脑脊髓型，延长的缓解)；病人已接受皮质类固醇制剂的某些治疗；在缓解期进行的免疫研究表明，外周血中T-淋巴细胞的刺激(反抑制基因)活性是28％。在本阶段，应避免用TBG治疗。
实施例2
病人B.，28，诊断：多发性硬化(脑脊髓型，忽轻忽重阶段，急性期)。持续时间：3年。神经病学状态：向右看时，外侧nistagmus；强烈的腱反射；足：D＞S。腹部反射：上端低，中和下端反射不存在。两侧趾(Babinsky′s)症。足阵挛对右侧更强烈。肢体没有全麻痹，紧张没有改变。运动失调。闭目立正姿势(Romberg position)不稳定。膝-足跟试验运动失调，排尿延时。
脊柱液：
蛋白质-0.76％
朗格试验(Lange reaction)-66644322。
眼科医生的检查：盲点颞部苍白。
TBG诱导期的外周血T-抑制基因活性-17％。
在无菌条件下，从病人臂静脉取出110ml血样。在density gra-dient of phycoll-urotrust中按标准方法分离单核细胞(MNCs)。分离出的MNCs与TBG(浓度为60μg/ml)一起培养。通过离心洗涤后，静脉输入细胞。观察第5天时症状的缓解情况。走路和排尿变得正常。闭目立正姿势变稳定。膝-足跟试验明显完成。免疫状态再研究显示TBG诱导的外周血的T抑制基因活性增加，增加38％。在第7天、14天和28天进行的Ouhterloni试验没有测得病人的抗-TBG抗体。
实施例3
病人H.，42，来到医院诊断为类风湿性关节炎(多关节炎，血清阳性，A-P(2期)关节功能不全(IJF)。TBG诱导下外周血T-抑制基因活性为22％。
病人的有病理改变的关节接受TBG注射，每次注射0.5ml，浓度为60μg/ml。在第4天观察到缓解。疼痛症状减弱。关节功能不全消退。再研究显示，TBG诱导下外周血T-抑制基因功能活性增加47％。在第7天、14天和28天进行的Ouherloni试验没有测出病人的抗-TBG抗体。
对105名供体和154名患有不同自身免疫疾病的病人的研究显示，使用剂量低于3μg/ml血的TBG产生不足的效果，而使用超过120μg/ml血的剂量也是不需要的。
抑制基因活性的正常值为63.4％±4.7，在急性期该值为20.5％±9.8，缓解期为47.7％±2.8，缓解开始阶段该值为66.6％±16.1(刺激活性)。
所以，TBG制剂用作治疗自身免疫疾病的试剂时显示了高的活性。本发明治疗自身免疫疾病的方法对不同的自身免疫疾病提供有效的治疗而不引起不希望有的副作用。
本发明可广泛用作治疗各种自身免疫疾病和诊断人免疫状态的抑制基因成分的试剂。
Claims (4)
1.将滋养性β-I-糖蛋白(TBG)用作治疗自身免疫疾病的试剂。
2.治疗自身免疫疾病的方法，它包括使用一种免疫校正制剂，其特征在于预先研究免疫状态，如果观察到抑制基因缺损的情况就以3～120μg/ml血的剂量使用作为免疫校正制剂的滋养性β-I-糖蛋白。
3.权利要求2的方法，其特征在于非肠道使用滋养性β-I-糖蛋白。
4.权利要求2的方法，其特征在于将60μg/ml浓度的滋养性β-I-糖蛋白与从外周血分离出的自身免疫细胞一起培养，并静脉使用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU9494008169A RU2056852C1 (ru) | 1994-03-18 | 1994-03-18 | Средство для лечения аутоиммунных заболеваний с иммунодефицитом супрессоров и способ лечения аутоиммунных заболеваний |
| RU94008169 | 1994-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1146156A true CN1146156A (zh) | 1997-03-26 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95192635A Pending CN1146156A (zh) | 1994-03-18 | 1995-03-16 | 自身免疫疾病的治疗剂及其治疗方法 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6150326A (zh) |
| EP (1) | EP0790059B1 (zh) |
| JP (1) | JPH09510473A (zh) |
| KR (1) | KR100382252B1 (zh) |
| CN (1) | CN1146156A (zh) |
| AT (1) | ATE260111T1 (zh) |
| AU (1) | AU699896B2 (zh) |
| BG (1) | BG62759B1 (zh) |
| CA (1) | CA2185892A1 (zh) |
| CZ (1) | CZ285856B6 (zh) |
| DE (2) | DE69532611D1 (zh) |
| ES (1) | ES2107980T1 (zh) |
| FI (1) | FI963671A (zh) |
| GE (1) | GEP20012377B (zh) |
| GR (1) | GR980300023T1 (zh) |
| HU (1) | HUT75720A (zh) |
| NO (1) | NO963911L (zh) |
| PL (1) | PL179765B1 (zh) |
| RU (1) | RU2056852C1 (zh) |
| SK (1) | SK281948B6 (zh) |
| UA (1) | UA26939C2 (zh) |
| WO (1) | WO1995025531A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0030729D0 (en) * | 2000-12-16 | 2001-01-31 | Univ Nottingham | Substituted-4-Quinolones |
| US20050032725A1 (en) * | 2002-10-09 | 2005-02-10 | Toerrx, Inc. | Molecules preferentially associated with effector T cells or regulatory T cells and methods of their use |
| RU2303995C1 (ru) * | 2006-04-28 | 2007-08-10 | Халлар Абдумуслимович Алиханов | Средство, обладающее иммунорегуляторным свойством и его применение для лечения аутоиммунных заболеваний |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2862449D1 (en) * | 1977-08-22 | 1984-11-22 | Nat Res Dev | Macromolecular covalent conjugates, methods for preparing and pharmaceutical compositions containing them |
| JPS61186322A (ja) * | 1985-02-13 | 1986-08-20 | Nippon Univ | 免疾調節剤 |
| IT1188646B (it) * | 1986-04-09 | 1988-01-20 | Ellem Ind Farmaceutica | Tripeptide ad attivita' immunostimolante |
| US4803072A (en) * | 1986-09-10 | 1989-02-07 | Smithkline Beckman Corporation | Immunomodulation |
| FR2609632B1 (fr) * | 1987-01-21 | 1991-03-29 | Shelly Marc | Nouvelle application therapeutique de la 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinon-6-one et les compositions pharmaceutiques destinees a cet usage |
| US5169835A (en) * | 1989-01-18 | 1992-12-08 | Oklahoma Medical Research Foundation | Pregancy specific proteins applications |
| FR2650183A1 (fr) * | 1989-07-25 | 1991-02-01 | Pasteur Institut | Proteines immunostimulantes, anticorps monoclonaux et polyclonaux correspondants, hybridomes correspondants et application de ces produits a des fins therapeutiques et de diagnostic |
| US5118669A (en) * | 1989-09-20 | 1992-06-02 | Hitachi Chemical Co., Ltd. | Peptides and intermediates therefor useful as antiallergic agents, vasodilators and immunoregulators |
| US5559097A (en) * | 1990-01-12 | 1996-09-24 | Idaho Research Foundation, Inc. | Use of a pregnancy specific protein as an immunosuppressive |
| RU1836957C (ru) * | 1990-03-25 | 1993-08-30 | 2-й Московский государственный медицинский институт им.Н.И.Пирогова | Способ получени трофобластического бета @ -гликопротеина |
| GB2251186A (en) * | 1990-12-04 | 1992-07-01 | Randall Neal Gatz | Polypeptide for use in treatment of autoimmune disease |
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1994
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1995
- 1995-03-16 UA UA96093436A patent/UA26939C2/uk unknown
- 1995-03-16 AT AT95913445T patent/ATE260111T1/de not_active IP Right Cessation
- 1995-03-16 US US08/716,139 patent/US6150326A/en not_active Expired - Fee Related
- 1995-03-16 CZ CZ962747A patent/CZ285856B6/cs not_active IP Right Cessation
- 1995-03-16 EP EP95913445A patent/EP0790059B1/en not_active Expired - Lifetime
- 1995-03-16 AU AU20874/95A patent/AU699896B2/en not_active Ceased
- 1995-03-16 DE DE69532611T patent/DE69532611D1/de not_active Expired - Lifetime
- 1995-03-16 WO PCT/RU1995/000047 patent/WO1995025531A1/ru active IP Right Grant
- 1995-03-16 GE GEAP19953411A patent/GEP20012377B/en unknown
- 1995-03-16 SK SK1187-96A patent/SK281948B6/sk unknown
- 1995-03-16 JP JP7524566A patent/JPH09510473A/ja not_active Ceased
- 1995-03-16 KR KR1019960705237A patent/KR100382252B1/ko not_active IP Right Cessation
- 1995-03-16 ES ES95913445T patent/ES2107980T1/es active Pending
- 1995-03-16 DE DE0790059T patent/DE790059T1/de active Pending
- 1995-03-16 PL PL95316311A patent/PL179765B1/pl unknown
- 1995-03-16 CA CA002185892A patent/CA2185892A1/en not_active Abandoned
- 1995-03-16 CN CN95192635A patent/CN1146156A/zh active Pending
- 1995-03-16 HU HU9602558A patent/HUT75720A/hu unknown
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1996
- 1996-09-17 FI FI963671A patent/FI963671A/fi not_active IP Right Cessation
- 1996-09-18 NO NO963911A patent/NO963911L/no not_active Application Discontinuation
- 1996-10-18 BG BG100921A patent/BG62759B1/bg unknown
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1998
- 1998-04-30 GR GR980300023T patent/GR980300023T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2056852C1 (ru) | 1996-03-27 |
| BG62759B1 (bg) | 2000-07-31 |
| ES2107980T1 (es) | 1997-12-16 |
| HU9602558D0 (en) | 1996-11-28 |
| KR100382252B1 (ko) | 2003-07-07 |
| SK281948B6 (sk) | 2001-09-11 |
| UA26939C2 (uk) | 1999-12-29 |
| AU2087495A (en) | 1995-10-09 |
| GR980300023T1 (en) | 1998-04-30 |
| AU699896B2 (en) | 1998-12-17 |
| SK118796A3 (en) | 1997-06-04 |
| BG100921A (en) | 1997-12-30 |
| ATE260111T1 (de) | 2004-03-15 |
| FI963671A (fi) | 1996-11-14 |
| EP0790059A4 (en) | 2000-11-02 |
| EP0790059A1 (en) | 1997-08-20 |
| US6150326A (en) | 2000-11-21 |
| NO963911D0 (no) | 1996-09-18 |
| CA2185892A1 (en) | 1995-09-28 |
| PL316311A1 (en) | 1997-01-06 |
| DE69532611D1 (de) | 2004-04-01 |
| CZ274796A3 (en) | 1997-06-11 |
| HUT75720A (en) | 1997-05-28 |
| GEP20012377B (en) | 2001-03-25 |
| JPH09510473A (ja) | 1997-10-21 |
| FI963671A0 (fi) | 1996-09-17 |
| CZ285856B6 (cs) | 1999-11-17 |
| NO963911L (no) | 1996-11-08 |
| PL179765B1 (pl) | 2000-10-31 |
| WO1995025531A1 (fr) | 1995-09-28 |
| KR970701557A (ko) | 1997-04-12 |
| DE790059T1 (de) | 1998-03-12 |
| EP0790059B1 (en) | 2004-02-25 |
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