CN100346822C - 白细胞失活元件 - Google Patents
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Abstract
本发明提供了一种降低白细胞活性的元件，该方法包括一个载体和一个与该载体连接并适合于与白细胞受体发生交互反应的配体。进一步地，本发明提供了一种用所述元件降低白细胞活性的方法。本发明的优点是激活的白细胞在与白细胞激活元件结合后，该细胞的破坏效果在几分钟内就被抑制。
Description
发明领域
本发明涉及到一种白细胞失活元件和一种降低白细胞活性的方法。
背景技术
在各种临床情况中，经常会发生急剧增加的致病性细胞免疫反应，出现这种情况的例子有：
-心脏手术中心肺机的动脉或静脉导管(参见Kirklin JK，Westaby S，Blackstone EH，Kirklin JW，Chenoweth DE，Pacifico AD.Complement and thedamaging effects of cardiopulmonary bypass.J Thorac Cardiovasc Surg.1983Dec；86(6)：845-57.)；
-多处受伤或患败血症(败血性休克)后的系统性免疫反应综合症(SIRS)(参见Stegmayr BG.Apheresis as therapy for patients with severe sepsis andmultiorgan dysfunction syndrome.Ther Apher.2001 Apr；5(2)：123-7.)；
-由于过强的免疫活性导致的多器官功能不全综合症(MODS)(参见Marshall JC.Inflammation，coagulopathy，and the pathogenesis of multiple organdysfunction syndrome.Crit Care Med.2001 Jul；29(7Suppl)：p.99-106.)。
在上述外科或临床并发症中，白细胞产生的非期待活性导致病人严重的致病性并发症，为了避免这种情况，应该将血流中激活的白细胞(特别是嗜中性白细胞)除去或直接使其失活。可利用目前通用的白细胞过滤器，将越来越多的激活的细胞从血液中过滤除去，但是，仍然活着的白细胞产生并分泌致病性物质(细胞因子、酶、氧自由基等)而导致现实疾病(参见ScholzM，Simon A，Matheis G，Dzemali O，Henrich D，Kleine P，Wimmer-Reinecker G，Moritz A.Leukocyte filtration fails to limit functional neutrophil activity duringcardiac surgery.Inflamm Res.2002 Jul；51(7)：363-8.)。有证据表明过滤网中的白细胞可能通过机械压力和通过与细胞外表面接触而再次激活，例如，更大量地分泌由激活的嗜中性白细胞产生的弹性蛋白酶(参见Scholz M，Wimmer-Greinecker G，Simon A，Dzemali O，Chang HY，Kleine P，Matheis G，Moritz A.Perioperative elastase activity in cardiac surgery and its role inendothelial leakage.Inflamm Res.2003 Oct；52(10)：433-8.)，此外，弹性蛋白酶还对管壁的细胞外基质发生作用，并阻断内皮细胞-细胞接触，从而使管壁的渗透性增加，产生水肿，发炎加重及其它症状(参见Scholz M，Wimmer-Greinecker G，Simon A，Dzemali O，Chang HY，Kleine P，Matheis G，Moritz A.Perioperative elastase activity in cardiac surgery and its role inendothelial leakage.Inflamm Res.2003 Oct；52(10)：433-8.)。
编程性细胞死亡是一种最重要的免疫系统调节元件(参见Winoto A.，Celldeath in the regulation of immune responses.Curr Opin Immunol.1997Jun；9(3)：365-70.)，免疫相关细胞的这种编程性死亡使免疫系统在一种免疫反应后，如抗微生物病原菌后的活性正常化。另外，在个体发育过程中，免疫系统必须杀死那些对内生结构或对来自于环境的天然抗原发生作用(例如：自身免疫性疾病或过敏)的免疫细胞。由所谓的抗原呈递细胞(aqc)激活的T细胞通常接受到几种信息，由apc加工的抗体在MHC-I或MHC-II分子组中呈递，假如T细胞受体与抗原的亲和力太弱或不存在共刺激信号时(如，通过附着分子)，该细胞就会编程性死亡。产生编程性细胞死亡的另一必要机制是通过Fas/FasL路径(参见Gottlieb RA，Babior BM.Regulation ofFas-mediated apoptosis.Curr Top Cell Regul.1997；35：69-105.)，在这个机制中，例如，管壁的内皮细胞或其他的上皮细胞能表达FasL以阻止组织进入激活的免疫细胞(参见Greenstein S，Bamard J，Zhou K，Fong M，Hendey B.Fasactivation reduces neutrophil adhesion to endothelial cells.J Leukoc Biol.2000Nov；68(5)：715-22.)。
国际专利申请公开WO 9738707(1997年10月23日公开)公开了传送可产生凋亡诱导分子源的装置。其中具体公开了可产生凋亡诱导分子源的经遗传工程修饰的细胞，该细胞可产生凋亡诱导分子FasL，而且所公开的装置中的细胞被膜包被。在这种装置中由于载体和细胞包被关系，凋亡诱导分子是由细胞表达并分泌，再穿过包被膜，然后进入体液中才能作用到靶分子上，因此产生凋亡诱导分子的过程复杂且其容易被体液所稀释，显然与靶分子接触的效率很低。因此亟需比现有技术尤其是国际专利申请公开WO 9738707所公开的装置更有效的降低白细胞活性的装置。
本发明所解决的问题
本发明的目的是提供一种元件，该元件适于降低白细胞活性，从而减少白细胞分泌的致病性物质。进一步地，本发明提供一种用上述元件降低白细胞活性方法。
解决问题的方法
本申请的发明人对被细胞肥大病毒感染的人眼视网膜色素上皮细胞进行研究后发现，由于与上皮细胞上的FasL接触，激活的嗜中性白细胞丧失了保持或提高与上皮细胞的结合的能力，这种令人惊讶的结果被认为是内皮和各个组织为抗炎性事件的一种保护机制。在细胞-细胞接触后几分钟内就能观察到嗜中性白细胞-效应器-机制的这种功能性丧失，该功能性丧失好像完全(极大程度)独立于嗜中性细胞中的编程性细胞死亡信号路径。基于这些令人惊讶的发现，如，Fas/FasL路径或白细胞-效应器作用的其他早期抑制机制可以用于急性过量免疫反应的试验和临床用途。
本发明的目的
本发明提供了一种降低白细胞活性的元件，该元件包括一种载体和一个与该载体连接并适合与白细胞受体发生交互作用的配体。进一步地，本发明提供了一种用所述元件降低白细胞活性的方法。
本发明的优点是细胞的破坏活性在激活的白细胞与白细胞失活元件(LIM)结合后的几分钟内就被抑制，这是由于白细胞细胞膜上的特异性受体与LIM中的相应配体发生了接触。该配体可以是蛋白，在与细胞膜上的受体接触后产生一个信号，该信号刺激白细胞从而降低分泌活性和免疫原性。要达到这个目的，一种可能的方法是通过受体-配体交互反应导入编程性细胞死亡，如Fas/FasL。
本发明的描述
本发明的元件适合用Shaldon导管导入到病人的血流中，或导入到心肺机的循环中。
该元件优选地包含一个直径如10cm的塑料外壳，其血液导入导管和血液导出导管与心肺机的管连接相适应。在该元件中有一个载体，如表面被修饰的三维折叠的聚酯膜，其用于结合激活的白细胞而通过受体诱导性信号使他们失活和死亡(如导入编程性细胞死亡)。该载体的材料可以是任何适于结合配体的材料，此处使用的术语“结合”包括配体与上述载体的共价和非共价结合，如，盐结合，疏水反应和亲水结合。进一步地，该配体可以是直接或非直接地与载体结合，其中非直接地结合包括为了更好地呈递配体通过一个结合介质的结合，如一个长链分子，或者通过含有该配体并通过其他的结合反应与载体结合的细胞结合。
本发明的LIM适于任何白细胞，如B-淋巴细胞、T淋巴细胞、粒性白细胞和嗜中性白细胞。
影响血流、血压或血流动性的该元件的其他参数与已用于临床的常规白细胞过滤器相同。
实施例1
12井培养板的井中装入聚酯膜(孔的大小为40μm)，与不同浓度的功能性激活的抗Fas(CD95)IgM抗体培养过夜，使用下列对照：
-没有膜的井
-有膜，但没有与抗体预培养的井
-有膜，但与不相关的IgM抗体预培养的井。
将Fas表达(Fas+)和Fas删除(Fas-；在表面不表达Fas)Jurkat细胞以1×106/ml的浓度加到井中培养24h。通过流式细胞仪用膜联蛋白结合测试法(annexin binding assay)定量检测编程性细胞死亡率和坏死率。
结果：培养后预处理井中的Fas-Jurkat细胞在膜联蛋白V结合性方面没有表现出明显地提高，相反，表现出明显的依赖于IgM抗体浓度的编程性细胞死亡诱导性。
| Fas+ | Fas- | |
| 0ng | 24.81％ | 24.29％(对照值) |
| 10ng | 31.38％ | 27.57％ |
| 50ng | 40.95％ | 26.20％ |
| 100ng | 89.31％ | 29.65％ |
在上述对照中，没有发现编程性细胞死亡诱导性，用新分离地嗜中性白细胞获得了相似的结果。
图1显示了本发明的结果。
Claims (8)
1.一种降低白细胞活性的元件，该元件包括一个载体和一个与该载体直接连接并适于与白细胞受体发生交互反应的配体，其中所述配体是FasL蛋白或抗白细胞Fas蛋白的抗体。
2.如权利要求1所述的元件，其中的配体是FasL蛋白。
3.如权利要求1所述的元件，其中的配体是一种抗白细胞Fas蛋白的抗体。
4.如权利要求1-3中任一权利要求所述的元件，其中所述元件用于导入血液循环或体外循环中。
5.如权利要求1-3中任一权利要求所述的元件，其中所述的载体为聚酯膜。
6.配体在制备权利要求1-5任一项所述的降低白细胞活性的元件中的用途，其中所述配体是FasL蛋白或抗白细胞Fas蛋白的抗体。
7.如权利要求6所述的用途，其中的白细胞在与配体接触后分泌的细胞因子和/或酶和/或氧自由基的量比接触前分的分泌量低。
8.如权利要求6或7所述的用途，其中与细胞连接的配体与白细胞受体的交互反应降低了白细胞与细胞结合的亲和力方面的活性。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10147638.8 | 2001-09-27 | ||
| DE10147638A DE10147638B4 (de) | 2001-09-27 | 2001-09-27 | Leukozyten-Inaktivierungs-Modul (LIM) |
Publications (2)
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|---|---|
| CN1558915A CN1558915A (zh) | 2004-12-29 |
| CN100346822C true CN100346822C (zh) | 2007-11-07 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028188330A Expired - Fee Related CN100346822C (zh) | 2001-09-27 | 2002-09-16 | 白细胞失活元件 |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US20040241171A1 (zh) |
| EP (1) | EP1430085B1 (zh) |
| JP (1) | JP5503826B2 (zh) |
| CN (1) | CN100346822C (zh) |
| AT (1) | ATE438661T1 (zh) |
| BR (1) | BR0212816A (zh) |
| CA (1) | CA2461900A1 (zh) |
| DE (4) | DE20121877U1 (zh) |
| HU (1) | HUP0401803A2 (zh) |
| MX (1) | MXPA04002736A (zh) |
| NO (1) | NO20041682L (zh) |
| PL (1) | PL368596A1 (zh) |
| RU (1) | RU2327490C2 (zh) |
| WO (1) | WO2003031473A1 (zh) |
| ZA (1) | ZA200402205B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE20121877U1 (de) | 2001-09-27 | 2003-09-18 | Leukocare Gmbh | Leukozyten-Inaktivierungs-Modul (LIM) |
| US20100306144A1 (en) * | 2009-06-02 | 2010-12-02 | Scholz Martin B | System and method for classifying information |
| JP6773217B2 (ja) * | 2017-04-28 | 2020-10-21 | ヤマハ株式会社 | 受信装置及び信号伝送システム |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012632A1 (en) * | 1995-10-05 | 1997-04-10 | Tkb Associates Limited Partnership | Methods for treatment of diseases associated with a deficiency of fas ligand activity |
| WO1997038707A1 (en) * | 1996-04-17 | 1997-10-23 | Cytotherapeutics, Inc. | Method and device for delivery of apoptosis-inducing molecules |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2927942B2 (ja) * | 1989-01-27 | 1999-07-28 | オーストラリアン メンブレイン アンド バイオテクノロジィ リサーチ インスティチュート | 受容体膜およびイオノホアのゲーテイング |
| DE69119683T2 (de) * | 1990-07-27 | 1996-10-02 | Pall Corp | Filtereinrichtung zur Entfernung von Leukozyten und Methode zur Verwendung |
| US5639376A (en) * | 1994-01-10 | 1997-06-17 | Hemasure, Inc. | Process for simultaneously removing leukocytes and methylene blue from plasma |
| WO1995018665A1 (en) * | 1994-01-10 | 1995-07-13 | Hemasure, Inc. | Device and process for removing leukocytes and viral inactivating agents from blood |
| JPH08173528A (ja) * | 1994-12-26 | 1996-07-09 | Terumo Corp | 血液処理システム |
| JPH1076004A (ja) * | 1996-09-05 | 1998-03-24 | Kanegafuchi Chem Ind Co Ltd | 体液処理用吸着材及び体液処理用吸着器 |
| WO1998046242A1 (en) * | 1997-04-11 | 1998-10-22 | Stanford University | Treatment of cancer by the administration of fas ligand expressing non-tumorigenic cells |
| US6204055B1 (en) * | 1999-04-12 | 2001-03-20 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Fas mediated signaling |
| DE60027863T2 (de) * | 1999-03-17 | 2006-12-07 | Jimro Co., Ltd., Takasaki | Apherese von leukozyten aus blut zur behandlung von hiv |
| JP2001103977A (ja) * | 1999-10-12 | 2001-04-17 | National Institute Of Animal Health | ブタＦａｓリガンドの構造遺伝子 |
| US6797514B2 (en) * | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
| DE20121877U1 (de) | 2001-09-27 | 2003-09-18 | Leukocare Gmbh | Leukozyten-Inaktivierungs-Modul (LIM) |
-
2001
- 2001-09-27 DE DE20121877U patent/DE20121877U1/de not_active Expired - Lifetime
- 2001-09-27 DE DE10147638A patent/DE10147638B4/de not_active Expired - Fee Related
-
2002
- 2002-09-16 DE DE50213747T patent/DE50213747D1/de not_active Expired - Lifetime
- 2002-09-16 MX MXPA04002736A patent/MXPA04002736A/es active IP Right Grant
- 2002-09-16 BR BR0212816-0A patent/BR0212816A/pt not_active IP Right Cessation
- 2002-09-16 CN CNB028188330A patent/CN100346822C/zh not_active Expired - Fee Related
- 2002-09-16 PL PL02368596A patent/PL368596A1/xx not_active Application Discontinuation
- 2002-09-16 US US10/489,831 patent/US20040241171A1/en not_active Abandoned
- 2002-09-16 CA CA002461900A patent/CA2461900A1/en not_active Abandoned
- 2002-09-16 JP JP2003534455A patent/JP5503826B2/ja not_active Expired - Fee Related
- 2002-09-16 RU RU2004112762/15A patent/RU2327490C2/ru not_active IP Right Cessation
- 2002-09-16 WO PCT/DE2002/003466 patent/WO2003031473A1/de active Application Filing
- 2002-09-16 AT AT02782679T patent/ATE438661T1/de not_active IP Right Cessation
- 2002-09-16 DE DE10294578T patent/DE10294578D2/de not_active Expired - Fee Related
- 2002-09-16 EP EP02782679A patent/EP1430085B1/de not_active Expired - Lifetime
- 2002-09-16 HU HU0401803A patent/HUP0401803A2/hu unknown
-
2004
- 2004-03-19 ZA ZA200402205A patent/ZA200402205B/en unknown
- 2004-04-26 NO NO20041682A patent/NO20041682L/no not_active Application Discontinuation
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012632A1 (en) * | 1995-10-05 | 1997-04-10 | Tkb Associates Limited Partnership | Methods for treatment of diseases associated with a deficiency of fas ligand activity |
| WO1997038707A1 (en) * | 1996-04-17 | 1997-10-23 | Cytotherapeutics, Inc. | Method and device for delivery of apoptosis-inducing molecules |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005507908A (ja) | 2005-03-24 |
| DE10147638B4 (de) | 2004-05-27 |
| US20080292643A1 (en) | 2008-11-27 |
| DE10294578D2 (de) | 2004-08-26 |
| MXPA04002736A (es) | 2005-09-08 |
| PL368596A1 (en) | 2005-04-04 |
| CN1558915A (zh) | 2004-12-29 |
| BR0212816A (pt) | 2004-10-05 |
| DE10147638A1 (de) | 2003-04-17 |
| NO20041682L (no) | 2004-04-26 |
| US20040241171A1 (en) | 2004-12-02 |
| ATE438661T1 (de) | 2009-08-15 |
| DE50213747D1 (de) | 2009-09-17 |
| HUP0401803A2 (hu) | 2004-11-29 |
| ZA200402205B (en) | 2004-08-16 |
| CA2461900A1 (en) | 2003-04-17 |
| WO2003031473A1 (de) | 2003-04-17 |
| DE20121877U1 (de) | 2003-09-18 |
| EP1430085B1 (de) | 2009-08-05 |
| US7850969B2 (en) | 2010-12-14 |
| JP5503826B2 (ja) | 2014-05-28 |
| EP1430085A1 (de) | 2004-06-23 |
| RU2327490C2 (ru) | 2008-06-27 |
| RU2004112762A (ru) | 2005-04-20 |
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