JP4344142B2 - Cns損傷の治療または予防のためのil−18阻害剤の使用 - Google Patents
Cns損傷の治療または予防のためのil−18阻害剤の使用 Download PDFInfo
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Description
外傷モデル
本研究に使用したマウスは、8〜16週齢の体重30〜35gのオスであった。そのマウスらを特定の無菌環境下で飼育し、4〜6匹の檻の中で、標準状態の温度および光を維持し、餌および水を適宜与えた。本研究は、イスラエルのエルサレムのヘブライ大学のインスティテューショナル アニマル ケア コミッティーのガイドラインに基づいて行なわれた。実験的CHIは、前もって開発された重錘落下器材(weight-drop device)を用いて行なった(Chen et al. 1996)。簡単に言えば、エーテル麻酔の誘導後、縦方向の正中切開を行ない、皮膚を剥がし、頭蓋を露出させた。左前部の前頭骨領域を識別し、付刃テフロン(登録商標)コーン(tipped teflon cone)を、前額面で中線に〜1mm横に設置した。頭部を固定し、75gの錘を18cmの高さからコーン上に落下させ、左脳半球に局所の損傷を与えた。外傷ののち、マウスは100%O2による支持酸化(supporting oxygeneration)を2分だけ受け、檻に戻された。
頭蓋内IL−18レベルを定量するために、C57BL/6(B6)株のマウス(総数 n=62)を、6つの別の群に割り当てた。(1)「正常対照」;未処理のB6マウス(n=10)。(2)「エーテル麻酔」;10分間エーテルで麻酔し、24時間後(n=10)または7日後(n=10)に骨頭切除したマウス。(3)「偽手術」;麻酔および縦方向の頭皮切開を受け、24時間後(n=15)または7日後に犠牲死させたマウス。(4)「外傷群」;実験的CHIを前記したように行ない、動物を、外傷後4時間(n=7)、24時間(n=7)、7日(n=7)にエーテル麻酔において骨頭切除した。(5)「TNF注入」;大脳内IL−18の調節におけるTNFの潜在的な役割を評価するために、マウスをエーテル麻酔し、10μlの滅菌リン酸緩衝生理食塩水(PBS)中200ngのマウス組換えTNF(R&D Systems, Abingdon, UK)を脳室内(i.c.v.)注入し、24時間後に犠牲死させた(n=10)。(6)「模擬注入(mock injection)」;これらの動物は、TNF注入動物に対する対照群として、ビヒクルのみ(10μl 滅菌PBS)をi.c.v.注入し、24時間後に犠牲死させた(n=6)。全てのマウスにおいて、骨頭切除後すぐに脳を摘出し、液体窒素において素早く凍結させ、解析まで−70℃で保存した。外傷群由来の脳は、損傷 対 無損傷の脳半球においてIL−18レベルを比較するために、左(同側)および右(反対側)の脳半球に分離した。ポリトン(Polyton)(Kinematica, Kriens, Switzerland)で、Tris 50mM(pH 7.2)、NaCl 150mM、Triton−X−100 1%(Boehringer Mannheim, Rotkreuz, Switzerland)およびプロテアーゼ阻害剤カクテル(cocktail)(Boehringer Mannheim)を含有する1:4で希釈された氷冷抽出緩衝液(W/W)を用いて、組織のホモジナイゼーションを行なった。ホモジネートは90分間氷上で振とうし、ついで15分間3,000gおよび4℃で遠心した。上清を等分し、解析まで−70℃で保存した。脳抽出物中の全タンパク質の濃度を、Bradfordアッセイ(Bio Rad Laboratories, Munich, Germany)で測定し、評価された全てのマウスにおいて、非常に一定していることが見出された(12.1±2.1mg/ml;平均±SD)。大脳内サイトカインレベルの定量は、取扱説明書(R&D Systems, Abingdon, UK)にしたがって、マウスIL−18に特異的なELISAによって行なった。アッセイの感度は5pg/mlであった。異なる動物群間の大脳内IL−18レベルの比較において、検出限界である5pg/ml未満の濃度は、全て4.9pg/mlという値を指定した。試料を2つのウェルに未希釈のものを入れ、最終濃度を2つの試料の平均ODから算出した。ODは分光光度計(Dynatech Laboratories Inc., Chantilly, VA)によって消光波長405nmで測定した。
ヘブライ大学株のオスのイスラエル生まれのマウス(n=40)を、IL−18BPの研究のために使用した。麻酔および実験的CHIを前記のように行なった。処置プロトコルに対して、動物を2つの群に分けた。A群(「対照群」、n=16)において、マウスを実験的CHIに供し、1時間後にビヒクルのみ(PBS)を注入し、ついで神経評価のために7日間観察した(以下参照)。B群(「研究群」、n=18)において、マウスは、CHI後t=1時間での神経スコアの測定直後、50μlのIL−18BPをi.p.注入された。同じ実験モデルで前もって測定したように、血液脳関門の透過性はCHI後1〜4時間の間は5〜6倍上昇するため(Chen et al. 1996)、IL−18BPはそれらの状況下の脳に対して利用可能である。マウスのさらなる2つの群をAおよびB群にしたがって処理し(それぞれ、C群:「対照群」;D群:「研究群」)、以下に記載するように、48時間後に骨頭切除し、引き続き外傷後浮腫の評価のために脳切開を行なった。
外傷後神経損傷の評価のために、神経重症度スコア(Neurological Severity Score)(NSS)が前もって開発され、有効なものとされている(Stahel et al., 2000)。
脳浮腫の程度を、以前に記載したように(Chen et al. 1996)、損傷した脳半球における組織の水分含量を測定することによって評価した。簡単に言えば、外傷後48時間でマウスを前記したように麻酔し、なおその時点は浮腫がこのモデル系においてなお有意である時点と一致する(Chen et al. 1996)。骨頭切除ののち、小脳および脳幹を摘出し、外傷部位に隣接する領域由来、および皮質の脳半球由来の〜20mgの皮質の断片を調製した。右(無損傷)脳半球を内在的な対照として使用した。組織切片の重量を測定し、24時間95℃で乾燥した。「乾燥」切片の重量を測定後、脳の水分含量のパーセンテージを以下のように算出した。
%H2O=[(湿重量−乾燥重量)×100]/湿重量
チューリッヒの大学病院の外傷部門に収容される、単独の重症なCHIの10人の患者(平均年齢±SD:37±10歳;幅24〜57歳;9人の男性および1人の女性)は、本研究に含まれる。全患者は、心肺機能蘇生ののち、グラスゴー コーマ スケール(GCS)スコア≦8を有した(Teasdale and Jennett, 1974)。CTスキャン評価ののち全患者は、頭蓋内圧(ICP)が15mmHgを超える場合、治療上CSFを排水するために脳室内カテーテルを受けた。ステロイドにより治療された患者はいなかった。胸部、腹部、骨盤、脊髄の損傷または長骨骨折を随伴するため、介入を必要とする複数の損傷を有する患者は、本研究では除外した。個々の結果は、グラスゴー アウトカム スケール(Glasgow Outcome Scale)(GOS)を用いて評価した(Jennett and Bond, 1975)。CSFおよび血清収集に対するプロトコルは、チューリッヒの大学病院の倫理委員会によって承認された。
CHI患者(n=10)のCSFおよびそれと一致する血清試料を、ある一定の時点で毎日収集した。対照CSFを、診断の脊椎穿刺を受けた患者から収集した(n=5)。それらの患者は、タンパク質、糖および細胞数の正常CSF値に基づき、炎症性CNS疾患の徴候を有さなかった(データは示さない)。CHI群において、たとえばICPが24時間以上、正常範囲(≦15mmHg)を保持しており、心室カテーテルが早急に除去される場合を除いて、試料収集を外傷後10日間行なった。合計106の一致するCSFおよび血清試料を本研究において解析される外傷患者から収集した。全ての試料を収集後すぐに遠心し、等分し、解析まで−70℃で保存した。CSFおよび血清におけるIL−18レベルの定量は、商業的に利用可能なキット(R&D Systems, Abingdon, UK)を用いるヒトIL−18に特異的なELISAにより行なった。マウスアッセイと同様に、ELISAの感度は5pg/mlであり、最終IL−18濃度は405nmの消光波長時で2つの試料において決定された平均ODから算出した。CHI患者と対照との間のIL−18CSFレベルの比較について、検出限界である5pg/ml以下の濃度は全て、4.9pg/mlの値を指定した。
データの統計解析を、商業的に利用可能なソフトウエア(Windows(登録商標)用SPSS 9.0)により行なった。神経スコア(NSSおよびΔNSS)などの本来は分配されないデータの解析のために、条件のないMann−Whitney−Uテストを使用した。不対スチューデントt検定(unpaired Student's t-test)を、異なるマウス群において大脳内IL−18濃度を比較するため、およびIL−18BP処置マウス 対 ビヒクル注入マウスにおける脳の水分含量の相違の解析のために使用した。CHI患者における毎日のCSF 対 一致する血清試料、または外傷 対 対照CSFのいずれかにおけるヒトIL−18レベルの比較を、反復測定分散分析(repeated measures ANOVA)に関する一般的な線形モデルを用いて決定した。<0.05のp値は、統計的に有意であるとみなした。
実施例1:マウスにおける大脳内IL−18レベル
図1に示すように、IL−18を、未処理(「正常」)対照マウスであるB6株(n=10)の脳ホモジネートにおけるELISAによって決定したところ、平均レベル27.7±1.7[±SEM]ng/mlであった。実験群において、エーテル麻酔のみまたは「偽」手術との組合わせ(すなわちエーテル麻酔および縦方向の頭皮切開)による誘導により、頭蓋内IL−18レベルは、それぞれ48.9±1.1ng/ml(「エーテル」群、n=8)および54.3±2.7ng/ml(「偽」群、n=13)に有意に上昇した(p<0.01 対 「正常」マウス、不対スチューデントt検定;図1)。「エーテル」処理された動物と「偽」処理された動物間の相違は、統計学的有意性はなかった(p=0.16)。
IL−18阻害剤が脳損傷における回復を促進させるという仮説について研究するために、IL−18BPの単独注入後の異なる時点での回復を比較した。外傷後1時間の神経重症度スコア(NSS)が最も正確に外傷の規模を示し、かつMRIおよび組織学において見られるように損傷組織の容積に相関することを前もって明らかにした。
IL−18レベルを、10人の重症なCHI患者由来の毎日のCSFおよび血清試料において、外傷から10日までの間評価した。患者の人口統計上の臨床データを表5に表す。
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Claims (13)
- 閉鎖性頭部外傷の3日後に単回投与することを特徴とする、IL−18結合タンパク質を含む閉鎖性頭部外傷の治療剤。
- 前記IL−18結合タンパク質が1つ以上の部位でグルコシル化されている請求項1記載の治療剤。
- 前記IL−18結合タンパク質が免疫グロブリン(Ig)融合を含む請求項1記載の治療剤。
- 前記IL−18結合タンパク質が、アミノ酸残基上の1つ以上の側鎖として存在する、1つ以上の官能基に結合された少なくとも1つの部分を含み、該部分がポリエチレングリコール(PEG)部分である請求項1記載の治療剤。
- 前記治療剤が、同時使用、連続使用または個別使用として、抗炎症剤をさらに含有する請求項1記載の治療剤。
- 前記抗炎症剤がCOX−阻害剤である請求項5記載の治療剤。
- 前記COX−阻害剤がCOX−2阻害剤である請求項6記載の治療剤。
- 前記治療剤が、同時使用、連続使用または個別使用として、抗酸化剤をさらに含有する請求項1記載の治療剤。
- 前記IL−18結合タンパク質が、0.001〜100mg/kg体重の量で使用される請求項1記載の治療剤。
- 前記IL−18結合タンパク質が、0.01〜10mg/kg体重の量で使用される請求項1記載の治療剤。
- 前記IL−18結合タンパク質が、0.1〜5mg/kg体重の量で使用される請求項1記載の治療剤。
- 前記IL−18結合タンパク質が、1〜3mg/kg体重の量で使用される請求項1記載の治療剤。
- 前記IL−18結合タンパク質が皮下に投与される請求項1記載の治療剤。
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IL (2) | IL159014A0 (ja) |
LT (1) | LT1390070T (ja) |
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Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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SI1622939T1 (sl) | 2003-05-13 | 2012-06-29 | Merck Serono Sa | Akrivne variante il-18 vezavnega proteina in medicinske uporabe le-tega |
JP5069000B2 (ja) * | 2004-06-30 | 2012-11-07 | 敦生 関山 | 非炎症性ストレス応答の指標剤およびその利用 |
PL1888100T3 (pl) * | 2005-06-03 | 2012-03-30 | Merck Serono Sa | Zastosowanie lizoform IL-18BP do leczenia i/lub zapobiegania neurologicznym chorobom zapalnym |
DK1885753T3 (da) | 2005-06-03 | 2011-10-03 | Ares Trading Sa | Fremstilling af rekombinant II-18-proteiner |
DK1891088T3 (da) | 2005-06-10 | 2012-01-30 | Ares Trading Sa | Fremgangsmåde til rensning af et IL-18-bindende protein |
US8685400B2 (en) * | 2007-07-30 | 2014-04-01 | University Of Miami | Modulating inflammasome activity and inflammation in the central nervous system |
WO2015032932A1 (en) * | 2013-09-05 | 2015-03-12 | Ab2 Bio Sa | Il-18 binding protein (il-18bp) in inflammatory diseases |
MX2017010919A (es) * | 2015-03-05 | 2017-12-07 | Ab2 Bio Sa | Proteina de union il-18 (il-18bp) y anticuerpos en enfermedades inflamatorias. |
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JPH0873453A (ja) * | 1994-09-02 | 1996-03-19 | Otsuka Pharmaceut Co Ltd | サイトカイン阻害剤 |
IL121860A0 (en) * | 1997-08-14 | 1998-02-22 | Yeda Res & Dev | Interleukin-18 binding proteins their preparation and use |
DE69925581T2 (de) * | 1998-03-09 | 2006-04-27 | Vertex Pharmaceuticals Inc., Cambridge | 1,2-diazepanderivate als inhibitoren des interleukin-1beta umwandelnden enzyms |
CA2276216A1 (en) * | 1998-06-24 | 1999-12-24 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | An artificial peptide capable of neutralizing the biological activity of interleukin-18 |
RS50926B (sr) * | 2000-05-05 | 2010-08-31 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Upotreba il-18 inhibitora za lečenje i/ili prevenciju ateroskleroze |
DE60106026T2 (de) * | 2000-06-23 | 2006-02-23 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | 2-arachidonylglycerol (2-ag)-ein hemmer des tumor nekrose faktors-alfa und neuroprotektor des gehirns bei geschlossenen kopfverletzungen |
AU2002224417A1 (en) * | 2000-10-18 | 2002-04-29 | Immunex Corporation | Methods for treating il-18 mediated disorders |
US6671553B1 (en) * | 2001-05-23 | 2003-12-30 | Pacesetter, Inc. | Implantable cardiac lead having terminating connector strain relief and method of manufacture |
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