JP4301942B2 - 過敏性疾患におけるil−18阻害剤の使用 - Google Patents
過敏性疾患におけるil−18阻害剤の使用 Download PDFInfo
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Classifications
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Description
したがって、好ましい態様において、機能的誘導体は、アミノ酸残基の1つ以上の側鎖に存在し、1つ以上の官能基に結合される少なくとも1つの部分を含む。その部分がポリエチレングリコール(PEG)である態様が最も好ましい。
る。
方法
実験的誘導接触過敏症(CHS)のマウスモデルを以下のすべての実施例において使用した。CHSの範囲は、局所的適用感作物質に対して、耳の腫れによって測定した。
剃毛した背中に、25μl DNFB(0.5% アセトン/オリーブオイル(4/1)中(ビヒクルとして))
2.日数5:攻撃
右耳の背中側と腹側に、各5μl DNFB(0.2%)
左耳の背中側と腹側に、各5μl ビヒクル
3.日数6:読み出し
耳の厚さを炎症の尺度としてモニター
対照耳に対して試験耳の腫れの増加(μm)としてスコアを表現
4.日数6または7:分析のための耳の処理
このモデルにおいて、腫れは日数6〜日数7の間で最高となる。IL−18は、日数0、日数1および日数2での感作の間、あるいは日数4、日数5および日数6での攻撃の間、動物につき250μgのIL−18BP(生理食塩水中)を毎日注射することにより中和された。
接触過敏症応答(CHS)は、T−細胞によって媒介されるハプテン特異的皮膚炎症である。多くのハプテンは、主にCD8+エフェクターT細胞からなるオリゴクローナルT細胞応答を生じるのに対し、CD4+T細胞は、CHS応答においてダウンレギュレーションの役割を有する(Bour, H., et al. 1995; Grabbe et al., 1998)。CHSにおけるIL−18の役割を調べるために、マウスをDNFBにより皮膚上で感作させ、ついで5日後、耳の皮膚へのハプテン塗布により攻撃した。ハプテン攻撃に付随して、マウスに250μg/マウス/日のrhIL−18BP、あるいは生理食塩水を腹腔注射した。IL−18BP、または対照としての生理食塩水を、最初のDNFB感作(日数0)ののち日数5〜8で3日間、毎日投与した。日数5でのDNFB攻撃は、両群において有意な耳の腫れを誘導した(図1A)。生理食塩水で処置したマウスにおける腫れの程度(三角)は、IL−18BPで処置し、すでに日数9でほとんど正常な状態に戻っていたマウス(四角)よりはるかに目立っていた。
接触過敏症/接触性皮膚炎のこの確立されたマウスモデルにおいて、3日間のIL−18の阻害剤による処置は、ハプテンでの処置によって導き出される腫れ/炎症の程度に有意で有益な効果を有した。
方法
C57BL/6マウスを、25μlの0.5%DNFB溶液を剃毛した腹部に上皮塗布(epicutaneous application)することにより感作した(日数0)。マウスは、日数5で耳への20μlの0.2%DNFBによる第1回目の攻撃を受けた。日数19で、マウスはDNFBによる第2回目の攻撃を受けた。耳の腫れは、日数0(ハプテン感作)、5(第1回目のハプテン攻撃)、6、7、8、9、12、14、16、19(第2回目のハプテン攻撃)、20、21、22、23、26、28、30で測定した。各群に対する平均値とSDを図2に示す。マウスを、日数19〜日数23まで毎日250μg/マウス/日で、IL−18BP腹腔内(n=5;図2、白抜き四角)または生理食塩水(n=5;図2、黒塗り四角)のいずれかで処置した。
図2に示すように、IL−18BP処置は、特に第2回目のハプテンによる攻撃後、有意に耳の腫れを減少させた。
方法
CHSをC57BL/6マウスに前記のように誘導した。CHSにより生じた浮腫をモニターするために、エバンスブルーを、DNFBによる攻撃の2時間前に静脈注射した。マウスは24時間後に殺され、血管から漏れて周囲の組織に蓄積された色素を抽出するために耳を処理した。血管漏出は、乾燥耳組織の1mg当たりの色素の量として評価し、血清中のエバンスブルーの濃度に対して補正し、そして対照の耳に対する攻撃した耳の比率として表わした。日数4および5でのIL−18BPによる処置ではビヒクル処置対照の56%まで腫れが減少した(図4、左パネル、p<0.01)が、これら2つの群の間に血管漏出における有意差はなかった(図4、右パネル)。両群は、非感作対照群と比較して、浮腫の有意な増加を示した(p<0.05およびp<0.01)。さらなる対照として、マウスを、1匹および1日当たり250μgの無関係なタンパク質であるBSAで処置した。これらのマウスは、ビヒクルで処理した対照動物と同様にCHSを発症した(1群につきn=10マウス)。
原理:エバンスブルーの注射(iv)および標的組織(耳)からの抽出
評価のための生データ:
・エバンスブルーの標準曲線(OD620/ng)
・血液中のエバンスブルー濃度(それぞれOD620/mlまたはμg/ml)
・耳の乾燥組織重量(同側および対側、mg)
・耳のエバンスブルー含量(同側および対側、それぞれOD620/ngまたはng/mg)
・実験的誘導CHSの日数5で、DNFBによるマウスの攻撃の2時間前にエバンスブルーα100μlをivで眼窩後(retroorbitally)に注射
・IL−18BPを攻撃の1時間前にipで注射
・日数6(DNFBによる耳の攻撃の24時間後)で腫れを測定し、動物を殺す
・血液試料を取り、以下の通り処理:
○ 血清30μlを970μlのホルムアミド中に添加(→1/33希釈)
○ 620nmでODを測定(→1OD620=33OD620/ml)
・同側および対側の耳を取り、以下の通り処理:
○ 80℃で24時間乾燥
○ 乾燥重量を測定
○ みじん切りにし、55℃で24時間緩やかに攪拌しながら1mlホルムアルデヒドで色素を抽出、
○ デブリβを除去するためにろ過し、キュベットに満たし、最上層に脂質を浮かべるために室温(RT)で数日間静置
○ 620nmでODを測定
計算すべき値:
基本的には、浮腫の原因である血管から周囲の組織への液体の漏出と血管から組織損傷部位への炎症細胞の管外遊出との2つのプロセスがCHS反応の間に観察される腫れに寄与している。
β試料調製フィルターワットマン5μmPTEEメッシュ、#6984.0350
方法
CHSは記載されたようにC57BL/6マウスで誘導された。動物を日数4〜6でIL−18BPまたはビヒクルで処置した。IL−18BP処置は、日数7でのビヒクル対照の58%まで腫れを減少した。マウスは日数7で殺し、攻撃された耳を回収し、群ごとにプールし(n=8)、そして酵素消化して単細胞懸濁液を得た。細胞を後のCD45陽性生細胞にゲートを設定するFACS分析により特徴づけた。耳調製物において検出されたαβT細胞、NK細胞、好中球および単球/マクロファージの数は、分析した全細胞の割合として表わす。ビヒクル対照と比較したIL−18BP処置後のこれらの種類の細胞の減少も計算された。
単細胞懸濁液を得るためのマウス耳の酵素消化は、Schuler, G. and Steunman, R.M. (1985)およびStingl et al. (1983)のプロトコールに基づいた。
2.70%エタノールですすぎ洗い
3.ピンセットの補助により裂く
4.HBSS1 7.5mlの上に37℃で皮膚側を下に置く
5.最終濃度1%を得るために5mlの2.5%トリプシン2(10×)を添加
6.37℃で35分インキュベート
7.耳の半分の皮膚側(halves dermal side)を、氷上の10mlのHBSS/80%FCS中に置かれたナイロンの篩(細胞ストレーナー)まで移動させ、細胞外マトリックスから細胞を取り除くために徐々にメッシュ(mesh)した。
9.冷HBSS/10%FCSで2回洗浄
10.細胞を計測
1.細胞をFACS染色緩衝液3に再懸濁、後の工程はすべて氷上で
2.染色当たり106個の細胞を使用
3.1μgのFC−ブラックを添加、10分
4.目的のマーカーに対する抗体と結合する抗−CD45抗体を添加、30分
5.2回洗浄
6.FACSにより0.5×106全イベントを得る
7.CD45+生細胞にゲートを設定したのち特異的マーカーを分析
攻撃部位での炎症性浸潤を見積もるために、攻撃を受けていない耳と攻撃された耳とから調製した単細胞懸濁液を、CD45+生細胞にゲートを設定したFACSにより分析した(図5)。攻撃を受けていない耳に存在するCD45+細胞は、主にγδT細胞と皮膚の樹状細胞であることが示された。攻撃24時間後の炎症性浸潤は、CD8およびCD4T細胞、好中球、単球およびNK細胞で構成されており、耳におけるCD45+細胞の総数は約2倍に増加する。腫れの減少に対応して、IL−18BP処置は、攻撃部位に浸潤している白血球の総数を減少させた。これは、炎症性浸潤の種々の種類の細胞全てに影響した。その減少は、細胞の種類によって20%から40%の間になった。
22.5%トリプシン/EDTA(10×)(ギブコ#35400−027)
31%ウシ血清アルブミンリン酸緩衝生理食塩水
方法
マウスをハプテンFITC(4mg/ml溶液50μl)またはビヒクル、アセトン/ジブチルフタレート(1:1)で、右と左のわき腹をそれぞれ染色した。鼠径部のリンパ節を染色後24時間で回収した。ハプテン結合ランゲルハンス細胞は、FACSにより、FITC染色わき腹を流れる(draining)リンパ節においてFITC+、CD11c+細胞として検出することができたが、ビヒクルのみで染色されたわき腹を流れる対側のリンパ節においては検出されなかった(1群につきn=5のドレーン(draining)リンパ節)。
抗体を提示するランゲルハンス細胞(LC)の流れているリンパ節への移動は、前炎症性サイトカインIL−1βおよびTNFαに依存し、そしてカスパーゼ−1によって制御されている(Antonopoulos et al., 2001; Kimber et al., 1992)。したがって、IL−18はLC輸送に寄与することが示されている(Cumberbatch et al., 2001)。よって、IL−18BPによる処置は、LC補充を減じ、したがって攻撃期間のあいだDNFBに対する免疫応答が減少する可能性がある。この仮説を検討するために、マウスをハプテンFITCまたはビヒクルで右と左のわき腹をそれぞれ染色した。皮膚ドレーン鼠径部リンパ節を染色後24時間で回収し、リンパ節当たりのFITC+細胞の数を評価した。染色の24時間前および1時間前に行なったIL−18BPによる動物の処置では、染色後24時間でのドレーンリンパ節に存在するハプテン提示LCの数は変化しなかった(図8)。したがって、このモデルにおいてはLC輸送に対してIL−18の大きな寄与はない。
方法
遅延型過敏症
マウスを106BALB/c脾臓細胞の静脈注射により感作し、日数5に、右支脚皿に13×106BALB/c脾臓細胞(50μlPBS)で攻撃した。対照の左支脚皿に50μlのPBSを投与した。右支脚皿の腫れは、攻撃後の値から攻撃前の値と左支脚皿で測定された任意の腫れを減じることにより種々の日数で計算する。
遅延型過敏症(DHT)は、CD8+T細胞の明らかなダウンレギュレーション効果と共にCD4+T細胞によって誘導される(Grabbe et al., 1998)。IL−18BPで処置されたマウス由来のCD4+T細胞の挙動は、DTHモデルにおいて研究される。C57BL/6動物は、106同種BALB/c脾臓細胞の静脈注射によって感作される。5日後、13×106BALB/c脾臓細胞を、10mg/kg組換えヒトIL−18BPipまたはビヒクルのいずれかと共に右支脚皿に注射する。局所的炎症は、24時間で支脚皿の腫れを測定することにより評価される。
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Claims (18)
- 接触過敏症の治療および/または予防のための医薬の製造のためのIL−18に対する抗体、IL−18受容体サブユニットのいずれかに対する抗体、およびIL−18結合タンパク質、またはその免疫グロブリン融合を含有する融合タンパク質、ポリエチレングリコール(PEG)に結合した機能的誘導体もしくは塩から選択されるIL−18阻害剤の使用。
- IL−18阻害剤がIL−18抗体である請求項1記載の使用。
- IL−18抗体がヒト化IL−18抗体である請求項2記載の使用。
- IL−18抗体がヒトIL−18抗体である請求項2記載の使用。
- IL−18阻害剤が、IL−18結合タンパク質、またはその免疫グロブリン融合を含有する融合タンパク質、ポリエチレングリコール(PEG)に結合した機能的誘導体もしくは塩である請求項1記載の使用。
- 医薬が、同時、連続または個別使用としてインターフェロンをさらに含む請求項1、2、3、4または5記載の使用。
- インターフェロンがインターフェロン−βである請求項6記載の使用。
- 医薬が、同時、連続または個別使用として腫瘍壊死因子(TNF)阻害剤であるTBPIおよび/またはTBPIIをさらに含む請求項1、2、3、4、5、6または7記載の使用。
- 医薬が、同時、連続または個別使用として抗炎症剤をさらに含む請求項1、2、3、4、5、6、7または8記載の使用。
- 抗炎症剤がCOX阻害剤である請求項9記載の使用。
- 医薬が、同時、連続または個別使用として抗アレルギー剤をさらに含む請求項1、2、3、4、5、6、7、8、9または10記載の使用。
- IL−18阻害剤が、0.001〜1000mg/kg体重、または0.01〜100mg/kg体重、または0.1〜10mg/kg体重、または5mg/kg体重の量で使用される請求項1、2、3、4、5、6、7、8、9、10または11記載の使用。
- IL−18阻害剤が皮下に投与される請求項1、2、3、4、5、6、7、8、9、10、11または12記載の使用。
- IL−18阻害剤が筋肉内に投与される請求項1、2、3、4、5、6、7、8、9、10、11、12または13記載の使用。
- IL−18阻害剤が局所的に投与される請求項1、2、3、4、5、6、7、8、9、10、11、12、13または14記載の使用。
- 接触過敏症の治療および/または予防のための医薬の製造における、IL−18に対する抗体、IL−18受容体サブユニットのいずれかに対する抗体、およびIL−18結合タンパク質、またはその免疫グロブリン融合を含有する融合タンパク質、ポリエチレングリコール(PEG)に結合した機能的誘導体もしくは塩から選択されるIL−18阻害剤のコード配列を含有する発現ベクターの使用。
- 接触過敏症の治療および/または予防のための医薬の製造における、細胞でのIL−18に対する抗体、IL−18受容体サブユニットのいずれかに対する抗体、およびIL−18結合タンパク質、またはその免疫グロブリン融合を含有する融合タンパク質、ポリエチレングリコール(PEG)に結合した機能的誘導体もしくは塩から選択されるIL−18阻害剤の内在的産生を誘導および/または促進させるためのベクターの使用。
- 接触過敏症の治療および/または予防のための医薬の製造における、IL−18に対する抗体、IL−18受容体サブユニットのいずれかに対する抗体、およびIL−18結合タンパク質、またはその免疫グロブリン融合を含有する融合タンパク質、ポリエチレングリコール(PEG)に結合した機能的誘導体もしくは塩から選択されるIL−18阻害剤を産生するために遺伝的に改変された細胞の使用。
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PCT/EP2002/008591 WO2003013577A2 (en) | 2001-08-10 | 2002-08-01 | Use of il-18 inhibitors in hypersensitivity disorders |
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EP (1) | EP1423138B1 (ja) |
JP (1) | JP4301942B2 (ja) |
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PT1885753E (pt) | 2005-06-03 | 2011-10-06 | Ares Trading Sa | Produção de proteína recombinante de ligação a il-18 |
CA2610804C (en) | 2005-06-10 | 2013-11-19 | Ares Trading S.A. | Process for the purification of il-18 binding protein |
MY157173A (en) | 2006-05-25 | 2016-05-13 | Glaxo Group Ltd | Modified humanised anti-interleukin-18 |
JP5937015B2 (ja) * | 2010-12-16 | 2016-06-22 | 株式会社明治 | 遅延型過敏症軽減剤 |
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US6087116A (en) * | 1997-03-12 | 2000-07-11 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Interleukin-18 (IL-18) receptor polypeptides and their uses |
IL121860A0 (en) * | 1997-08-14 | 1998-02-22 | Yeda Res & Dev | Interleukin-18 binding proteins their preparation and use |
WO1999046248A1 (en) * | 1998-03-09 | 1999-09-16 | Vertex Pharmaceuticals Incorporated | 1,2-diazepane derivatives as interleukin-1beta converting enzyme inhibitors |
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