JP4972113B2 - デキストラン硫酸エステルを含有する新規治療薬 - Google Patents
デキストラン硫酸エステルを含有する新規治療薬 Download PDFInfo
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- JP4972113B2 JP4972113B2 JP2009064780A JP2009064780A JP4972113B2 JP 4972113 B2 JP4972113 B2 JP 4972113B2 JP 2009064780 A JP2009064780 A JP 2009064780A JP 2009064780 A JP2009064780 A JP 2009064780A JP 4972113 B2 JP4972113 B2 JP 4972113B2
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- dextran sulfate
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Description
本発明は従来の治療のこれらおよび他の欠点を改良する。
本発明は、超急性血液媒介炎症反応(IBMIR)の治療法となることを目的とする。
本発明は、IBMIRに起因する移植されるべき細胞類の形態崩壊の治療法となることを他の目的とする。
さらに、本発明は、IBMIRに起因する移植されるべき細胞類の組織不適合の治療法となることを目的とする。
これらおよび他の目的は、付属の特許請求の範囲により定義される本発明により明らかとなる。
本発明の概要は、デキストラン硫酸エステルおよびその誘導体を含有することを特徴とする超急性血液媒介炎症反応(IBMIR)の治療薬に関する。この炎症の新規な形は、非血管新生の細胞集合体または組織が生体内または生体外で外来血に接触することが契機となる。IBMIRの非常に重要な例は、同種または異種の細胞がレシピエント哺乳類、特に人が患者として、その体内に移植される場合である。IBMIRはそれに続いて、形態崩壊と移植した細胞集合体または組織の破壊に至り、構造または組織の喪失となる。さらに、IBMIRはまた一般には移植されるべき細胞類の組織不適合となる。
更なる目的と利点を有する本発明は、添付の図面と共に、次の説明を参照して最もよく理解され得る。
図1は、豚膵島を人血で灌流する間に発生するC3aに対するLMW−DSの効果を図解するものである。
図2は、豚膵島を人血で灌流する間に発生するsC5b−9に対するLMW−DSの効果を図解するものである。
図3は、LMW−DSの存在下に人血清で培養する際の補体系に対するLMW−DSの直接の効果を図解するものである。
IBMIRは比較的最近認知された炎症反応で外来血に接触した細胞または細胞集合体が契機となる。IBMIRは細胞上の組織因子の発現が特徴で、それはトロンビンの局所生成の契機となる。その後、活性血小板が細胞表面に接着し凝集と補体系の両方の活性化を促進する。さらに、白血球は補充されて細胞に湿潤する。これらの効果は共に外来血との接触後初めの数時間以内で細胞形態の崩壊と破壊を引き起こす。IBMIRはまた後のフェーズにおける、続く細胞媒介特異免疫応答を加速する。
平均分子量5000Daで硫黄含量約17%の低分子量デキストラン硫酸エステル(LMW−DS)をSigma Chemicals社(セントルイス、ミズーリ州、米国)から入手した。平均分子量が1000000Daを超え、硫黄含量が16−19%の高分子量デキストラン硫酸エステル(HMW−DS)は、Amersham Bioscience社(ウプサラ、スウェーデン)から購入した。低分子量デキストラン(LMW−D;分子量5000Da)と高分子量デキストラン(HMW−D;分子量>1000000Da)はFluka Chemical(ブーフス、スイス)とSigma Chemicals社(セントルイス、ミズーリ州、米国)からそれぞれ購入した。
全血と接触する全ての材料には、製造者の推奨によりコーリン ヘパリン 表面(コーリンシステム AB社、ウプサラ、スウェーデン)を付した。ヘパリンの表面の濃度は0.5μg/cm2であり、これは0.1U/cm2に相当し、抗−トロンビン結合能は2−4pmol/cm2である。
少なくとも14日間薬服用をしていない健康なボランティアからの、新鮮な人の血を表面ヘパリン処理をした60−mlの注射器(18目盛り、ミクロランス;ベクトン ディッキンス社、フラックリン レーク、NJ)に収集した。注射器のカニューレはヘパリンで表面処理をしたシリコーン チューブに接続されている。サンプリングの間、注射器は連続して回転させた。
ボムホルト ガード ブリーディング アンド リサーチ センターから入手の同系交配された胸腺欠損のオスのマウス(nu/nu ブラック−6、ボムマイス)、20−25gをレシピエントとして使用した。全ての動物は標準食餌と水を自由に摂取可能である。
Wennbergら[20]の方法に従い、シグマ ケミカル(パロ アルト、CA,USA)からのステプトゾトシンの静脈注射により糖尿病を胸腺欠損マウスに誘発させた。ステプトゾトシンの投与は、胸腺欠損マウスの体重あたり250mg/kgであった。血中のグルコース(β−グルコース)濃度が2日またはそれ以上の日で連続して20mmol/l(>360mg/dl)を超えると、対象の動物は糖尿病に罹患したとした。
4日間培養後、5種の単離からの5μlのAPI(〜5000IEQ)が、11匹の雄の同系交配された糖尿病誘発の胸腺欠損マウスの門脈を経由して肝臓へ移植され、これはイソフルレン麻酔をして外科手術をした。5匹のマウスがLMW−DSで静脈処理をされた。0.15mgのLMW−DSを移植の10分間前に注入し、追加の0.3mgを移植の6時間後に注入した。その後、LMW−DSは、移植後1日に2回の割合で投与され、1−2日、3−4日そして5−6日で、1、0.5および0.25mgという傾斜投与をそれぞれした。6匹(未処理)のマウスは、同様に等価の量の塩水を同様にして注入された。
全てのデータは、平均値±標準誤差(mean±SEM)で示し、フリードマン分散分析(表1)、ステュデントのペア−化t−試験(表3)、ウイルコクソン符号付順位検定(Wilcoxon signed rank test)(表4)およびシェッフの事後比較(post hoc test)に続く一要因分散分析(表5)を用いて比較した。移植膵島の形態比較では、血塊形成の頻度とリンパ球湿潤強度を、ウイルコクソン ランク サム 試験で評価した。P−値<0.05は統計的に有意と見られる。
クエン酸塩を含むVacutainer(商品名)管内へ4人の健康なボランティアの血を採取した。全血(980μl)をReoRox(商品名)レオメーター(グローバル ヘモスタシス インターナショナル社、グーテンベルグ、スウェーデン)中のポリプロピレン試料カップで37℃で2μlのAPIと共に培養した。異なる種類のデキストランの存在または不存在下に1MのCaCl2の20μlを添加して凝固が開始した。6秒ごとに、カップをその垂直軸でねじれ振動をさせ、そして制動をして振動の振動数を求める。血塊形成時間は、制動の最大値の時間に等しい。
凝集と補体活性化の両者を減少させる(表3を参照)。LMW−DS処理の血液中の血小板の有意な増加がLMW−DS 0.01mg/ml濃度で観察され、これはこの低いLMW−DS濃度の通常のレベル血球数が回復することを示す。凝集活性化生成物TAT、FXIa−AT、FXIIa−ATはLMW−DSの0.01mg/mlで抑制されるが、しかしFXIa−ATはLMW−DSの0.1〜1mg/mlの範囲の投与で再度わずかに増加する。
PAPはLMW−DSの不存在で増加し、その一方でLMW−DSの0.01mg/mlでは有意に抑制された。
人の血漿をポリプロピレン管で保温することにより、補体カスケードに対するLMW−DSの直接の効果を調べた。最終濃度0、0.01、0.1、または1mg/mlのLMW−DSが血漿(1ml)に加えられた。5、10、15、30、45および60分間、37℃で血漿を保温後に、100μlの血漿を10mMのEDTAを含む管に移した。これらの試料は、補体成分C3aとsC5b−9の分析まで−70℃で保管された。
グルコメーター エリート(商品名)測定器(バイエル社、ゲティンゲン、スウェーデン)を使用して、レシピエントの尾から得た血液で、血液中のグルコースを測定した。測定は、毎日午前12時前に行い、数値はmmol/l(1mmol/l〜18mg/dl)で示した。
移植片の機能喪失は、B−グルコースのレベルが二日またはそれ以上の日数連続して11.1mmol/lを越えるならば(>200mg/dl)、それが生じたと見なした。移植後の正常血糖値(<200mg/dl)の継続を、移植片が生存した期間とした。
[1] Shapiro A M, et al.,"Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen", NEngl JMed, Vol.
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Claims (3)
- デキストラン硫酸エステルまたはその薬学的に許容される誘導体を含有することを特徴とする超急性血液媒介炎症反応(IBMIR)の治療薬であり、
前記IBMIRが、移植されるべき細胞類が外来レシピエント内に移植され、それに続いて移植されるべき細胞類が血液に接触することにより生じるものであり、
前記移植されるべき細胞類が次のいずれかであるもの;
― 非血管新生の細胞集合体 または
― 非血管新生組織
ただし、ランゲルハンス膵島を除く。 - デキストラン硫酸エステルまたはその薬学的に許容される誘導体を含有することを特徴とする超急性血液媒介炎症反応(IBMIR)による移植されるべき細胞類の形態崩壊の治療薬であり、
前記移植されるべき細胞類が次のいずれかであるもの;
― 非血管新生の細胞集合体 または
― 非血管新生組織
ただし、ランゲルハンス膵島を除く。 - デキストラン硫酸エステルまたはその薬学的に許容される誘導体を含有することを特徴とする超急性血液媒介炎症反応(IBMIR)による移植されるべき細胞類の組織不適合の治療薬であり、
前記移植細胞が次のいずれかであるもの;
― 非血管新生の細胞集合体 または
― 非血管新生組織
ただし、ランゲルハンス膵島を除く。
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