JP6928479B2 - 拒絶反応抑制剤 - Google Patents
拒絶反応抑制剤 Download PDFInfo
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- JP6928479B2 JP6928479B2 JP2017095113A JP2017095113A JP6928479B2 JP 6928479 B2 JP6928479 B2 JP 6928479B2 JP 2017095113 A JP2017095113 A JP 2017095113A JP 2017095113 A JP2017095113 A JP 2017095113A JP 6928479 B2 JP6928479 B2 JP 6928479B2
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- ripasudil
- transplantation
- corneal
- rejection
- cornea
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Description
(1)Rhoキナーゼ阻害剤を含有してなる角膜移植後の拒絶反応抑制剤。
(2)Rhoキナーゼ阻害剤がリパスジル若しくはその塩又はそれらの溶媒和物である前記(1)に記載の拒絶反応抑制剤。
(3)リパスジル若しくはその塩又はそれらの溶媒和物が、リパスジル塩酸塩水和物である前記(2)に記載の拒絶反応抑制剤。
(4)リパスジル塩酸塩水和物が、リパスジル一塩酸塩二水和物である前記(3)に記載の拒絶反応抑制剤。
(5)液剤である、前記(1)から(4)のいずれかに記載の拒絶反応抑制剤。
(6)点眼剤である、前記(1)から(5)のいずれかに記載の拒絶反応抑制剤。
(7)角膜が、霊長類の角膜である、前記(1)から(6)のいずれかに記載の拒絶反応抑制剤。
(8)角膜が、ヒトの角膜である、前記(1)から(7)のいずれかに記載の拒絶反応抑制剤。
(9)リパスジル若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体を混合する工程を含有してなる、前記(1)から(8)のいずれかに記載の拒絶反応抑制剤の製剤を製造する方法。
(10)必要な患者に有効量のRhoキナーゼ阻害剤を投与することを特徴とする角膜移植後の拒絶反応抑制方法。
(11)Rhoキナーゼ阻害剤がリパスジル若しくはその塩又はそれらの溶媒和物である前記(10)に記載の方法。
(12)リパスジル若しくはその塩又はそれらの溶媒和物が、リパスジル塩酸塩水和物である前記(11)に記載の方法。
(13)リパスジル塩酸塩水和物が、リパスジル一塩酸塩二水和物である前記(12)に記載の方法。
(14)液剤の投与によるものである、前記(10)から(13)のいずれかに記載の方法。
(15)点眼剤の投与によるものである、前記(10)から(14)のいずれかに記載の方法。
(16)角膜が、霊長類の角膜である、前記(10)から(15)のいずれかに記載の方法。
(17)角膜が、ヒトの角膜である、前記(10)から(16)のいずれかに記載の方法。
また、本発明の角膜移植後の拒絶反応抑制剤は、患者の負担が少ない点眼剤として提供することができる。
以下、Rhoキナーゼ阻害剤の代表的な化合物の1種であるリパスジルを例にして説明する。
本発明の点眼薬は、本発明の有効成分であるリパスジル若しくはその塩又はそれらの溶媒和物、及び点眼薬に許容される担体を含有するものであり、市販品である「グラナテック点眼液0.4%」をそのまま用いることもできる。
点眼剤として使用する場合には、有効成分を約0.0001〜5w/v%、好ましくは約0.01〜4w/v%の濃度で使用することができる。投与期間は、角膜移植当日から継続投与が好ましい。
角膜移植モデルマウスに対するリパスジルの作用(1)
文献(J Biol Methods 2015 2(3);e27、以下文献A)に記載の方法に従って角膜移植モデルマウスを作成し、実験に供した。即ち、6−8週齢の雄性C57BL/6マウスから6−8週齢の雄性Balb/cマウスに対し同種異型角膜移植を行った。
角膜移植を行ったマウスは、PBS点眼2回/日(P群:コントロール群)、リパスジル点眼2回/日(R2群)及びリパスジル点眼3回/日(R3群)の3群(各群5匹)に群分けした。
点眼量は一回一眼あたり0.1μL/とし、リパスジルとしては、グラナテック点眼液0.4%を用いた。
移植後、56日目まで毎日点眼を行い、この間7日毎に細隙灯顕微鏡にて角膜移植片の血管新生スコア、混濁スコア(各スコア化の方法は文献Aによる)並びに生存期間を評価した。実験最終日の56日目には、上記の評価に加え、角膜の血管内皮細胞(CD31)、血管内皮細胞増殖因子(VEGF−A)及びリンパ管(Lyve−1)発現量をreal−time PCR法にて計量した。
さらに、図5に示すように、56日目のCD31(A)、VEGF−A(B)及びLyve−1(C)のいずれも、P群に比べてR3群では有意な減少を示した(one−way ANOVA,Bonferroni’s Multiple Comparison Test、***:p<0.001)。
以上の結果から、リパスジル点眼が移植後角膜の定着に有用であることが判明した。
角膜移植モデルマウスに対するリパスジルの作用(2)
実施例1と同様の処置(手術並びに点眼)、群構成(P群、R2群及びR3群)の角膜移植モデルマウスを用い、移植後14日目の頸部リンパ節細胞を採取し、フローサイトメトリー(FACS)にて、CD4+T細胞並びに炎症性サイトカインであるIFNγ及びIL−17の発現を計測し、また、免疫寛容に関与するCD4+CD25+Foxp3+制御性T細胞(Treg)、CD4+CD25+Foxp3−制御性T細胞(exTreg)及びFoxp3の発現量(Mean Fluorescein Intensity, MFI)を計測した。さらに、同じく移植後14日目の角膜におけるfoxp3、IL−10及びTGFβ1の発現量をreal−time PCR(qPCR)で測定した。
また、角膜移植後14日目の角膜において、foxp3はR2及びR3群で(図8A)、IL−10(図8B)及びTGFβ1(図8C)はいずれもR3群で有意に発現が増加していた(one−way ANOVA,Bonferroni’s Multiple Comparison Test、**:p<0.01,***:p<0.001)。
以上の結果から、リパスジル点眼が移植後角膜において制御性T細胞(Treg)を誘導することにより、免疫反応を抑制していることが判明した。
ヒト移植角膜に対する効果
角膜ヘルペスで角膜穿孔を起こした症例(69歳男性)に対し、角膜移植を施術したところ、術後1ヶ月後に強い充血を認め、角膜移植片内にも血管侵入を認めた。周辺虹彩前癒着を認め、2次性緑内障を認めたためグラナテック点眼液0.4%を処方した。点眼後3週間では、図9のように血管新生が抑制された。図9における黄色い点線の枠内の新生血管をImage Jで解析し数値化したものが図10である。図10からも、リパスジルが血管新生抑制効果を示すことが支持された。
Claims (3)
- リパスジル若しくはその塩又はそれらの溶媒和物を含有する角膜移植後の拒絶反応抑制剤。
- リパスジル若しくはその塩又はそれらの溶媒和物が、リパスジル一塩酸塩二水和物である請求項1に記載の拒絶反応抑制剤。
- 点眼剤である、請求項1又は2に記載の拒絶反応抑制剤。
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