JPWO2020179104A1 - α−ガラクトシルセラミド及び/又はα−ガラクトシルセラミドでパルスされた樹状細胞を含有する医薬組成物 - Google Patents
α−ガラクトシルセラミド及び/又はα−ガラクトシルセラミドでパルスされた樹状細胞を含有する医薬組成物 Download PDFInfo
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Abstract
Description
(2)薬剤性心筋障害が、アントラサイクリン系薬剤によって引き起こされる心筋障害である、(1)に記載の医薬組成物。
(3)薬剤性心筋障害が、ドキソルビシンによって引き起こされる心筋障害である、(1)に記載の医薬組成物。
(4)薬剤性心筋障害を発症した又は発症するおそれのある対象に対して、薬剤性心筋障害を引き起こし得る薬剤と組み合わせて用いるための、α-GalCer及び/又はα-GalCerでパルスされた樹状細胞を含有する医薬組成物。
(5)薬剤性心筋障害を発症した又は発症するおそれのある対象に対して、薬剤性心筋障害を引き起こし得る薬剤の投与前及び投与後に投与するための、α-GalCer及び/又はα-GalCerでパルスされた樹状細胞を含有する医薬組成物。
(6)薬剤性心筋障害を引き起こし得る薬剤が、アントラサイクリン系薬剤、アルキル化剤、代謝拮抗薬、微小管阻害薬及び分子標的薬よりなる群から選択される、(4)又は(5)に記載の医薬組成物。
(7)薬剤性心筋障害を引き起こし得る薬剤が、アントラサイクリン系薬剤である、(4)又は(5)に記載の医薬組成物。
(8)薬剤性心筋障害を引き起こし得る薬剤が、ドキソルビシンである、(4)又は(5)に記載の医薬組成物。
8週齢雄性C57BL/6マウスを3群(Control群、DOX群、DOX+α-GC群)に分け、DOX+α-GC群にα- GalCer(KRN7000(フナコシ);0.1μg/g体重)を、Control群及びDOX群にPBSを腹腔内投与した。投与の4日後、DOX群及びDOX+α-GC群にドキソルビシン(Doxorubicin hydrochloride, D1515(SIGMA-ALDRICH);20 mg/kg体重)を、Control群にVehicle(PBS)を腹腔内投与した。DOX又はPBS投与から3日後に、DOX+α-GC群にα- GalCer(0.1μg/g体重)を、Control群及びDOX群にPBSを腹腔内投与した。DOX又はPBS投与から14日後に、各群のマウスに対して心エコー検査を行って心機能を評価し、その後に心臓を採取して、心筋組織線維化の病理学的評価及び定量的リアルタイムRT-PCR法での炎症性サイトカイン発現評価を行った。試験スケジュールを図1に示す。
IFN-γ:TaqMan Gene Expression Assays, Mm01168134_m1
TNF-α:TaqMan Gene Expression Assays, Mm00443258_m1
IL-1β:TaqMan Gene Expression Assays, Mm00434228_m1
TGF-β1:TaqMan Gene Expression Assays, Mm01178820_m1
IL-4:TaqMan Gene Expression Assays, Mm00445259_m1
IL-10:TaqMan Gene Expression Assays, Mm01288386_m1
GAPDH:Mouse GAPD (20X), Probe dye VIC-MGB
CD11c:TaqMan Gene Expression Assays, Mm00498701_m1
MHC II (H2-A1):TaqMan Gene Expression Assays, Mm00439211_m1
MCP1 (CCL2):TaqMan Gene Expression Assays, Mm00441242_m1
iNOS (NOS2):TaqMan Gene Expression Assays, Mm00440502_m1
IL-1β:TaqMan Gene Expression Assays, Mm00434228_m1
Retnla:TaqMan Gene Expression Assays, Mm00445109_m1
Arg1:TaqMan Gene Expression Assays, Mm00475988_m1
GAPDH:Mouse GAPD (20X), Probe dye VIC-MGB
(1)α- GalCerをパルスした樹状細胞の調製
健常成人ドナーから連続式血液成分分離装置を用いてアフェレーシス細胞液を採取した。50 mL遠心チューブ中のFicoll-Paque PREMIUM(GEヘルスケア・ジャパン)20 mLにアフェレーシス細胞液26.6 mLを積層し、400×gで30分間、20℃で遠心し、単核球細胞層を回収した。単核球細胞層を同量の生理食塩水で洗浄し、400×gで10分間、20℃で遠心した。沈渣にアルブミネート加AIM-V培地(AIM-V培地(GIBCO Invitrogen Corporation)20容量に対して4.4%献血アルブミネート(日本製薬)1容量を添加したもの)を加えて液量を45 mLにした懸濁液を再度遠心した。この操作をさらに1回繰り返した後、得られた沈渣を自己血漿加アルブミネート加AIM-V培地(AIM-V培地40容量に対して健常成人ドナーの血漿を1容量、4.4%献血アルブミネートを2容量添加したもの)に懸濁し、細胞濃度が2.7×108個/mL以下となるように液量を調節して細胞浮遊液とした。細胞浮遊液13.8 mLを25 mL凍結バッグに分注し、抗凝固液ACD-A液(テルモ)2 mL及び凍害保護液CP-1(極東製薬工業)9.2 mLを各バッグに添加した後、-80℃で凍結保存した。
8週齢雄性C57BL/6マウスを4群(Control群(n=6)、DOX+PBS群(n=11)、DOX+DC群(n=10)、DOX+α-GC/DC群(n=10))に分け、DOX+DC群に上記(1)で得たDC 3×106個/匹を、DOX+α-GC/DC群に上記(1)で得たα-GC/DC 3×106個/匹を、Control群及びDOX+PBS群にPBSを腹腔内投与した。投与の4日後、DOX+PBS群、DOX+DC群及びDOX+α-GC/DC群にドキソルビシン(20mg/kg体重)を、Control群にVehicle(PBS)を腹腔内投与した。DOX又はPBS投与から3日後に、DOX+DC群に上記(1)で得たDC 3×106個/匹を、DOX+α-GC/DC群に上記(1)で得たα-GC/DC 3×106個/匹を、Control群及びDOX+PBS群にPBSを腹腔内投与した。DOX又はPBS投与から14日後に、実施例1と同様にして、各群のマウス(Control群; n=6、DOX+PBS群; n=9、DOX+DC群; n=5、DOX+α-GC/DC群; n=9)に対して心エコー検査を行って心機能を評価した。さらに、DOX又はPBS投与から14日間における各群のマウスの生存率を測定した。
Claims (8)
- 薬剤性心筋障害の予防及び/又は治療のための、α−ガラクトシルセラミド及び/又はα−ガラクトシルセラミドでパルスされた樹状細胞を含有する医薬組成物。
- 薬剤性心筋障害が、アントラサイクリン系薬剤によって引き起こされる心筋障害である、請求項1に記載の医薬組成物。
- 薬剤性心筋障害が、ドキソルビシンによって引き起こされる心筋障害である、請求項1に記載の医薬組成物。
- 薬剤性心筋障害を発症した又は発症するおそれのある対象に対して、薬剤性心筋障害を引き起こし得る薬剤と組み合わせて用いるための、α−ガラクトシルセラミド及び/又はα−ガラクトシルセラミドでパルスされた樹状細胞を含有する医薬組成物。
- 薬剤性心筋障害を発症した又は発症するおそれのある対象に対して、薬剤性心筋障害を引き起こし得る薬剤の投与前及び投与後に投与するための、α−ガラクトシルセラミド及び/又はα−ガラクトシルセラミドでパルスされた樹状細胞を含有する医薬組成物。
- 薬剤性心筋障害を引き起こし得る薬剤が、アントラサイクリン系薬剤、アルキル化剤、代謝拮抗薬、微小管阻害薬及び分子標的薬よりなる群から選択される、請求項4又は5に記載の医薬組成物。
- 薬剤性心筋障害を引き起こし得る薬剤が、アントラサイクリン系薬剤である、請求項4又は5に記載の医薬組成物。
- 薬剤性心筋障害を引き起こし得る薬剤が、ドキソルビシンである、請求項4又は5に記載の医薬組成物。
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