JP6375051B2 - 細菌株を含む組成物 - Google Patents
細菌株を含む組成物 Download PDFInfo
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Description
(1)IL−17又はTh17経路によって媒介される疾患又は状態を治療又は予防する方法に使用するための、バクテロイデス属の細菌株を含む組成物。
(2)アレルギー性喘息又は好中球性喘息などの喘息;関節リウマチ、変形性関節症、乾癬性関節炎、又は若年性特発性関節炎などの関節炎;多発性硬化症;視神経脊髄炎(デビック病);強直性脊椎炎;脊椎関節炎;乾癬;全身性紅斑性狼瘡;クローン病又は潰瘍性大腸炎などの炎症性腸疾患;セリアック病;慢性閉塞性肺疾患(COPD);乳がん、結腸がん、肺がん、又は卵巣がんなどのがん;ブドウ膜炎;強膜炎;血管炎;ベーチェット病;アテローム性動脈硬化症;アトピー性皮膚炎;肺気腫;歯周炎;アレルギー性鼻炎;及び同種異系移植片拒絶からなる群から選択される疾患又は状態を治療又は予防する方法に使用するための、上記(1)に記載の組成物。
(3)好中球性喘息又はアレルギー性喘息などの喘息を治療又は予防する方法に使用するための、上記(2)に記載の組成物。
(4)喘息の治療において、好中球増加又は好酸球増加を低減させる方法に使用するための、上記(3)に記載の組成物。
(5)関節リウマチを治療又は予防する方法に使用するための、上記(2)に記載の組成物。
(6)関節リウマチにおける関節の腫脹を低減させる方法に使用するための、上記(5)に記載の組成物。
(7)多発性硬化症を治療又は予防する方法に使用するための、上記(2)に記載の組成物。
(8)疾患の発生率又は疾患の重症度を低減させる方法に使用するための、上記(7)に記載の組成物。
(9)肺がん、乳がん、又は肝臓がんなどのがんを治療又は予防する方法に使用するための、上記(2)に記載の組成物。
(10)腫瘍のサイズを低減させる、腫瘍の増殖を低減させる、転移を予防する、又は血管新生を予防する方法に使用するための、上記(9)に記載の組成物。
(11)ブドウ膜炎を治療又は予防する方法に使用するための、上記(2)に記載の組成物。
(12)ブドウ膜炎における網膜損傷を低減又は予防する方法に使用するための、上記(11)に記載の組成物。
(13)IL−17又はTh17経路によって媒介される疾患又は状態の治療又は予防において、IL−17の産生を低減させる又はTh17細胞の分化を低減させる方法に使用するための、上記(1)〜(12)のいずれかに記載の組成物。
(14)IL−17レベル又はTh17細胞が上昇している患者に使用するための、上記(1)〜(13)のいずれかに記載の組成物。
(15)細菌株が、バクテロイデス・コプロコーラの細菌株である、上記(1)〜(14)のいずれかに記載の組成物。
(16)細菌株が、バクテロイデス・コプロコーラの細菌株の16s rRNA配列と少なくとも95%、96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有する、上記(1)〜(15)のいずれかに記載の組成物。
(17)細菌株が、配列番号1、2、3又は4と少なくとも95%、96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有する、上記(1)〜(15)のいずれかに記載の組成物。
(18)細菌株が、配列番号4と少なくとも95%、96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有するか、又は細菌株が、配列番号4によって表される16s rRNA配列を有する、上記(17)に記載の組成物。
(19)細菌株が、バクテロイデス・シータイオタオミクロンの細菌株である、上記(1)〜(14)のいずれかに記載の組成物。
(20)細菌株が、バクテロイデス・シータイオタオミクロンの細菌株の16s rRNA配列と少なくとも95%、96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有する、上記(1)〜(14)のいずれかに記載の組成物。
(21)細菌株が、配列番号5と少なくとも95%、96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有する、上記(1)〜(14)のいずれかに記載の組成物。
(22)細菌株が、配列番号5によって表される16s rRNA配列を有する、上記(21)に記載の組成物。
(23)細菌株が、バクテロイデス・フラジリスの細菌株である、上記(1)〜(14)のいずれかに記載の組成物。
(24)関節リウマチを治療又は予防する方法に使用するための、バクテロイデス・コプロコーラ種の細菌株を含む、上記(1)に記載の組成物。
(25)好中球性喘息又はアレルギー性喘息などの喘息を治療又は予防する方法に使用するための、バクテロイデス・コプロコーラ種の細菌株を含む、上記(1)に記載の組成物。
(26)多発性硬化症を治療又は予防する方法に使用するための、バクテロイデス・コプロコーラ種の細菌株を含む、上記(1)に記載の組成物。
(27)がんを治療又は予防する方法に使用するための、バクテロイデス・コプロコーラ種の細菌株を含む、上記(1)に記載の組成物。
(28)ブドウ膜炎を治療又は予防する方法に使用するための、バクテロイデス・コプロコーラ種の細菌株を含む、上記(1)に記載の組成物。
(29)関節リウマチを治療又は予防する方法に使用するための、バクテロイデス・シータイオタオミクロン種の細菌株を含む、上記(1)に記載の組成物。
(30)好中球性喘息又はアレルギー性喘息などの喘息を治療又は予防する方法に使用するための、バクテロイデス・シータイオタオミクロン種の細菌株を含む、上記(1)に記載の組成物。
(31)多発性硬化症を治療又は予防する方法に使用するための、バクテロイデス・シータイオタオミクロン種の細菌株を含む、上記(1)に記載の組成物。
(32)がんを治療又は予防する方法に使用するための、バクテロイデス・シータイオタオミクロン種の細菌株を含む、上記(1)に記載の組成物。
(33)ブドウ膜炎を治療又は予防する方法に使用するための、バクテロイデス・シータイオタオミクロン種の細菌株を含む、上記(1)に記載の組成物。
(34)関節リウマチを治療又は予防する方法に使用するための、バクテロイデス・フラジリス種の細菌株を含む、上記(1)に記載の組成物。
(35)好中球性喘息又はアレルギー性喘息などの喘息を治療又は予防する方法に使用するための、バクテロイデス・フラジリス種の細菌株を含む、上記(1)に記載の組成物。
(36)多発性硬化症を治療又は予防する方法に使用するための、バクテロイデス・フラジリス種の細菌株を含む、上記(1)に記載の組成物。
(37)がんを治療又は予防する方法に使用するための、バクテロイデス・フラジリス種の細菌株を含む、上記(1)に記載の組成物。
(38)ブドウ膜炎を治療又は予防する方法に使用するための、バクテロイデス・フラジリス種の細菌株を含む、上記(1)に記載の組成物。
(39)経口投与用である、上記(1)〜(38)のいずれかに記載の組成物。
(40)1又は2以上の薬学的に許容される賦形剤又は担体を含む、上記(1)〜(39)のいずれかに記載の組成物。
(41)細菌株が凍結乾燥されている、上記(1)〜(40)のいずれかに記載の組成物。
(42)上記(1)〜(14)、及び(24)〜(38)のいずれかに記載の使用のための、上記(1)〜(41)のいずれかに記載の組成物を含む食品。
(43)上記(1)〜(14)、及び(24)〜(38)のいずれかに記載の使用のための、上記(1)〜(41)のいずれかに記載の組成物を含むワクチン組成物。
(44)IL−17又はTh17経路によって媒介される疾患又は状態を治療又は予防する方法であって、それを必要とする患者にバクテロイデス属の細菌株を含む組成物を投与することを含む、前記方法。
(45)受託番号42408として寄託されたバクテロイデス・コプロコーラ株又はその派生物の細胞。
(46)上記(45)に記載の細胞を含む組成物。
(47)薬学的に許容される担体又は賦形剤を含む、上記(46)に記載の組成物。
(48)受託番号42408として寄託されたバクテロイデス・コプロコーラ株又はその派生物の生物学的に純粋な培養物。
(49)治療に使用するための、受託番号42408として寄託されたバクテロイデス・コプロコーラ株又はその派生物の細胞。
(50)上記(1)〜(14)のいずれかに規定の方法に使用するための、上記(49)に記載の細胞。
本発明の組成物は、バクテロイデス属の細菌株を含む。実施例は、この属の細菌がIL−17又はTh17経路によって媒介される疾患及び状態を治療又は予防するために有用であることを実証している。好ましい細菌株は、バクテロイデス・コプロコーラ種の細菌株である。さらに好ましい細菌株は、バクテロイデス・シータイオタオミクロン種又はバクテロイデス・フラジリス種の細菌株である。
実施例において実証されるように、本発明の細菌組成物は、Th17炎症応答を低減させるために有効である。特に、本発明の組成物による治療によって、IL−17及びTh17経路によって媒介される状態の動物モデルにおいて、IL−17Aレベル及び他のTh17経路のサイトカインの低減、並びに臨床上の改善がもたらされる。したがって、本発明の組成物は、炎症性疾患及び自己免疫疾患、特にIL−17によって媒介される疾患又は状態を治療又は予防するために有用でありうる。特に、本発明の組成物は、IL−17炎症応答の上昇を低減又は予防するために有用でありうる。
好ましい実施形態において、本発明の組成物は、喘息の治療又は予防に使用するためのものである。実施例は、本発明の組成物が、チリダニ抽出物による感作及びチャレンジ後の気道への好中球及び/又は好酸球の動員の低減をもたらすことを実証しており、そのため本発明の組成物が喘息の治療又は予防において有用でありうる。喘息は、気道の炎症及び制限によって特徴付けられる慢性疾患である。喘息における炎症は、IL−17及び/又はTh17細胞によって媒介されうることから、本発明の組成物は、喘息の予防又は治療にとって特に有効でありうる。喘息の炎症は、好酸球及び/又は好中球によって媒介されうる。
好ましい実施形態において、本発明の組成物は、関節リウマチ(RA,rheumatoid arthritis)の治療又は予防に使用するためのものである。実施例により、本発明の組成物が、マウスモデルにおけるRAの臨床兆候の低減をもたらすこと、軟骨及び骨損傷を低減させること、並びにIL−17炎症応答を低減させることが実証されており、そのため本発明の組成物は、RAの治療又は予防において有用でありうる。RAは、関節に主に罹患する全身性の炎症障害である。RAは、関節の腫脹、滑膜過形成、並びに軟骨及び骨の破壊が起こる炎症応答に関連している。例えば、IL−17は軟骨細胞及び骨芽細胞においてマトリクス産生を阻害して、マトリクスメタロプロテナーゼの産生及び機能を活性化することにより、並びにRA疾患の活動度がIL−17レベル及びTh17細胞数と相関することによりMiossec and Kolls (2012) Nat Rev Drug Discov. 11(10):763-76、Yang et al. (2014) Trends Pharmacol Sci. 35(10):493-500、IL−17及びTh17細胞は、RAにおいて重要な役割を有し、それにより本発明の組成物は、RAの予防又は治療にとって特に有効でありうる。
好ましい実施形態において、本発明の組成物は、多発性硬化症の治療又は予防に使用するためのものである。実施例により、本発明の組成物が、多発性硬化症のマウスモデル(EAEモデル)における疾患の発生率及び疾患の重症度の低減をもたらすことが実証されており、そのため、本発明の組成物は、多発性硬化症の治療又は予防において有用でありうる。多発性硬化症は、特に脳及び脊柱のニューロンの髄鞘に対する損傷に関連する炎症障害である。多発性硬化症は、次第に無能力となり、エピソードが進行する慢性疾患である。例えばIL−17レベルは多発性硬化症の病変と相関しうる、IL−17は血液脳関門の内皮細胞の堅固な接合を破壊しうる、及びTh17細胞が中枢神経系に遊走してニューロンの喪失を引き起こしうることから(Amedei et al. (2012) Int J Mol Sci. 13(10):13438-60、Shabgah et al. (2014) Postepy. Dermatol. Alergol. 31(4):256-61)、IL−17及びTh17細胞は、多発性硬化症において重要な役割を有しうる。したがって、本発明の組成物は、多発性硬化症を予防又は治療するために特に有用でありうる。
好ましい実施形態において、本発明の組成物は、がんの治療又は予防に使用するためのものである。IL−17及びTh17経路は、がんの発生及び進行において中心的な役割を有することから、本発明の組成物は、がんの治療又は予防にとって有用でありうる。
Thermodox(Celsion社製);Cometriq(Exellxis社製);Lonsurf(Taiho Pharmaceuticals社製);Camptosar(Pfizer社製);UFT(Taiho Pharmaceuticals社製);及びTS-1(Taiho Pharmaceuticals社製)からなる群から選択される抗がん剤を含む。
さらに好ましい実施形態において、本発明の組成物は、ブドウ膜炎の治療又は予防に使用するためのものである。本発明の組成物は、ブドウ膜炎の動物モデルにおいて疾患の発生率及び疾患の重症度の低減をもたらし、そのためブドウ膜炎の治療又は予防において有用でありうる。ブドウ膜炎は、ブドウ膜の炎症であり、それによって網膜組織の破壊が起こりうる。ブドウ膜炎は、異なる解剖学的形態(前部、中間部、後部、又はびまん性)で存在する場合があり、全身性の自己免疫障害を含む、異なるが関連する原因により起こりうる。IL−17及びTh17経路は、ブドウ膜炎に中心的に関係していることから、本発明の組成物は、ブドウ膜炎の予防又は治療にとって特に有効でありうる。参考文献Zhang (2015) Inflammation. Aug 23、Sun et al. (2015) Cytokine. 74(1):76-80、Mucientes et al. (2015) Br J Ophthalmol. 99(4):566-70、Jawad et al. (2013) Ocul Immunol Inflamm. 21(6):434-9、Maya et al. (2014) J. Ophthalmology. 310329、Chi et al. (2007) J. Allergy and Clinical Immunology. 119(5):1218-1224、Chi et al. (2008) Investigative Ophthalmology &Visual Science. 49(7): 3058-3064、Luger and Caspi (2008) Semin. Immunopathol. 30(2): 134-143は、ブドウ膜炎の患者においてインターロイキン−17Aの血清レベルが上昇していること、IL−17A遺伝子バリアントと全ブドウ膜炎との特異的関連、実験的自己免疫性ブドウ膜炎の病原性におけるTh17関連サイトカインの役割、単相性実験的自己免疫性ブドウ膜炎におけるTh17細胞と調節性T細胞との不均衡、ブドウ膜炎及び活動性アダマンチアデス−ベーチェット病及びフォークト−小柳−原田(VKH,Vogt-Koyanagi-Harada)病の患者におけるIL−17Aの上方調節、ブドウ膜炎の眼におけるセクキヌマブ(抗IL−17A抗体)及びTh17による非感染性ブドウ膜炎の治療について記述している。
好ましくは、本発明の組成物は、本発明の細菌株の腸管への送達及び/又は腸管での部分的若しくは完全な定着を可能にするために、消化管に投与される。一般的に、本発明の組成物は経口投与されるが、それらは直腸、鼻腔内、又は口腔内若しくは舌下経路によって投与されてもよい。
一般的に、本発明の組成物は、細菌を含む。本発明の好ましい実施形態において、組成物は凍結乾燥形態で製剤化される。例えば、本発明の組成物は、本発明の細菌株を含む顆粒剤又はゼラチンカプセル、例えば硬ゼラチンカプセルを含みうる。
本発明に使用するための細菌株は、例えば参考文献Handbook of Microbiological Media, Fourth Edition (2010) Ronald Atlas, CRC Press、Maintaining Cultures for Biotechnology and Industry (1996) Jennie C. Hunter-Cevera, Academic Press、Strobel (2009) Methods Mol Biol. 581:247-61に詳述されている標準的な微生物学の技術を使用して培養することができる。
(a)細菌株の凍結保存株を提供するステップ;
(b)凍結保存株を融解して液体保存株を提供するステップ;
(c)液体保存株を固体又は液体培地に添加するステップ;及び
(d)固体又は液体培地をインキュベートして、細菌株の培養物を提供するステップを含みうる。
1.20%グリセロール保存株500μlをYCFA寒天に播く。
2.プレートを嫌気性フード内で48/72時間放置して、成熟コロニーを生成させる。
3.単一コロニー又は1%液体継代培養のいずれかに由来する細菌を、容量10mlで培養する。
4.成熟コロニーの形態が得られた後、コロニーを有するプレートを2/3日に限って使用する。
本発明者らは、本発明の細菌株がIL−17又はTh17経路によって媒介される疾患又は状態を治療又は予防するために有用であることを特定した。これは、おそらく、本発明の細菌株が宿主免疫系に効果を及ぼした結果である。したがって、本発明の組成物は、また、ワクチン組成物として投与した場合に、IL−17又はTh17経路によって媒介される疾患又は状態を予防するためにも有用でありうる。特定のそのような実施形態において、本発明の細菌株を、殺滅、不活化、又は弱毒化させてもよい。特定のそのような実施形態において、組成物は、ワクチンアジュバントを含んでもよい。特定の実施形態において、組成物は、注射による投与、例えば皮下注射による投与用である。
本発明の実践は、特に示されていなければ、当業者の能力範囲内である化学、生化学、分子生物学、免疫学、及び薬理学の通常の方法を使用する。そのような技術は、文献に十分に説明されている。例えば、参考文献Gennaro (2000) Remington: The Science and Practice of Pharmacy. 20th edition, ISBN: 0683306472及びMolecular Biology Techniques: An Intensive Laboratory Course, (Ream et al., eds., 1998, Academic Press)、Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.)、Handbook of Experimental Immunology, Vols. I IV (D.M. Weir and C.C. Blackwell, eds, 1986, Blackwell Scientific Publications)、Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition (Cold Spring Harbor Laboratory Press)、Handbook of Surface and Colloidal Chemistry (Birdi, K.S. ed., CRC Press, 1997)、Ausubel et al. (eds) (2002) Short protocols in molecular biology, 5th edition (Current Protocols)、PCR (Introduction to Biotechniques Series), 2nd ed. (Newton & Graham eds., 1997, Springer Verlag)等を参照されたい。
概要
マウスに、本発明による細菌株を含む組成物を投与して、次いでチリダニ(HDM,house dust mite)抽出物をチャレンジして、アレルギー性炎症応答を誘発した。HDMに対する炎症応答は、好酸球及び好中球成分を含み、IL−17及びTh17経路によって媒介され、喘息のモデルである。本発明の組成物によって処置したマウスが示した炎症応答の程度及び特徴を対照群と比較した。本発明の組成物は、炎症応答を軽減させて、好酸球及び好中球の動員を低減させることが見出され、このことは、本発明の組成物が、IL−17及びTh17媒介疾患、例えば好酸球増加、好中球増加、及び喘息を処置するために有用でありうることを示している。
675:バクテロイデス・コプロコーラ
群:
1.陰性対照群。媒体対照による処置(経口投与)
3.治療用細菌接種株675による処置(経口投与)
7.陽性対照群。デキサメタゾンによる処置(腹腔内投与)
8.無処置対照群
1群当たりのマウスの数=5
−14〜13日目:媒体対照を毎日経口投与(群1)
−14〜13日目:治療用細菌接種物を毎日経口投与(群2〜6)
0、2、4、7、9、11日目:容量30μlのPBS中のHDM(チリダニ抽出物−カタログ番号:XPB70D3A25、ロット番号:231897、Greer Laboratories社製、Lenoir, NC, USA)15μgを鼻腔内投与(群1〜8)
0、2、4、7、9、11日目:デキサメタゾンの投与(腹腔内投与、3mg/kg、Sigma-Aldrich社製、カタログ番号D1159)(群7)
14日目:分析のため全ての動物の屠殺。
マウスの総数=40
14日目に、動物を致死量のペントバルビタール(Streuli Pharma AG社製、Uznach、カタログ番号:1170139A)の腹腔内注射により屠殺した直後に気管支肺胞洗浄(BAL,bronchoalveolar lavage)を行った。
マウス。雌性7週齢BALB/cマウスをCharles River Laboratoriesから購入して、1ケージあたり全5匹ずつ無作為にケージ(換気ケージ、Indulab AG社製、Gams, Switzerland、ケージタイプ:“The Sealsafe(商標)−IVCケージ。製品番号1248L)に割付した。ケージには、試験番号、群番号、及び実験開始日のラベルを貼った。マウスを毎週モニターして、試験開始(試験日−14日)前7日間、施設に馴化させた。試験日−14日目で、動物は8週齢であった。飲料水及び食事を自由に与えた。ケージエンリッチメントが存在した。動物の毎日の世話は、地域当局の承認番号2283.1(Service de la consommation et des affaires veterinaires du Canton de Vaudによる発行及び承認)に従って実施した。飲料水及び食事を自由に与え、1日1回交換した。ケージエンリッチメントが存在した。実験動物の飼育、遺伝子改変動物の作製、及び動物実験法に関するFVO(スイス連邦獣医局(Federal Veterinary Office))の法令455.163の下で、スイスの当局によって示された動物福祉規則を遵守した。
実験結果を図1〜9に示す。
概要
マウスに、本発明による細菌株を含む組成物を投与して、次いでチリダニ(HDM)抽出物の皮下投与によって感作し、鼻腔内投与によりHDMをチャレンジして、重度の好中球性喘息の炎症応答のモデルとした。本発明の組成物で処置したマウスが示した炎症応答の程度及び特徴を対照群と比較した。本発明の組成物は、抗IL−17抗体の投与を含む陽性対照と同等に炎症応答を軽減させて、特に好中球の動員を低減させることが見出された。したがって、データは、本発明の組成物がIL−17及びTh17媒介状態、例えば好中球増加及び喘息を処置するために有用でありうることを示している。
675:バクテロイデス・コプロコーラ
群:
1.陰性対照群、媒体対照による処置(経口投与)
3.治療用細菌接種株675による処置(経口投与)
7.陽性対照群。抗IL−17による処置(腹腔内投与)
8.無処置対照群
9.健康なマウス(ベースライン)
1群当たりのマウスの数(群1〜8)=5
−14〜17日目:媒体対照を毎日経口投与(群1)
−14〜17日目:治療用細菌接種物を毎日経口投与(群2〜6)
0日目:CFAと混合したHDMによる感作(皮下投与)(群1〜8)
7日目:CFAと混合したHDMによる感作(皮下投与)(群1〜8)
13、15、17日目:抗IL−17中和抗体の腹腔内投与(群7)
14、15、16、17日目:鼻腔当たり30μlのPBS中のHDMをチャレンジ(群1〜8)
18日目:分析のため全ての動物の屠殺。
14日目に、動物を致死量のペントバルビタール(Streuli Pharma AG社製、Uznach、カタログ番号:1170139A)の腹腔内注射により屠殺した直後に気管支肺胞洗浄(BAL)を行った。細胞をBAL液から単離して、白血球百分率を決定した(細胞数200個/試料)。
マウス。雌性7週齢C57BL/6マウスをCharles River Laboratoriesから購入して、1ケージあたり全5匹ずつ無作為にケージ(換気ケージ、Indulab AG社製、Gams, Switzerland、ケージタイプ:“The Sealsafe(商標)−IVCケージ。製品番号1248L)に割付した。ケージには、試験番号、群番号、及び実験開始日のラベルを貼った。マウスを毎週モニターして、試験開始(試験日−14日)前7日間、施設に馴化させた。試験日−14日目で、動物は8週齢であった。飲料水及び食事を自由に与えた。ケージエンリッチメントが存在した。動物の毎日の世話は、地域当局の承認番号2283.1(Service de la consommation et des affaires veterinaires du Canton de Vaudによる発行及び承認)に従って実施した。飲料水及び食事を自由に与え、1日1回交換した。ケージエンリッチメントが存在した。実験動物の飼育、遺伝子改変動物の作製、及び動物実験法に関するFVO(スイス連邦獣医局)の法令455.163の下で、スイスの当局によって示された動物福祉規則を遵守した。
実験結果を図10〜18に示す。
材料及び方法
株
675:バクテロイデス・コプロコーラ
細菌培養物を、以下の増殖スキームに従って嫌気性のワークステーション(Don Whitley Scientific社製)の中で投与のために増殖させた。
− 月曜日/水曜日/金曜日:グリセロール保存株を氷に移して、グリセロール保存株からYCFAプレートで画線培養する。プレートを最長3日間、以下のように使用する。
− 毎日午後:プレート培養物のそれぞれの株から単一コロニーを取り上げ、YCFAを含有する8mlのHungateチューブに一晩移した(ON1)。
− 午前:80μl(1%)のON1を新しい8mlチューブに継代する(DC1)。ON1培養物を午前の強制経口投与のために使用する。
− 午後:DC1培養物を午後の強制経口投与のために使用する。
成体雄性DBA/1マウスを実験群に無作為に割付して、2週間馴化させた。0日目に、動物に、4mg/mlヒト型結核菌(Mycobacterium tuberculosis)H37Raを補充したフロイント不完全アジュバント中にII型コラーゲン(CII,type II collagen)100マイクログラムを含有する乳剤100マイクロリットルを皮下注射によって投与した。21日目に、動物に、フロイント不完全アジュバント中にII型コラーゲン100μを含有する追加免疫用の乳剤を皮下注射によって投与した。
全ての群はn=15(主な試験群に関してn=12、サテライト群に関してn=3)であった。
−14日目から実験終了まで、動物の体重を週に3回測定した。データをグラフにした(平均値±SEM)。
−14日目から実験終了まで、動物を、異常な姿勢(丸くなる)、異常な被毛の状態(立毛)、及び異常な活動レベル(活動の低減又は増加)を含む、非特異的臨床兆候に関して毎日チェックした。
21日目から45日目の実験終了まで、動物を、後肢及び前肢の腫脹、橈骨手根(手首)関節の腫脹、及び脛骨足根骨(足首)関節の腫脹を含む関節炎の臨床兆候に関して週に3回スコア化した。各脚を以下の尺度を使用してスコア化した:(0)正常、(1)わずかに腫脹、(2)軽度の腫脹、(3)中等度の腫脹、及び(4)重度の腫脹。それぞれの脚スコアを加算することにより臨床スコアを計算した。1匹の動物に関して可能性がある最大臨床スコアは(16)であった。2回連続して(12)に等しいスコアを有する動物、及びいずれか1回の折に(12)より大きいスコアを有する動物を間引いた。データをグラフにした(平均値±SEM)。
21日目に、1群あたり3匹のサテライト動物を間引いて脾臓を摘出した。脾細胞をII型コラーゲンの存在下又は非存在下で72時間培養した。72時間後、細胞をトリチウム化チミジンの存在下で一晩パルスした。チミジンの取り込みを測定することによって、細胞の増殖を定量した。データをグラフにした(平均値±SEM)。上清を採取して、重要なサイトカインの存在に関して試験した。
脾細胞培養物からの最終上清を、LuminexによってTNF−α、IL−6、IFN−γ、IL−4、IL−10、及びIL−17を定量するために試験した。データをグラフにした(平均値±SEM)。
−14日目、0日目、及び45日目に、便試料を各動物から収集して、直後に急速凍結して、−80℃で保存した。盲腸(内容物を含む)を直ちに急速凍結して、−80℃で保存した。細菌を播くことによって、細菌同定試験を毎日実施した。
実験の終了時に、後肢を組織固定液で保存した。試料を脱灰液に移した。組織試料を処理して切片にして、ヘマトキシリン・エオシンで染色した。試験計画に対して盲検の適任の組織病理学者が、炎症、関節軟骨損傷、及び下層の骨幹端骨損傷を含む、関節炎の兆候に関して切片をスコア化した。詳細なスコア化システムを使用した(以下を参照されたい)。データをグラフにした(平均値±SEM)。生データ及び分析したデータも同様に代表的な写真と共に提供した。
生存及び非特異的臨床所見
一部の動物は、関節炎の臨床兆候の重症度により、又は非特異的臨床所見の重症度により、試験の予定終了前に間引いた。
体重データを−14日目から0日目まで記録して、初回(−14日)の体重のパーセントとして表記して、二元配置ANOVAの後に、−14日目との多重比較、次いで媒体処置群との多重比較のためにダネット事後検定によって分析した。データを図19に示す。実験の予定終了日以前に間引いた動物からのデータを分析から除外した。
臨床スコアデータを二元配置ANOVAの後、媒体処置群における日毎の多重比較のために、次いでそれぞれの日の実験群と媒体処置群の間の多重比較のためにダネット事後検定によって分析した。データを図21に示す。実験終了前に間引いた動物から記録されたデータを分析から除外した。関節炎の臨床兆候の重症度により動物を間引いた場合、最後に記録されたスコアを、翌日に報告して、統計分析に使用した。
アッセイを検証するために、脾細胞を、陽性対照刺激として可溶性抗CD3及び抗CD28(抗CD3/CD28)の存在下で培養して、細胞の増殖能を確認した。
抗CD3/CD28刺激培養に由来する組織培養上清中のそれぞれのサイトカインのレベルを、luminex分析によって測定した。これらは、測定した全てのサイトカインに関して強い応答を示した(媒体群における平均レベルは以下の通りであった:IL−4=6,406pg/ml;IL−6=306pg/ml;IL−10=10,987pg/ml;IL−17A=11,447pg/ml;IFN−γ=15,581pg/ml;TNF−α=76pg/ml)。
IL−17と共に、IFN−γは、CIAモデルにおいて疾患を駆動する主要なサイトカインである。図23における散布図は、CII刺激後のIFN−γレベルを実証しており、群の中央値は、生物治療薬と比較して媒体処置群ではより高かった(図27を参照されたい)。
IL−17Aのレベルは、媒体処置群に関してCII刺激培養において50pg/mlであった。このサイトカインのレベルは、媒体処置群と比較して生物治療薬群ではより低いように思われた(図27を参照されたい)。
媒体処置群におけるIL−10のレベルはCII刺激及び培地対照培養に関してそれぞれ、13pg/ml及び2.1pg/mlであった。炎症及び炎症促進性サイトカインの誘導は抗炎症フィードバック機構を伴いうることから、媒体処置群ではより高レベルのIL−10(抗炎症性サイトカインである)が予想されうる。
炎症性サイトカイン、例えばIL−6及びTNF−αは、典型的には、抗CII培養において高レベルで産生されない。しかし、それらのレベルは、免疫調節の結果として変化しうる。CII刺激培養におけるIL−6のレベルは控えめであり、10pg/mlに達した。培地対照培養より高いものの、これらの差は、小さすぎて統計分析を行うための論理的根拠を提供できなかった。
この群の脾細胞培養は異なる日に設定されており、したがって媒体処置群とは異なる。直接比較は適切ではない場合があるが、生物治療薬#675による処置は、IFN−γ、IL−17A、及びIL−6レベルを低下させるために有効であったように思われる。
細菌の増殖は、分光光度計を使用して600nmでの光学密度を測定することによって、確認した。細菌の同一性は、画線培養したプレートの写真を参照写真と比較することによって確認した。
組織病理学の結果を図66〜71に示す。このモデルに関して予想されるように、関節炎の有無又は存在する変化の重症度に関して個体内及び個体間変動が観察された。
臨床スコアの増加は、DBA/1マウスのこの関節炎モデルについて予想されるように、II型コラーゲンの最初の投与後28日目から観察された。生物治療薬#675は、このモデルの関節炎を処置するために有効であることが示された。生物治療薬#675で処置した動物は、媒体処置群と比較して異なる時期に免疫されており、このことはより高い臨床スコアが観察されたことを説明しうる。しかし、生物治療薬#675は、組織病理学的分析において実証されたように関節における病理学的疾患を低減させるために有効であった。
実施例1で試験したマウスにさらなる分析を行って、アレルギー性喘息の炎症応答に及ぼす本発明の組成物の効果をさらに特徴付けた。
14日目での血液抜き取り及び血清調製。動物の血液試料を心穿刺によって収集した。14000gで5分間遠心分離することによって、血液試料から血清を単離して、−20℃で保存した。
BAL液及び血清中の総IgE及びチリダニ(HDM)特異的IgG1抗体産生を、ELISAアッセイによって測定した。
左の肺葉をホルマリンで固定した後、パラフィンに包埋して、切片を作製し、ヘマトキシリン・エオシン及びPASで染色した。その後の組織学スコア化は以下のように盲検的に行った:試料あたり無作為な5つの視野を炎症(気管支周囲浸潤及び血管周囲浸潤)及び粘液産生に関してスコア化した。炎症性浸潤を以下のグレード化システムによってスコア化した:
0−正常
1−軽度の炎症性浸潤
2−中等度の炎症性浸潤
3−顕著な炎症性浸潤
4−重度の炎症性浸潤
5−非常に重度の炎症性浸潤
それぞれの視野において、気道のサイズを測定して、粘液細胞数/umを定量した。
炎症メディエータの定量のために単離した右肺葉(残りの全ての肺葉)を急速凍結した後、CCL11、IFN−ガンマ、IL−1アルファ、IL−1ベータ、IL−4、IL−5、IL−9、IL−17A、CXCL1、CCL3、CXCL2、及びCCL5を、市販の多重アッセイ(Merck-Millipore社)によって測定した。分析は、製造業者の説明書に従って実施した。
実験の結果を図28〜46に示す。
実施例2で試験したマウスにさらなる分析を行って、重度の喘息に関連する好中球の応答に及ぼす本発明の組成物の効果をさらに特徴付けた。
18日目での臓器の摘出。後続の組織学的分析のために左の肺葉のコレクションをホルマリンに入れた。右肺葉(残りの全ての肺葉)のコレクション及び血清を採取して急速凍結して後続の分析を行った。残りのBAL液を後続の分析のために急速凍結した。
0−正常
1−軽度の炎症性浸潤
2−中等度の炎症性浸潤
3−顕著な炎症性浸潤
4−重度の炎症性浸潤
5−非常に重度の炎症性浸潤
実験結果を図47〜64に示す。
概要
マウスに、本発明による細菌株を含む組成物を投与して、次いでマウスをミエリン乏突起膠細胞糖タンパク質によって免疫して、実験的自己免疫性脳脊髄炎(EAE,experimental autoimmune encephalomyelitis)を誘発した。EAEは、ヒト多発性硬化症の最も一般的に使用される実験モデルである。本発明の組成物は、疾患の発生率及び疾患の重症度に対して顕著な効果を有することが見出された。
675:受託番号NCIMB 42408として寄託された細菌
群:
1.陰性対照群。媒体対照による処置(経口投与)
3.治療用細菌接種株675による処置(経口投与)
9.陽性対照群。デキサメタゾンによる処置(腹腔内投与)
10.無処置対照群。
1群当たりのマウスの数=10
−14〜27日目:媒体対照の毎日経口投与(群1)
−14〜27日目:治療用細菌接種物の毎日経口投与(群4)
0〜28日目:デキサメタゾンの週に3回腹腔内投与(群9)
0日目:MOG35−55(ミエリン乏突起膠細胞糖タンパク質−2mg/ml)及びCFA(2mg/ml MTB)を1:1で混合して、1mg/ml溶液を得た。ペプチド−CFA混合物100μlを、各後肢に皮下注射した。百日咳毒素(300ng)を腹腔内投与した。
1日目:百日咳毒素の腹腔内投与(300ng)。
7日目以降:疾患の発生率及び体重を週に3回測定。
マウスを疾患の発生率及び疾患の重症度に関して週に3回分析した。スコア化は盲検で行った。疾患の重症度は、0〜5までの範囲の臨床スコアを使用して評価し、5はマウスの死亡を示した(以下の臨床スコアスコア化システムを参照されたい)。
表記の日にマウスの体重を測定して、疾患活動度スコア及び疾患の発生率を観察した。
0−非免疫マウスと比較して運動機能に明白な変化はない。
0.5−尾の先端を引きずる。
1.0−尾を引きずる。
1.5−尾を引きずり、後肢が阻害される。
2.0−尾を引きずり、後肢の虚弱。
又は−歩行を観察すると頭部の傾きの明白な兆候がある。平衡が不良である。
2.5−尾を引きずり、後肢を引きずる。
又は−マウスが時に倒れるほど強い頭部の傾きが見られる。
3.0−尾を引きずり、後肢の完全な麻痺。
3.5−尾を引きずり、後肢の完全な麻痺。
これに加えて、マウスはケージの中を移動するが、横向きに寝かせると、立つことができない。
後肢は完全に体の片面に寄っている。
4.0−尾を引きずり、後肢の完全な麻痺及び前肢の部分麻痺。
マウスはケージの中の移動が最小限であるが、覚醒して餌を食べる
4.5−完全な後肢の麻痺及び前肢の部分麻痺。ケージの中を移動しない。
マウスを直ちに安楽死させてケージから出す。
5.0−マウスを重度の麻痺により安楽死させる。
動物が、1に等しい又は1より大きい疾患活動度スコアを有する場合、プラスの疾患発生率スコアを有すると考えられる。
試験結果を図72及び73に示す。
本明細書に記述される少なくとも1つの細菌株を含有する本明細書において記述される組成物を、25℃又は4℃で密封容器の中で保存して、容器を30%、40%、50%、60%、70%、75%、80%、90%又は95%の相対湿度を有する雰囲気中に置く。1か月、2か月、3か月、6か月、1年、1.5年、2年、2.5年、又は3年後に、細菌株の少なくとも50%、60%、70%、80%又は90%が、標準的なプロトコールによって決定したコロニー形成単位で測定した場合に残っている。
配列番号1(バクテロイデス・コプロコーラの16S rRNAの遺伝子、部分配列:株M11−AB200223)
1 agagtttgat cctggctcag gatgaacgct agctacaggc ttaacacatg caagtcgagg
61 ggcagcatga acttagcttg ctaagtttga tggcgaccgg cgcacgggtg agtaacacgt
121 atccaacctt ccgtttactc agggatagcc tttcgaaaga aagattaata cctgatagta
181 tggtgagatt gcatgatggc accattaaag atttattggt aaacgatggg gatgcgttcc
241 attaggtagt aggcggggta acggcccacc tagcctgcga tggatagggg ttctgagagg
301 aaggtccccc acattggaac tgagacacgg tccaaactcc tacgggaggc agcagtgagg
361 aatattggtc aatgggcgag agcctgaacc agccaagtag cgtgaaggat gaaggtccta
421 cggattgtaa acttctttta tacgggaata aagtttccta cgtgtaggat tttgtatgta
481 ccgtatgaat aagcatcggc taactccgtg ccagcagccg cggtaatacg gaggatgcga
541 gcgttatccg gatttattgg gtttaaaggg agcgcagacg ggagattaag tcagttgtga
601 aagtttgcgg ctcaaccgta aaattgcagt tgatactggt ttccttgagt gcagttgagg
661 caggcggaat tcgtggtgta gcggtgaaat gcttagatat cacgaagaac cccgattgcg
721 aaggcagctt gctaaactgt aactgacgtt catgctcgaa agtgtgggta tcaaacagga
781 ttagataccc tggtagtcca cacggtaaac gatggatact cgctgttggc gatatactgt
841 cagcggccaa gcgaaagcat taagtatccc acctggggag tacgccggca acggtgaaac
901 tcaaaggaat tgacgggggc ccgcacaagc ggaggaacat gtggtttaat tcgatgatac
961 gcgaggaacc ttacccgggc ttaaattgca gacgaattac gaggaaactt gtaagccgca
1021 aggcgtctgt gaaggtgctg catggttgtc gtcagctcgt gccgtgaggt gtcggcttaa
1081 gtgccataac gagcgcaacc ctcgtggtca gttactaaca ggttaagctg agggctctgg
1141 ccagactgcc atcgtaagat gtgaggaagg tggggatgac gtcaaatcag cacggccctt
1201 acgtccgggg ctacacacgt gttacaatgg gaggtacaga aggccgctac ccggcaacgg
1261 gatgccaatc cccaaaacct ctctcagttc ggactggagt ctgcaacccg actccacgaa
1321 gctggattcg ctagtaatcg cgcatcagcc acggcgcggt gaatacgttc ccgggccttg
1381 tacacaccgc ccgtcaagcc atgaaagccg ggggtacctg aagtgcgtaa ccgcaaggag
1441 cgccctaggg taaaaccggt aattggggct aagtctaaca aggtaaccaa g
配列番号2(バクテロイデス・コプロコーラの16S rRNAの遺伝子、部分配列:株M16−AB200224)
1 agagtttgat cctggctcag gatgaacgct agctacaggc ttaacacatg caagtcgagg
61 ggcagcatga acttagcttg ctaagtttga tggcgaccgg cgcacgggtg agtaacacgt
121 atccaacctt ccgtttactc agggatagcc tttcgaaaga aagattaata cctgatagta
181 tggtgagatt gcatgatggc accattaaag atttattggt aaacgatggg gatgcgttcc
241 attaggtagt aggcggggta acggcccacc tagcctgcga tggatagggg ttctgagagg
301 aaggtccccc acattggaac tgagacacgg tccaaactcc tacgggaggc agcagtgagg
361 aatattggtc aatgggcgag agcctgaacc agccaagtag cgtgaaggat gaaggtccta
421 cggattgtaa acttctttta tacgggaata aagtttccta cgtgtaggat tttgtatgta
481 ccgtatgaat aagcatcggc taactccgtg ccagcagccg cggtaatacg gaggatgcga
541 gcgttatccg gatttattgg gtttaaaggg agcgcagacg ggagattaag tcagttgtga
601 aagtttgcgg ctcaaccgta aaattgcagt tgatactggt ttccttgagt gcagttgagg
661 caggcggaat tcgtggtgta gcggtgaaat gcttagatat cacgaagaac cccgattgcg
721 aaggcagctt gctaaactgt aactgacgtt catgctcgaa agtgtgggta tcaaacagga
781 ttagataccc tggtagtcca cacggtaaac gatggatact cgctgttggc gatatactgt
841 cagcggccaa gcgaaagcat taagtatccc acctggggag tacgccggca acggtgaaac
901 tcaaaggaat tgacgggggc ccgcacaagc ggaggaacat gtggtttaat tcgatgatac
961 gcgaggaacc ttacccgggc ttaaattgca gacgaattac gaggaaactt gtaagccgca
1021 aggcgtctgt gaaggtgctg catggttgtc gtcagctcgt gccgtgaggt gtcggcttaa
1081 gtgccataac gagcgcaacc ctcgtggtca gttactaaca ggttaagctg agggctctgg
1141 ccagactgcc atcgtaagat gtgaggaagg tggggatgac gtcaaatcag cacggccctt
1201 acgtccgggg ctacacacgt gttacaatgg gaggtacaga aggccgctac ccggcaacgg
1261 gatgccaatc cccaaaacct ctctcagttc ggactggagt ctgcaacccg actccacgaa
1321 gctggattcg ctagtaatcg cgcatcagcc acggcgcggt gaatacgttc ccgggccttg
1381 tacacaccgc ccgtcaagcc atgaaagccg ggggtacctg aagtgcgtaa ccgcaaggag
1441 cgccctaggg taaaaccggt aattggggct aagtctaaca aggtaaccaa
配列番号3(バクテロイデス・コプロコーラの16S rRNAの遺伝子、部分配列:株M158−AB200225)
1 agagtttgat cctggctcag gatgaacgct agctacaggc ttaacacatg caagtcgagg
61 ggcagcatga acttagcttg ctaagtttga tggcgaccgg cgcacgggtg agtaacacgt
121 atccaacctt ccgtttactc agggatagcc tttcgaaaga aagattaata cctgatagta
181 tggtgagatt gcatgatagc accattaaag atttattggt aaacgatggg gatgcgttcc
241 attaggtagt aggcggggta acggcccacc tagcctncga tggatagggg ttctgagagg
301 aaggtccccc acattggaac tgagacacgg tccaaactcc tacgggaggc agcagtgagg
361 aatattggtc aatgggcgag agcctgaacc agccaagtag cgtgaaggat gaaggtccta
421 cggattgtaa acttctttta tacgggaata aagtatccta cgtgtaggat tttgtatgta
481 ccgtatgaat aagcatcggc taactccgtg ccagcagccg cggtaatacg gaggatgcga
541 gcgttatccg gatttattgg gtttaaaggg agcgcagacg ggagattaag tcagttgtga
601 aagtttgcgg ctcaaccgta aaattgcagt tgatactggt ttccttgagt gcagttgagg
661 caggcggaat tcgtggtgta gcggtgaaat gcttagatat cacgaagaac cccgattgcg
721 aaggcagctt gctaaactgt aactgacgtt catgctcgaa agtgtgggta tcaaacagga
781 ttagataccc tggtagtcca cacggtaaac gatggatact cgctgttggc gatatactgt
841 cagcggccaa gcgaaagcat taagtatccc acctggggag tacgccggca acggtgaaac
901 tcaaaggaat tgacgggggc ccgcacaagc ggaggaacat gtggtttaat tcgatgatac
961 gcgaggaacc ttacccgggc ttaaattgca gacgaattac gaggaaactt gtaagccgca
1021 aggcgtctgt gaaggtgctg catggttgtc gtcagctcgt gccgtgaggt gtcggcttaa
1081 gtgccataac gagcgcaacc ctcgtggtca gttactaaca ggttaagctg aggactctgg
1141 ccagactgcc atcgtaagat gtgaggaagg tggggatgac gtcaaatcag cacggccctt
1201 acgtccgggg ctacacacgt gttacaatgg gaggtacaga aggcagctac ccggcgacgg
1261 gatgccaatc cccaaaacct ctctcagttc ggactggagt ctgcaacccg actccacgaa
1321 gctggattcg ctagtaatcg cgcatcagcc acggcgcggt gaatacgttc ccgggccttg
1381 tacacaccgc ccgtcaagcc atgaaagccg ggggtacctg aagtgcgtaa ccgcaaggag
1441 cgccctaggg taaaaccggt aattggggct aagtcgtaac aaggtaacca a
配列番号4(バクテロイデス・コプロコーラ株675のコンセンサス16S rRNA配列
GTCTGGCTCAKGATGAACGCTAGCTACAGGCTTAACACATGCAAGTCGAGGGGCAGCATGAACTTAGCTTGCTAAGTTTGATGGCGACCGGCGCACGGGTGAGTAACACGTATCCAACCTCCCGCTTACTCAGGAATAGCCTTTCGAAAGAAAGATTAATGCCTGATGGTATCTTAAGCACACATGTAATTAAGATTAAAGATTTATCGGTAAGCGATGGGGATGCGTTCCATTAGGTAGTAGGCGGGGTAACGGCCCACCTAGCCGACGATGGATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAAACTCCTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGGCGCGAGCCTGAACCAGCCAAGTAGCGTGAAGGATGAAGGTCCTATGGATTGTAAACTTCTTTTATACGGGAATAAAGTGGTCCACGTGTGGGCCTTTGCATGTACCGTATGAATAAGCATCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGATGCGAGCGTTATCCGGATTTATTGGGTTTAAAGGGAGCGCAGACGGGGGATTAAGTCAGTTGTGAAAGTTTGCGGCTCAACCGTAAAATTGCAGTTGATACTGGTTCCCTTGAGTGCAGTTGAGGCAGGCGGAATTCGTGGTGTAGCGGTGAAATGCATAGATATCACGAAGAACCCCGATTGCGAAGGCAGCCTGCTAAGCTGTAACTGACGTTGAGGCTCGAAAGTGTGGGTATCAAACAGGATTAGATACCCTGGTAGTCCACACGGTAAACGATGGATACTCGCTGTTGGCGATATACTGTCAGCGGCCAAGCGAAAGCATTAAGTATCCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACCCGGGCTTAAATTGCAGACGAATTACTTGGAAACAGGTAAGCCGCAAGGCGTCTGTGAAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAGTGCCATAACGAGCGCAACCCTCGTGGCCAGTTACTAGCAGGTAACGCTGAGGACTCTGGCCAGACTGCCATCGTAAGATGCGAGGAAGGTGGGGATGACGTCAAATCAGCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGAGGTACAGAAGGCAGCTACCCGGCGACGGGATGCCAATCTCCAAAGCCTCTCTCAGTTCGGACTGGAGTCTGCAACCCGACTCCACGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCACGGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGCCGGGAGTACCTGAAGTGCGTAACCGCAAGGAGCGCCCTAGGGTAAAACCGGTAATTGGGGCTAAGTCNTACGGGG
配列番号5(バクテロイデス・シータイオタオミクロンの16S rRNAの遺伝子、部分配列−M58763)
1 cttntacaat gaagagtttg atcctggctc aggatnaacg ctagctacag gcttaacaca
61 tgcaagtcna ggggcagcat ttcagtttgc ttgcaaactg gagatggcga ccggcgcacg
121 ggtgagtaac acgtatccaa cctgccgata actcggggat agcctttcga aagaaagatt
181 aatacccnat ggtataatca gaccgcatng tcttrttatt aaagaatttc ggttatcgat
241 ggggatgcgt tccattaggc agttggtgag gtaacggctc acnnaacctt cgatggatag
301 gggttctgag aggaaggtcc cccacattgg aactgagaca cggtccaaac tcctacggga
361 ggcagcagtg aggaatattg gtcaatgggc gcaggcctga accagccaag tagcgtgaag
421 gatgactgcc ctatgggttg taaacttctt ttatatggga ataaagtttt ccacgtgtgg
481 aattttgtat gtaccatatg aataaggatc ggctaactcc gtgccagcag ccncgntnat
541 acggagnatc cgagcgttat ccggatttat tgggtttaaa gggagcgtag gtggacagtt
601 aagtcagttg tgaaagtttg cggctcaacc gtaaaattgc agttgatact ggctgtcttg
661 agtacagtag aggtgggcgg aattcgtggt gtagcggtga aatgcttaga tatcacgaag
721 aactccgatt gcgaaggcag ctcactggac tgcaactgac actgatgctc gaaagtgtgg
781 gtatcaaaca ggattagata ccctggtagt ccacacagta aacgatgaat actcgctgtt
841 tgcgatatac agtaagcggc caagcgaaag cattaagtat tccacctggg gagtacgccg
901 gcaacggtga aactcaaagg aattgacggg ggccngcaca agcggaggaa catgtggttt
961 aattcgatga tacgcgagga accttacccg ggcttaaatt gcatttgaat atattggaaa
1021 cagtatagcc gyaaggcaaa tgtgaaggtg ctgcatggtt gtcgtcagct cgtgccgtga
1081 ggtgtcggct taagtgccat aacgagcgca acccttatct ttagttacta acaggtcatg
1141 ctgaggactc tagagagact gccgtcgtaa gatgtgagga aggtggggat gacgtcaaat
1201 cagcacngcc cntacgtccg gggctacaca cgtgttacaa tggggggtac agaaggcagc
1261 tacctggtga caggatgcta atcccaaaag cctctctcag ttcggatcga agtctgcaac
1321 ccgacttcgt gaagctggat tcgctagtaa tcgcgcatca gccatggcgc ggtgaatacg
1381 ttcccgggcn ttgtacacac cgcccgtcaa gccatgaaag ccgggggtac ctgaagtacg
1441 taaccgcaag gagcgtccta gggtaaaact ggtaattggg gc
配列番号6(株675染色体配列)−電子版の配列表を参照されたい。
配列番号7(株675プラスミド配列)−電子版の配列表を参照されたい。
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Claims (29)
- IL−17又はTh17経路によって媒介される疾患又は状態を治療又は予防する方法に使用するための、配列番号4と少なくとも95%同一である16s rRNA配列を有し、IL−17又はTh17炎症応答を低減する効果を有するバクテロイデス属の細菌株を含む組成物。
- 喘息;関節炎;多発性硬化症;視神経脊髄炎(デビック病);強直性脊椎炎;脊椎関節炎;乾癬;全身性紅斑性狼瘡;炎症性腸疾患;セリアック病;慢性閉塞性肺疾患(COPD);がん;ブドウ膜炎;強膜炎;血管炎;ベーチェット病;アテローム性動脈硬化症;アトピー性皮膚炎;肺気腫;歯周炎;アレルギー性鼻炎;及び同種異系移植片拒絶からなる群から選択される疾患又は状態を治療又は予防する方法に使用するための、請求項1に記載の組成物。
- 喘息が、アレルギー性喘息又は好中球性喘息であり、
関節炎が、関節リウマチ、変形性関節症、乾癬性関節炎、又は若年性特発性関節炎であり、
炎症性腸疾患が、クローン病又は潰瘍性大腸炎であり、
がんが、乳がん、結腸がん、肺がん、又は卵巣がんである、請求項2に記載の組成物。 - 喘息を治療又は予防する方法に使用するための、請求項2又は3に記載の組成物。
- 喘息の治療において、好中球増加又は好酸球増加を低減させる方法に使用するための、請求項4に記載の組成物。
- 関節リウマチを治療又は予防する方法に使用するための、請求項2に記載の組成物。
- 関節リウマチにおける関節の腫脹を低減させる方法に使用するための、請求項6に記載の組成物。
- 多発性硬化症を治療又は予防する方法に使用するための、請求項2に記載の組成物。
- 疾患の発生率又は疾患の重症度を低減させる方法に使用するための、請求項8に記載の組成物。
- がんを治療又は予防する方法に使用するための、請求項2又は3に記載の組成物。
- がんが、肺がん、乳がん又は肝臓がんである、請求項10に記載の組成物。
- 腫瘍のサイズを低減させる、腫瘍の増殖を低減させる、転移を予防する、又は血管新生を予防する方法に使用するための、請求項10又は11に記載の組成物。
- ブドウ膜炎を治療又は予防する方法に使用するための、請求項2に記載の組成物。
- ブドウ膜炎における網膜損傷を低減又は予防する方法に使用するための、請求項13に記載の組成物。
- IL−17又はTh17経路によって媒介される疾患又は状態の治療又は予防において、IL−17の産生を低減させる又はTh17細胞の分化を低減させる方法に使用するための、請求項1〜14のいずれかに記載の組成物。
- IL−17レベル又はTh17細胞が上昇している患者に使用するための、請求項1〜15のいずれかに記載の組成物。
- 細菌株が、バクテロイデス・コプロコーラの細菌株である、請求項1〜16のいずれかに記載の組成物。
- 細菌株が、配列番号4と少なくとも96%、97%、98%、99%、99.5%又は99.9%同一である16s rRNA配列を有するか、又は細菌株が、配列番号4によって表される16s rRNA配列を有する、請求項1〜17のいずれかに記載の組成物。
- 経口投与用である、請求項1〜18のいずれかに記載の組成物。
- 1又は2以上の薬学的に許容される賦形剤又は担体を含む、請求項1〜19のいずれかに記載の組成物。
- 細菌株が凍結乾燥されている、請求項1〜20のいずれかに記載の組成物。
- 食品である、請求項1〜21のいずれかに記載の組成物。
- ワクチン組成物である、請求項1〜21のいずれかに記載の組成物。
- 配列番号4と少なくとも95%同一である16s rRNA配列を有し、IL−17又はTh17炎症応答を低減する効果を有するバクテロイデス属の細菌株を含む組成物を含む、IL−17又はTh17経路によって媒介される疾患又は状態の治療又は予防剤。
- 受託番号NCIMB 42408として寄託された株又はその派生物の細胞。
- 請求項25に記載の細胞を含む組成物。
- 薬学的に許容される担体又は賦形剤を含む、請求項26に記載の組成物。
- 受託番号NCIMB 42408として寄託された株又はその派生物の生物学的に純粋な培養物。
- 受託番号NCIMB 42408として寄託された株又はその派生物の細胞を含む、治療に使用するための組成物。
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MA41060B1 (fr) | 2015-06-15 | 2019-11-29 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
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SG10201912324XA (en) | 2015-06-15 | 2020-02-27 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
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GB201520497D0 (en) | 2015-11-20 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
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