JP6983263B2 - 粘膜へ化合物を送るための媒体、それに関連する組成物、方法、及びシステム - Google Patents
粘膜へ化合物を送るための媒体、それに関連する組成物、方法、及びシステム Download PDFInfo
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Description
特に、精製されたOMVsは、機能性Tregsのインビトロにおける分化をPSA依存的に強い抑制活性を伴うように導く。PSAを含むOMVsで動物を処置することは、実験的な大腸炎を防止し、消化管における炎症誘発サイトカイン反応を抑制する。これらの発見は、共生細菌が小胞の分泌によって有利な微生物因子を提供することを明らかにし、また、IBDのためのプロバイオティクス療法における運送(デリバリー)の新しいやり方へと設計されるプロセスを明らかにする。
B. fragilis 株NCTC 9343をアメリカンタイプカルチャーコレクションから得た。その同系のPSA欠失変異株と、mpi44変異株(PSAのみ産生するが他の多糖を産生しない)とは、「M.J. Coyne, A.O. Tzianabos, B.C. Mallory, V.J. Carey, D.L. Kasper and L.E. Comstock, (2001) Polysaccharide biosynthesis locus required for virulence of Bacteroides fragilis, Infect. Immun. 69: 4342-4350.」に記載されている。細菌は、1L ddH20中に37g BHI (BD #237200)、0.5μ g/mlヘミン (Sigma H5533)、及び0.5μg/ml ビタミンK(Sigma V3501)を含む富栄養培地、又は、1LのRPMI (Invitrogen SKU#11835-030)中に、8g グルコース、1% FBS、0.5μg/ml ヘミン、及び0.5μg/ml ビタミンKを含む特製の最少培地のいずれかにて育てられた。C57BL/6及び Balb/c株のSPFマウスをTaconic Farms (Germantown, NY)から購入した。TLR2 ノックアウトマウス及びIL-10 ノックアウトマウスをJackson laboratoriesから購入した。IL-10GFPマウスをシンシナティ小児病院のクリストファーカープ研究所から購入した。Foxp3GFPマウスは、ロサンゼルスのカリフォルニア大学のTalal Chatila研究所から譲り受けた。
パーコール(GE Healthcare #17- 0891-01)不連続濃度勾配遠心分離を野生型B.fragilis及びΔB.fragilis(Patrick S, Reid JH. (1983) Separation of capsulate and non- capsulate Bacteriodes fragilis on a discontinuous density gradient. J Med Microbiol. 16(2): 239-41.)のEDLの単離のために用いた。即ち、20%、40%、60%、80%のパーコール勾配(PBSで希釈)を14ml試験管(各層2ml)中に調製した。次に、PBS中に再度懸濁させたB. fragilis培養物を20%パーコール層の上部に注意深く加えた。さらに、勾配を室温にて800gで20分間遠心分離処理した。EDLに富んだ細菌を分離後に、40%〜60%の界面部分から取り戻した。
斯かる方法には、E.coliからのOMVsの調製のために既に記載されている方法(Amanda L. Horstman and Meta J. Kuehn. (2000) Enterotoxigenic Escherichia coli secretes active heat-labile enterotoxin via outer membrane vesicles. J Biol Chem. 275: 12489-12496.)を適用した。即ち、EDLに富んだB.fragilisを特製のMM中で育てた。4℃にて2時間、40,000gにて遠心分離することにより細菌がない培地の上清からOMVsを回収し、さらにPBSで2回洗浄し、0.45μmの細長いカラム(Millipore #20-218)で濾過した。精製したOMVsの全タンパク質濃度をブラッドフォード法(Biorad #500-0205)によって測定した。FITCで標識されたOMVsを既に知られた方法によって調製した(Nicole C. Kesty and Meta J. Keuhn. (2004) Incorporation of heterologous outer membrane and periplasmic proteins into Escherichia coli outer membrane vesicles. J Biol Chem. 279: 2069-2076)。即ち、OMVsを室温で1時間、染色緩衝液(lmg/ml FITC (Thermo Scientific #46424), 100mM NaCl, 50mM Na2CO3, pH 9.2)中においた。標識されたOMVsを4℃で30分間40,000gで遠心分離することにより回収し、PBS+200ml NaClで2回洗浄した。
EDLに富んだB. fragilisの超薄膜切片を既に知られた方法によって作製した(Patrick S, McKenna JP, O'Hagan S, Dermott E. (1996) A comparison of the haemagglutinating and enzymic activities of Bacteroides fragilis whole cells and outer membrane vesicles. Microb Pathog. 20(4): 191-202.)。即ち、カコジル酸緩衝液の2.5%(v/v)グルタールアルデヒド(Sigma, G5882)溶液中で4℃にて終夜、サンプルを固定し、さらに、暗所にて室温で3時間、四酸化オスミウム(1%、w/v)中で固定を行った。いずれの固定処理においても、ルテニウムレッド(lmg/ml, Sigma R2751)を配合した。そして、濃度勾配のある一連のアルコールで脱水した後に、固定処理したサンプルをエポキシ樹脂に包埋した。超薄膜切片を切り出し、フォルムバー/炭素被覆銅グリッド(EMS #FCF200-Cu)上にてTEMによる観察の前に、2%酢酸ウラニル及びクエン酸鉛によってネガティブ染色した。
この方法には、既に知られた手法を適用した(Patrick S, McKenna JP, O'Hagan S, Dermott E. (1996) A comparison of the haemagglutinating and enzymic activities of Bacteroides fragilis whole cells and outer membrane vesicles. Microb Pathog. 20(4): 191-202.)。即ち、精製したOMVの小さな1滴をフォルムバー/炭素被覆金グリッド(EMS #FF200-Au)上に置き、自然乾燥させた。これらのグリッドの“OMVs”の側が下になるように抗体及び洗浄液の小滴の上にグリッドを浮かべることにより、室温にて免疫金標識を行った。具体的には、0.12%グリシンに5分間おいた後、10%FBS中でサンプルを10分間ブロック処理した。続いて、5nmの金が結合した第2の抗体IgG(Dr. Paul Webster, House Ear Institute, ロサンゼルス から贈呈)をサンプルに塗布し、PBSで再び4分間の洗浄を5回行った。標識後、サンプルを1%グルタールアルデヒド中で5分間固定し、液滴がグリッドを透過するように、PBSの1分間の洗浄を4回、H2Oの1分間の洗浄を4回行い、よく洗浄した。2%メチルセルロースの3〜5%酢酸ウラニルの液滴上にグリッドを氷温で10分間置くことにより対比染色を行った。最後に、輪状針金を用いてグリッドを染色液から取り除き、自然乾燥させた。メチルセルロースの薄膜によって覆われたサンプルを輪状針金から取り除き、透過型電子顕微鏡観察(TEM)に用いた。
全細胞抽出物又はOMVs(B. fragilis変異株mpi44由来)から精製されたPSAをSDS-PAGEに供し、続いて、PSAの存在を現すべく、ゲルを糖タンパク質染色キット(G bioscience #786-254)により染色した。
この操作としては、既に知られた方法(Scheiffele and Fuss. (2001) Induction of TNBS colitis in mice. Current Protocols in Immunology.15.19.1-15.19.14.)を採用した。即ち、野生型(Balb/c)オスのマウスを、TNBS投与の前に、PBS、WT-OMV(5μg)、又はΔPSA-OMV(5μg)で1日おきに1週間、経口的に処置した。処置されたマウスをイソフルランで麻酔し、2%TNBS(50% EtOH中、Sigma P2297)の直腸への投与を3.5Fカテーテル(Instech Solomon; SIL-C35)によって行った。TNBS投与の後、経口投与をさらに2回続け、最後の処置の後、マウスを1〜2日間分析した。
マウスの結腸を中性の10%ホルマリン緩衝液(ScyTek Laboratories CAS#50-00-0)中で固定し、H & E 染色のためにパシフィックパソロジー(Pacific Pathology)によって処理した。各結腸部位の大腸炎スコアを病理学者(Dr. Gregory Lawson, David Geffen School of Medicine, UCLA, ロサンゼルス)によって盲検方式により評価した。組織構造画像を20倍の倍率で光学顕微鏡(Zeiss)を用いて取得した。
Trizol試薬(Invitrogen #15596-018)を用いてマウス組織から、又は、RNeasy ミニキット(Qiagen #74104)を用いて精製細胞からRNAを収集した。iSCRIPT cDNA 合成キット(BioRad #170-8890)をcDNAの変換のために用い、IQ SYBR Green supermix (BioRad #172-8882)をリアルタイムPCRのために用いた。本試験において用いたプライマーは、TNF (F- 5'ACG GCA TGG ATC TCA AAG AC 3' (配列番号1)); (R- 5' GTG GGT GAG GAG CAC GTA GT 3') (配列番号2); IL-17 (F- 5' TTA AGG TTC TCT CCT CTG AA 3'(配列番号3)); (R- 5' TAG GGA GCT AAA TTA TCC AA 3') (配列番号4); IL- 10 (F- 5' GGT TGC CAA GCC TTA TCG GA 3'(配列番号5)); (R- 5' ACC TGC TCC ACT GCT TGC T 3') (配列番号6); Foxp3 (F- 5' GCA ATA GTT CCT TCC CAG AGT TCT 3'(配列番号7));R- 5' GGA TGG CCC ATC GGA TAA G 3'(配列番号8);アクチン (F-5' TTC GTT GCC GGT CCA CA 3'(配列番号9); R-5' ACC AGC GCA GCG ATA TCG-3' (配列番号10)である。
インビトロで分化したBMDCをLab-Tek IIの8ウェルチャンバースライド(Nunc #154534)に50,000細胞/ウェルとなるように播種した。FITCで標識したOMVを培養細胞に10μg/mlで添加した。2時間の培養後、細胞を4%PFA中で室温にて2時間固定処理した。PBSで5分間の洗浄を3回行った後、WGA(Invitrogen W849)のテトラメチルローダミン複合体の1μg/mlによって4℃で1時間染色処理した。そして、プロロングゴールド褪色防止剤(P36930)を、膜染色の後、十分に洗浄した細胞に塗布した。LSM 510顕微鏡、及び、油浸Plan- Neofluar 63x/1.25を用いて蛍光画像を取得した。
OMV取得操作又は活性操作由来のBMDCを収集し、5%マウス血清中で氷温にて30分間ブロック処理した。ブロック処理の後、氷温にて30分間、抗CD11c-APC、抗-MHCII-FITC、又は、抗-CD86-PE (ebioscience社)で染色し、フローサイトメトリーの前に4℃にてFACS緩衝液(HBSS (Ca2+/Mg2+なし)、 1% FBS、2mM EDTA、10mM HEPES)で2回洗浄した。同様に、インビトロでのBMDC-T細胞共培養物由来の細胞をブロック処理し、回収の前にPMA/イオノマイシンを用いて4〜4.5時間再刺激したこと以外は、抗-CD4-APC/抗-CD25-PEを用いて同様に染色した。全てのフローサイトメトリーは、BD FACSCaliburを用いて行い、結果は、FlowJoを用いて解析した。
骨髄を異なるマウス株から収集し、既に知られているように(Mazmanian, Liu, Tzianabos, and Kasper (2005) An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System. Cell 122: 1 107-118)、20ng/ml GM-CSF (Miltenyi Biotec #9517571)の存在下にて8日間、インビトロで分化させた(細胞純度 > 90%)。CD4+ 脾臓のT細胞を、磁気ビーズ精製法(Miltenyi Biotec #130-090-860)によって単離した(細胞純度 > 95%)。OMVで標的化されたBMDCs(10μl/ml OMVs, 100,000細胞/ml, 12〜24時間)をHBSSで洗浄し、そして、抗-CD3を0.01μl/mlとなるように添加(0日、図3C、3D, 3E,3F、図4A)、2ng/mlTGFbを添加(0日、図3C、D及びF、図4A)、及び、5ng/ml II-2を添加(1日及び3日、全てインビトロDC-T細胞共培養法)した丸底の96ウェルプレート中でCD4+T細胞(1,000,000細胞/ml)とともに培養した。培養4日後、上清をELISA法(ebioscience #88- 7104-77)のために収集し、又は、細胞を染色若しくはフローサイトメトリーのために回収した。
BMDC(WT- OMV又はAPSA-OMVで標識化)−T細胞共培養物から精製されたCD4+CD25+細胞をTreg(Miltenyi Biotec, #130-091-041)源として用いた。マイトマイシンC(Sigma M4278)で処理されたCD4欠失マウス脾臓をAPCs(100,000 細胞/ml)として用いた。マウス脾臓から直接的に精製されたCD4+CD25-T細胞を37℃にて10分間、CFSEで標的化し、続いて、PBSで最初の洗浄を行い、培地で2回目の洗浄を行い、キラー細胞(Teff)として直ちに使用した(500,000 細胞/ml)。この操作は、5μg/mlの抗-CD3(ebioscience #16-0031-86)を添加した、200μl容積の96ウェル丸底プレートにおいて行った。Teff:Treg比は、滴定され、細胞は、培養後2〜3日後にFACS分析のために収集された。
スチューデントT検定及び一元ANOVAをそれぞれ一対比較及び2群以上の比較のために採用した。統計的な有意差を示す群を識別すべく、ANOVAによる群間の有意差を、ポストホックテストとしてのNewman-Keuls 検定を使用することにより解析した。全てのエラーバーは、SEM(誤差範囲)を示している。NS:有意差なし、* p<0.05; *** p<0.01; *** p<0.001。
免疫調製性莢膜多糖PSAをB. fragilisのOMVsへ活性的に入れる。
OMVsは、PSA濃度依存的に、実験的な大腸炎及び腸の炎症から動物を保護する。
OMVsを含有するPSAがTNFα/IL-17発現を抑制し、IL-10発現を高める。
B. fragilis由来のOMVsを含むPSAが樹枝状細胞反応を含む
OMVsを含有するPSAが、DCs IL-10によってCD4+T細胞におけるIL-10の発現を誘発する。
OMVsを含むPSAは、DCsを直接的なFoxp3 Tregの発達及び/又は拡張へ仕向ける。
CD4 + T細胞におけるFoxp3の転写の増加と矛盾せず、CD4+ Foxp3 + T細胞の比率が、PSA-OMV処置でなく、WT-OMV処置に応じて増加した(図3F)。総称して、PSAを含むOMVsは、完全にインビトロな培養系において、直接的にTregの発達及び/又は拡張へとDCを仕向ける。
PSA含有OMVsは、IL-10が媒介するFoxp3 Treg抑制作用を誘発する。
PSAは、Foxp3 Tregにおける様々な生物標識の組み合わせを誘発する。
1 . Xavier, R.J. & Podolsky, D.K. Unravelling the pathogenesis of inflammatory bowel disease.Nature 448, 427-434 (2007).
2. Mazmanian, S.K., Round, J.L. & Kasper, D.L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620-625 (2008).
3. Braun, J. & Wei, B. Body traffic: ecology, genetics, and immunity in inflammatory bowel disease. Annu Rev Pathol 2, 401-429 (2007).
4. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol (2009).
5. Scheiffele and Fuss. (2001) Induction of TNBS colitis in mice. Current Protocols in Immunology.15.19.1-15.19.14.
6. Mazmanian, Liu, Tzianabos, and Kasper (2005) An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System. Cell 122:1 107-118
7. MJ. Coyne, A.O. Tzianabos, B.C. Mallory, V.J. Carey, D.L. Kasper and L.E. Comstock, (2001) Polysaccharide biosynthesis locus required for virulence of Bacteroides fragilis, Infect. Immun. 69: 4342-4350.
8. Patrick S, Reid JH. (1983) Separation of capsulate and non-capsulate Bacteriodes fragilis on a discontinuous density gradient. J Med Microbiol. 16(2): 239-41
9. Amanda L. Horstman and Meta J. Kuehn. (2000) Enterotoxigenic Escherichia coli secretes active heat-labile enterotoxin via outer membrane vesicles. J Biol Chem. 275: 12489-12496.
10. Nicole C. Kesty and Meta J. Keuhn. (2004) Incorporation of heterologous outer membrane and periplasmic proteins into Escherichia coli outer membrane vesicles. J Biol Chem. 279: 2069-2076.
11 . Patrick S, McKenna JP, O'Hagan S, Dermott E. (1996) A comparison of the
haemagglutinating and enzymic activities of Bacteroides fragilis whole cells and outer membrane vesicles. Microb Pathog. 20(4): 191-202.
12. Round et al. (2010) Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. PNAS, 107 (27). 12204-12209.
Claims (5)
- 薬物としての使用のための薬用組成物であって、
前記薬用組成物が、水性環境を取り囲む脂質膜で形成され多糖A(PSA)を含む外膜小胞を有し、
前記脂質膜がBacteroides fragilisの外膜から得られたものであり、
前記薬物としての使用が、炎症性疾患の治療に有用な他の1種以上の薬物又は処置と組み合わされる、薬用組成物。 - さらに賦形剤を含む請求項1記載の薬用組成物。
- 前記PSAが低分子量PSA(L−PSA)である請求項1または2に記載の薬用組成物。
- 前記炎症性疾患が炎症性腸疾患である、又は、前記炎症性疾患が炎症性腸疾患を含む、請求項1〜3のいずれか1項に記載の薬用組成物。
- 前記炎症性疾患が多発性硬化症である、又は、前記炎症性疾患が多発性硬化症を含む、請求項1〜3のいずれか1項に記載の薬用組成物。
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US20160143940A1 (en) | 2016-05-26 |
US20190314400A1 (en) | 2019-10-17 |
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US20110251156A1 (en) | 2011-10-13 |
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