JP5932970B2 - 末梢免疫機能を調節するための方法及び組成物 - Google Patents
末梢免疫機能を調節するための方法及び組成物 Download PDFInfo
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Description
本出願は、2011年4月6日に出願された米国仮特許出願第61/516,637号及び2011年9月30日に出願された米国仮特許出願第61/541,248号に基づく優先権を主張し、その開示は、すべての目的のために、本明細書全体において参照として組み込まれる。
適用なし。
間葉系幹細胞(MSC)は、骨髄から接着細胞を選択することにより得ることができ、そして接着細胞においてNotch細胞内ドメイン(NICD)の発現によりSB623細胞を形成するように誘導することができる。1つの実施態様において、MSCの培養物は、NICDをコードする配列を含むポリヌクレオチドと接触し(例えば、トランスフェクションにより)、続いて薬剤選択により、トランスフェクトした細胞を濃縮しそしてさらに培養する。例えば、米国特許第7,682,825号(2010年3月23日);米国特許出願公開第2010/0266554号(2010年10月21日);及び国際公開第2009/023251号(2009年2月19日)を参照し;それらすべての開示は、間葉系幹細胞の分離及び間葉系幹細胞のSB623細胞(それらの文書において「神経前駆細胞(neural precursor cell)」及び「神経再生細胞(neural regenerating cell)」を意味する)への転換を記載する目的のために、それらの全体について、参照により組み込まれる。また以下の実施例1も参照。
上記のように、SB623細胞は、培養MSCにおいてNICDの発現によりMSCに由来する。培養において操作を受けているMSCは、しばしば老化するので;そこから由来するSB623細胞を、老化について試験した。
SB623細胞は、MSCと共通する多くの表面マーカーを発現する。これらは、CD29、CD44、CD73、CD90、CD105及び血管内皮細胞接着分子‐1(VCAM‐1又はCD106)が挙げられる。MSCと比較して、SB623細胞においてCD44及びCD73のレベルが高く、そしてVCAM‐1レベルが低かった。SB623細胞はまた、細胞間接着分子‐1(ICAM‐1又はCD54)を発現し、そしてそれは、通常、MSCで発現していない。図5及び6を参照。MSC及びSB623細胞は、表面マーカーCD31、CD34及びCD45を発現しない。
SB623細胞を、非血縁ドナー由来の105CFSE標識末梢血T細胞及び105末梢血単核細胞を含む混合リンパ球反応(MLR)に添加した。T細胞活性化の初期マーカー、CD69のレベルを測定して、T細胞活性化を調節するSB623細胞の能力を調べた。対照混合リンパ球反応において、CD69の表面発現を強力に誘導した。しかしながら、104SB623細胞の存在下で1日後、表面CD69を発現する、MLRにおけるCD4+T細胞(すなわち、ヘルパーT細胞)の分画が、有意に減少した。実施例4を参照。
単球の樹状細胞(抗原提示細胞の1種)への分化及びさらに樹状細胞の成熟は、単球の、サイトカイン、インターロイキン‐4(IL‐4)及び顆粒球/マクロファージコロニー刺激因子(GM‐CSF)への暴露によりインビトロにおいて刺激することができる。この分化は、インターロイキン‐6(IL‐6)又は血管内皮増殖因子(VEGF)により阻止することができ、そしてそれら両方は、SB623細胞により分泌されることが知られるサイトカインの中の1つである。例えば、Tateら、(2010) Cell Transplant. 19: 973-984及び国際公開第2009/023251号を参照。
SB623細胞に転換することができる前記細胞は、任意の種類の非最終分化細胞であってもよい。例えば、米国特許第5,843,780号;6,200,806号及び7,029,913号において開示されたような全能性幹細胞などが、前駆細胞として使用することができる。全能性幹細胞は、培養し(例えば、米国特許第6,602,711号及び7,005,252号)そして様々な種類の多能性細胞に分化することができ(例えば、米国特許第6,280,718号;6,613,568号及び6,887,706号)、それはまた、開示された方法の実施において前駆細胞として使用することができる。
Notchタンパク質は、すべての後生動物で見られる、細胞内シグナル伝達を通じて細胞分化に影響を及ぼす膜貫通受容体である。Notch細胞内ドメインのNotchリガンド(例えば、デルタ(Delta)、セレート(Serrate)、ジャグド(Jagged))との接触は、Notchタンパク質の2つのタンパク質分解切断をもたらし、その2番目は、γ‐セクレターゼにより触媒され、そして細胞質中にNotch細胞内ドメイン(NICD)を放出する。マウスNotchタンパク質において、この切断は、アミノ酸gly 1743及びval 1744の間で起こる。NICDは、核に移行し、そこで転写因子として働き、さらなる転写調節タンパク質(例えば、MAM、ヒストンアセチラーゼ)を漸加して、様々な標的遺伝子(例えば、Hes1)の転写抑制を緩和する。
細胞培養のための標準的な方法は、当該技術分野において公知である。例えば、R. I. Freshney "Culture of Animal Cells: A Manual of Basic Technique," Fifth Edition, Wiley, New York, 2005を参照。
自己免疫疾患は、正常の健全な組織を攻撃する免疫反応に起因する。典型的な自己免疫疾患は、限定されないが、筋委縮性側索硬化症、強直性脊椎炎、血小板減少性紫斑病、橋本甲状腺炎、ギラン・バレー症候群、悪性貧血、皮膚筋炎(dermatosyositis)、アジソン病、1型糖尿病、関節リウマチ、全身性エリテマトーデス(「狼瘡」)、皮膚筋炎、シェーグレン症候群、多発性硬化症、重症筋無力症、多発性筋炎、胆汁性肝硬変、乾癬、反応性関節炎、グレーブス病、潰瘍性大腸炎、炎症性腸疾患、血管炎、クローン病、及びセリアック病‐スプルー(グルテン過敏性腸疾患)が挙げられる。
本明細書に開示されるように、SB623細胞を含む治療用組成物をまた提供する。そのような組成物は、典型的に細胞及び医薬的に許容される担体を含む。
成人ドナー由来の骨髄穿刺液を、Lonza Walkersville,Inc(Walkersville,MD)から入手し、そして10%ウシ胎児血清(Hyclone,Logan,UT)、2mMのL‐グルタミン(Invitrogen,Carlsbad,CA)及びペニシリン/ストレプトマイシン(Invitrogen)を補充したα‐MEM(Mediatech,Herndon,VA)に播種した。細胞を、37℃、5%CO2で3日間培養し、接着細胞の単層を得た。非接着細胞の除去後、培養を同じ条件で2週間継続した。この間に、細胞を0.25%のトリプシン/EDTAを使用して、2回継代した。2代継代由来の細胞の一部をMSCとして凍結した。
細胞増殖を定量するために、100万のMSC又はSB623細胞を播種し、そして3日間培養した。3日目に、生細胞をトリパンブルー排除によりカウントした。図2は、より少ない生細胞が、MSC培養物と比較して、SB623培養物に存在したことを示す。
表面マーカーを測定するために、MSC又はSB623細胞を、0.25%のトリプシン/EDTA(Invitrogen,Carlsbad,CA)を使用して培地から採取し、PBS/2%FBSで洗浄し及び1mlのPBS/2%FBSに再懸濁した。細胞を、CD29、CD31、CD34、CD44、CD45、CD73、CD90への蛍光色素コンジュゲート抗体(すべてBD Biosciences,San Jose,CA)、又はCD105への蛍光色素コンジュゲート抗体(Invitrogen,Carlsbad,CA)で、氷上で15分間インキュベートした。細胞を、その後、PBS/2%FBSで1回洗浄し、そしてFACSCalibur(商標)フローサイトメーター(BD Biosciences,San Jose,CA)を行った。CellQuestPro(商標)ソフトウェア(BD Biosciences)を、データ分析のために使用した。結果を、対照としてIgGを使用して、dMFI(「デルタ平均蛍光強度(delta mean fluorescence intensity)」として表し;すなわち、IgGに関するMFIを、所定の表面マーカーに関して取得したMFIから差し引き、dMFIを得た。
同種異系混合リンパ球反応のための細胞を、健康な、非血縁者由来の末梢血のサンプル10mlから得た。レスポンダー(responder)T細胞を得るために、RosetteSep T‐cell enrichment kit(Stemcell Technologies,Vancouver,BC,Canada)をメーカーの説明に従って使用した。濃縮したT細胞(レスポンダー細胞(responder cell))を5μMの5‐(‐6‐)カルボキシフルオレセインジアセテート(CFSE)で、室温で2分間標識した(Invitrogen,Carlsbad,CA)。血清クエンチング及びPBSで3回洗浄後、標識したレスポンダー細胞を、96穴U底プレートのウェル中に、105細胞を含んで、0.1mlの完全リンパ球培地(RPMI(Mediatech,Manassas,VA))+10%FBS(Lonza,Allendale,NJ)中に播種した。
SB623細胞の免疫抑制特性を、また、異種移植モデル系において示した。異種リンパ球反応を、刺激細胞として、Sprague‐Dawleyラットグリア混合細胞(星状膠細胞及び小グリア細胞を含む)、並びにレスポンダー細胞として、メーカーの説明に従ってPKH26で標識した、ヒト末梢血T細胞を使用して確立した。グリア混合細胞を得るために、生後9日目のラットの脳を採取し、そして0.25%トリプシンで処理する前に、30分間粉砕した。細胞懸濁物を、70μMのセルストレーナーを通じて濾過し、そして遠心分離前にFicoll(商標)で覆った。グリア混合細胞を、アッセイにおいて使用する前に、DMEM/F12/10%FBS/pen‐strep中で14日間培養した。異種反応を、5日間にわたって、同種異系MLR(100,000グリア混合細胞:100,000CFSE標識ヒトT細胞;及び任意により、10,000MSC又はSB623細胞)において使用したものと同じ細胞比率を使用して行った。ヒトCD3ゲートT細胞(CD4+及びCD8+T細胞の両方を含む)におけるPKH26希釈を、フローサイトメトリーにより評価した。
調節性T細胞(Tregs)は、免疫反応を弱め又は抑制することができる。従って、Tregsの発生を支持するためのSB623細胞の能力を調べた。この目的を達成するために、実施例2で記載したように精製した、末梢血由来の濃縮T細胞をインターロイキン‐2(IL‐2)の存在下で培養し、そしてそれは、未感作T細胞のTregsへの分化を刺激することを示し、MSC又はSB623細胞との共培養のこのプロセスに対する影響を評価した。共培養物は、T細胞とSB623細胞の比率10:1又はT細胞とMSCの比率10:1(105T細胞:104MSC又はSB623細胞)を含む。表面マーカーCD4及びCD25の共発現、サイトカインインターロイキン‐10(IL‐10)の分泌、及び転写因子FoxP3の分子内産生を、Tregsのためのマーカーとして使用した。
MSC及びSB623細胞の共培養の、T細胞により産生される炎症性及び抗炎症性サイトカインの相対量に対する影響を、ホルボールミリスチン酸アセテート(PMA)及びイオノマイシンでの処理により準最適に活性化したT細胞におけるIL‐10(抗炎症性サイトカイン)及びインターフェロン‐ガンマ(INF‐γ、炎症性サイトカイン)を測定することにより評価した。これらの実験のために、T細胞を末梢血から濃縮して、IL‐2の非存在下で培養を行った以外は、上記のように(実施例6)MSC又はSB623と培養し、又は共培養した。7日目に、25ng/mlの非活性化用量のホルボールミリスチン酸アセテート(PMA)/0.5μMイオノマイシン(Io)(両方ともSigma‐Aldrich,St Louis,MO)を、3μg/mlのブレフェルジンA(eBioscience,San Diego,CA)の存在下、添加し、そして6時間後、細胞を採取し、IL‐10及びIFN‐γの細胞内発現に関して分析した。これらの実験で使用したPMAの非活性化用量及びイオノマイシンは、T細胞増殖を誘導しなかったが、T細胞によるサイトカイン合成を誘導するためには十分であった。IL‐10レベルを、実施例6に記載したように、Alexa488‐コンジュゲート抗ヒトIL‐10抗体(eBioscience,San Diego,CA)を使用して測定した。IFN‐γレベルを、PE‐標識抗ヒトIFN‐γ抗体(eBioscience,San Diego,CA)を使用して、FACSにより測定した。
MSC及びSB623細胞により分泌される公知の2つのサイトカイン、TGFβ‐1及びIL‐6(上記実施例3を参照)は、また、Th17ヘルパーT細胞(すなわち、IL‐17を分泌するヘルパーT細胞)の成長に役割を果たす。従って、T細胞を、Th17ヘルパーT細胞の成長を刺激することが知られている、IL‐23の存在下培養し、そしてMSC又はSB623細胞との共培養のTh17細胞数に対する影響を測定した。
単球(CD14を発現)の樹状細胞(CD1aを発現)への成長の通常の進行は、インターロイキン‐4(IL‐4)及び顆粒球/マクロファージコロニー刺激因子(GM‐CSF)の存在下、単球を培養することにより、インビトロにおいて再現することができる。インビトロにおける単球との共培養の場合、MSCは、単球の樹状細胞への分化を阻止することができ、一部分では、効果は、MSCによるインターロイキン‐6(IL‐6)の分泌により媒介される。Chomaratら、(2000)Nature Immunology 1:510-514; Djouadら、(2007) Stem Cells 25: 2025-2032。米国特許出願公開第2010/0266554号(2010年10月21日)を参照。MSC及びSB623によってまた分泌される、VEGFは、また、樹状細胞分化に関係する。従って、SB623細胞の単球分化に対する影響を調べた。
単球から分化後、樹状細胞は、CD86表面マーカーを発現する細胞へと成熟する。この成熟を、腫瘍壊死因子‐アルファ(TNF‐α)の存在下、樹状細胞を培養することによりインビトロで再現することができる。IL‐6及びVEGFが、樹状細胞の成熟を阻止することを示す。Parkら、(2004) J. Immunol. 173: 3844-3854; Takahashiら、(2004) Cancer Immunol. Immunother 53: 543-550。SB623細胞がこれらのサイトカインの両方を分泌するので、SB623共培養の樹状細胞分化に対する影響を調べた。
CD14細胞表面マーカーを発現するヒト末梢血単球(すなわち、マクロファージ前駆体)を、抗CD14コート磁気ビーズ(Miltenyi Biotec,Auburn,CA)を使用して、磁気選択により軟膜の細胞から得た。CD14+単球の分離培養物を、顆粒球/マクロファージコロニー刺激因子(GM‐CSF)に暴露して、それらをM1(炎症性)マクロファージに転換し;又はマクロファージコロニー刺激因子に暴露して、それらをM2(抗炎症性)マクロファージに転換し;又はSB623細胞又はMSCのいずれかと共培養した。
Claims (32)
- 対象における末梢免疫反応を調節するための免疫抑制細胞を含む組成物であって;ここで前記免疫抑制細胞が以下:
(a)間葉系幹細胞の培養物を用意し;
(b)ステップ(a)の細胞培養物と、Notch細胞内ドメイン(NICD)をコードする配列を含むポリヌクレオチド(前記ポリヌクレオチドが、Notchタンパク質の全長をコードしない)とを接触させ;
(c)ステップ(b)のポリヌクレオチドを含む細胞を選択し;及び
(d)ステップ(c)の選択された細胞を、選択なしでさらに培養すること
により得られ;ここで前記末梢免疫反応の調節が以下:
(i)末梢T細胞活性化の抑制、
(ii)末梢ヘルパーT細胞機能の抑制、
(iii)末梢調節性T細胞(TregS)の集団の拡大、
(iv)炎症性サイトカインの末梢産生の減少、
(v)抗炎症性サイトカインの末梢産生の刺激、
(vi)末梢単球の樹状細胞への分化の阻害、及び
(vii)樹状細胞の成熟の阻害
の1つ以上から選択される、組成物。 - 前記末梢免疫反応が、末梢炎症性反応であり、同種異系移植、虚血又は壊死に起因する、請求項1に記載の組成物。
- 前記末梢免疫反応の調節が、末梢T細胞活性化の抑制及び/又は末梢ヘルパーT細胞機能の抑制である、請求項1に記載の組成物。
- 前記末梢T細胞活性化が、T細胞によるCD69の発現、CD4+T細胞の増殖、及び/又はHLA‐DRの発現を含み;そして前記末梢ヘルパーT細胞機能が、サイトカイン分泌及び/又は関節リウマチの病状に関係する、請求項3に記載の組成物。
- 前記末梢免疫反応の調節が、末梢調節性T細胞(Tregs)の集団の拡大である、請求項1に記載の組成物。
- 前記末梢免疫反応の調節が、炎症性サイトカインの末梢産生の減少である、請求項1に記載の組成物。
- 前記サイトカインが、インターフェロン‐ガンマ(IFN‐γ)であり、及びT細胞によって産生される、請求項6に記載の組成物。
- 前記サイトカインが、腫瘍壊死因子‐アルファ(TNF‐α)であり、及び単球によって産生される、請求項6に記載の組成物。
- 前記末梢免疫反応の調節が、抗炎症性サイトカインの末梢産生の刺激である、請求項1に記載の組成物。
- 前記サイトカインが、インターロイキン‐10(IL‐10)であり、及びヘルパーT細胞、調節性T細胞、又は単球によって産生される、請求項9に記載の組成物。
- 前記末梢免疫反応の調節が、末梢単球の樹状細胞への分化の阻害及び/又は樹状細胞の成熟の阻害である、請求項1に記載の組成物。
- 前記成熟が、前記樹状細胞によるCD86の発現の増加を伴う、請求項11に記載の組成物。
- 移植片対宿主病を減少するための、請求項1に記載の組成物。
- 移植による拒絶反応を阻害するための、請求項1に記載の組成物。
- 末梢自己免疫疾患を処置するための、請求項1に記載の組成物。
- 前記末梢自己免疫疾患が、多発性硬化症、潰瘍性大腸炎、慢性閉塞性肺疾患(COPD)、喘息、狼瘡及び1型糖尿病からなる群から選択される、請求項15に記載の組成物。
- 対象における末梢免疫反応を調節するためのNotch細胞内ドメインを発現している間葉系幹細胞を含む組成物であって、ここで前記末梢免疫反応の調節が、以下:
(i)末梢T細胞活性化の抑制、
(ii)末梢ヘルパーT細胞機能の抑制、
(iii)末梢調節性T細胞(T reg S)の集団の拡大、
(iv)炎症性サイトカインの末梢産生の減少、
(v)抗炎症性サイトカインの末梢産生の刺激、
(vi)末梢単球の樹状細胞への分化の阻害、及び
(vii)樹状細胞の成熟の阻害
の1つ以上から選択される、組成物。 - 前記末梢免疫反応が、末梢炎症性反応であり、同種異系移植、虚血又は壊死に起因する、請求項17に記載の組成物。
- 前記末梢免疫反応の調節が、末梢T細胞活性化の抑制及び/又は末梢ヘルパーT細胞機能の抑制である、請求項17に記載の組成物。
- 前記末梢T細胞活性化が、T細胞によるCD69の発現、CD4 + T細胞の増殖、及び/又はHLA‐DRの発現を含み;そして前記末梢ヘルパーT細胞機能が、サイトカイン分泌及び/又は関節リウマチの病状に関係する、請求項19に記載の組成物。
- 前記末梢免疫反応の調節が、末梢調節性T細胞(T reg s)の集団の拡大である、請求項17に記載の組成物。
- 前記末梢免疫反応の調節が、炎症性サイトカインの末梢産生の減少である、請求項17に記載の組成物。
- 前記サイトカインが、インターフェロン‐ガンマ(IFN‐γ)であり、及びT細胞によって産生される、請求項22に記載の組成物。
- 前記サイトカインが、腫瘍壊死因子‐アルファ(TNF‐α)であり、及び単球によって産生される、請求項22に記載の組成物。
- 前記末梢免疫反応の調節が、抗炎症性サイトカインの末梢産生の刺激である、請求項17に記載の組成物。
- 前記サイトカインが、インターロイキン‐10(IL‐10)であり、及びヘルパーT細胞、調節性T細胞、又は単球によって産生される、請求項25に記載の組成物。
- 前記末梢免疫反応の調節が、末梢単球の樹状細胞への分化の阻害及び/又は樹状細胞の成熟の阻害である、請求項17に記載の組成物。
- 前記成熟が、前記樹状細胞によるCD86の発現の増加を伴う、請求項27に記載の組成物。
- 移植片対宿主病を減少するための、請求項17に記載の組成物。
- 移植による拒絶反応を阻害するための、請求項17に記載の組成物。
- 末梢自己免疫疾患を処置するための、請求項17に記載の組成物。
- 前記末梢自己免疫疾患が、多発性硬化症、潰瘍性大腸炎、慢性閉塞性肺疾患(COPD)、喘息、狼瘡及び1型糖尿病からなる群から選択される、請求項31に記載の組成物。
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