JP2013523886A - 制御性t細胞の阻害のための方法および組成物 - Google Patents
制御性t細胞の阻害のための方法および組成物 Download PDFInfo
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Abstract
Description
癌免疫療法の主な目的は、先天性免疫反応と適応性免疫反応の活性化により腫瘍の排除を促進することであり、免疫寛容メカニズムを克服すると同時に腫瘍特異的リンパ球を誘導する二重の能力を付与されたワクチン接種戦略の進展に依存する。癌免疫療法の使用は、適切に設計された癌ワクチンで腫瘍排除、及び長期寛解を潜在的にもたらすことができる。悪性細胞を標的化し正常細胞を回避するという免疫療法における特異性はまた、最小限の毒性につながることもできる。
[概要]
一態様では、本発明は、患者における疾患の免疫寛容を抑制する方法に関する。本方法は、同種異系Th1細胞を含む治療用組成物を患者に投与することによりTreg細胞の免疫抑制活性を低減することを含み、Treg細胞の活性を低減および/または阻害することは、患者における疾患抗原の免疫寛容を低下させる。
本発明は、疾患抗原の免疫寛容を抑制すること、及び/又は患者における腫瘍免疫回避メカニズムを無効にする方法を含む。また、本方法は、疾患抗原に対する免疫、特にTh1免疫を刺激することも含む。免疫寛容の抑制と抗疾患抗原免疫の刺激との両方は、疾患抗原源及び同種異系Th1細胞、好ましくはアジュバントとしての活性化された同種異系Th1細胞を含む治療用組成物の投与により発生されることができる。一般的に、同種異系Th1細胞は、活性化したエフェクター/メモリーTh1(emTh−1)細胞である。また、この治療用組成物は、疾患関連抗原及び/又は疾患関連抗原を含有する可溶化物、好ましくはシャペロンリッチ細胞可溶化物(CRCL)等の疾患組織から単離されたシャペロンタンパク質の混合物、も含むことができる
本発明において、免疫寛容の抑制方法は、Treg細胞の抑制活性を弱めることを含むことができる。本方法は、ナイーブT細胞(CD4+CD25−FoxP3−)から、本願においてiTregと称されるTreg細胞(CD4+CD25−FoxP3+)への転換を阻害することができる。自然発生のTreg(nTreg)細胞とiTreg細胞との両方の抑制活性を、低下または排除することができる。本発明の方法は、有利には、Tregの免疫抑制活性を阻害すると同時に、患者における通常のエフェクターTリンパ球の機能を促進する。治療用組成物のTregへの阻害活性は、IFN−γに依存し、IFN−γは、好ましい組成物において宿主先天性免疫細胞と宿主適応性免疫細胞からIFN−γの生成を次には増加するemTh1細胞によって生成される。
[実施例]
材料および方法
マウス−特定病原体を含まない条件下でマウスを収容し、アリゾナ大学動物実験委員会(University of Arizona Institutional Animal Care and Use Committee)のガイドラインに従って飼育した。国立がん研究所(メリーランド州ベセスダ)から、メスのBALB/c(H2d)、C57BL6(H2b)、重症複合免疫不全症SCID(H2d)およびNude(H2d)マウスを入手した。ジャクソン免疫研究所(Jackson Immunoresearch Laboratories)(カリフォルニア州サクラメント)から、IFN−γ−受容体-/-(H2d)マウスを購入した。ジャクソン免疫研究所から、内因性プロモーターの制御下で緑色蛍光タンパク質(GFP)とFoxP3を共発現するFoxP3−EGFP(H2d)マウスを入手した。GFP発現は、FoxP3+Tregの正確な同定および単離を可能にする。ジャクソン免疫研究所から、コンジェニックThy1.1マウス(Cby.PL(B6)−Thy1a/ScrJ)を入手した。これらの動物は、Tリンパ球特異的Thy1.1対立遺伝子を持っている。Thy1.2マウスからのドナーT細胞は、抗=Thy1.2抗体を用いて、レシピエントThy1.1マウスT細胞と区別されることができる。6〜8週齢のマウスを使用した。
[0070] ELISAによるサイトカイン生成の検出−取扱説明書(イーバイオサイエンス(eBiosciences))に従って、酵素結合免疫吸着法(ELISA)キットを使用し、細胞培養物上清中のIFN−γおよびTNF−αの濃度を決定した。
図2A〜2Gのデータは、TGF−βに誘発された、ナイーブT細胞のFoxP3+Tリンパ球への転換を、emTh−1上清が有意に阻害したことを示す(図2Aおよび図2B)。さらに、活性化エフェクター(CD25+FoxP3-)細胞数は、同種異系emTh−1上清により補完された(図2C)。効果は投与量に依存して見られた(図2E)。FoxP3EGFP−トランスジェニックマウスから単離されたナイーブCD4+CD25-FoxP3-T細胞の、TGF−βに誘発された転換が、emTh−1上清の存在下又は不存在下にて行われた。次に、GFP陽性(即ち、FoxP3発現)細胞を選別し、GFP陽性(即ち、FoxP3発現)細胞の抑制活性を評価した。その結果、これらの残留FoxP3発現iTregの機能を弱めることが実証された(図2F)。加えて、すでに転換されたFoxP3+iTregに添加されたemTh−1上清は、その免疫抑制機能を有意に弱めた(図2G)。
Claims (43)
- 患者における疾患の免疫寛容を抑制する方法であって、前記方法は、
同種異系Th1細胞を含む治療用組成物を患者に投与することにより、Treg細胞の免疫抑制活性を低減することを含み、
前記Treg細胞の活性を低減および/または阻害することは、前記患者における疾患抗原の免疫寛容を低下させる、方法。 - 前記Treg細胞はCD4+CD25+FoxP3+である請求項1に記載の方法。
- 前記Treg細胞の抑制活性は、ナイーブT細胞(CD4CD25−FoxP3−)のiTreg細胞への転換を低減することにより阻害される請求項1に記載の方法。
- 前記Treg細胞の抑制活性は、nTreg細胞の阻害によることである請求項1に記載の方法。
- 前記治療用組成物は同種異系emTh−1細胞を含む請求項1に記載の方法。
- 前記治療用組成物は、疾患抗原または前記疾患抗原と関連する可溶化物をさらに含む請求項1に記載の方法。
- 前記治療用組成物は、前記疾患抗原のシャペロンリッチ細胞可溶化物をさらに含む請求項6に記載の方法。
- 前記治療用組成物はIFN−γをさらに含む請求項1に記載の方法。
- 前記治療用組成物は、TGF−βの活性と相互作用して前記TGF−βの活性を低下させる成分をさらに含む請求項1に記載の方法。
- 前記治療用組成物はCD40Lをさらに含む請求項1に記載の方法。
- 前記疾患は癌である請求項1に記載の方法。
- 前記疾患は感染症である請求項1に記載の方法。
- 患者における治療免疫効果を刺激する方法であって、前記方法は、
同種異系Th1細胞を含む治療用組成物を患者に投与することにより、Treg細胞の免疫抑制活性を低減することを含み、
前記Treg細胞の活性を低減および/または阻害することは、前記患者における疾患に対する治療効果を誘発する、方法。 - 前記Treg細胞はCD4+CD25+FoxP3+である請求項13に記載の方法。
- 前記Treg細胞の抑制活性は、ナイーブT細胞(CD4CD25−FoxP3−)のiTreg細胞への転換を低減することにより阻害される請求項13に記載の方法。
- 前記Treg細胞の抑制活性は、nTreg細胞の阻害によることである請求項13に記載の方法。
- 前記治療用組成物は同種異系emTh−1細胞を含む請求項13に記載の方法。
- 前記治療用組成物は、疾患抗原または前記疾患抗原と関連する可溶化物をさらに含む請求項13に記載の方法。
- 前記治療用組成物は、前記疾患抗原のシャペロンリッチ細胞可溶化物をさらに含む請求項18に記載の方法。
- 前記治療用組成物はIFN−γをさらに含む請求項13に記載の方法。
- 前記治療用組成物は、TGF−βの活性と相互作用して前記TGF−βの活性を低下させる成分をさらに含む請求項13に記載の方法。
- 前記治療用組成物はCD40Lをさらに含む請求項13に記載の方法。
- 前記疾患は癌である請求項13に記載の方法。
- 前記疾患は感染症である請求項13に記載の方法。
- 前記治療効果は、エフェクター−T細胞の抗腫瘍機能を促進すること、前記疾患抗原の免疫寛容の抑制することを含む請求項13に記載の方法。
- 患者における免疫抑制機能を弱める方法であって、前記方法は、
同種異系Th1細胞を含む治療用組成物を患者に投与することにより、Treg細胞の免疫抑制活性を低減することを含み、
前記Treg細胞の活性を低減および/または阻害することは、前記患者における免疫抑制機能を低下させる、方法。 - 前記Treg細胞はCD4+CD25+FoxP3+である請求項26に記載の方法。
- 前記Treg細胞の抑制活性は、ナイーブT細胞(CD4CD25−FoxP3−)のiTreg細胞への転換を低減することにより阻害される請求項26に記載の方法。
- 前記Treg細胞の抑制活性は、nTreg細胞の阻害によることである請求項26に記載の方法。
- 前記治療用組成物は同種異系emTh−1細胞を含む請求項26に記載の方法。
- 前記治療用組成物は、疾患抗原または前記疾患抗原と関連する可溶化物をさらに含む請求項26に記載の方法。
- 前記治療用組成物は、前記疾患抗原のシャペロンリッチ細胞可溶化物をさらに含む請求項31に記載の方法。
- 前記治療用組成物はIFN−γをさらに含む請求項26に記載の方法。
- 前記治療用組成物は、TGF−βの活性と相互作用して前記TGF−βの活性を低下させる成分をさらに含む請求項26に記載の方法。
- 前記治療用組成物はCD40Lをさらに含む請求項26に記載の方法。
- 前記疾患は癌である請求項26に記載の方法。
- 疾病患者における免疫寛容を抑制し治療効果を促進する方法であって、前記方法は、活性化Th1細胞と疾患抗原源を投与することを含み、前記Th1細胞と前記疾患抗原は同一箇所に投与される方法。
- 前記Th1細胞と前記疾患抗原は皮内注射によって投与される請求項37に記載の方法。
- 前記活性化Th1細胞は前記疾患抗原源の前に投与される請求項37に記載の方法。
- 前記Th1細胞は同種異系emTh−1細胞である請求項37に記載の方法。
- 前記疾患抗原源はCRCLである請求項37に記載の方法。
- 前記Th1細胞と前記疾病抗原源は、前記患者が治療効果を示すまで、少なくとも3回、約3〜10日の間隔をおいて投与される請求項37に記載の方法。
- 疾患抗原源とアジュバントを含む組成物であって、前記疾患抗原はシャペロンタンパク質内に含有され、前記アジュバントは活性化同種異系Th1細胞を含む組成物。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |