JP4256431B2 - 移植片−対−宿主疾患を抑制するサイトカイン、細胞およびマイトジェンの使用 - Google Patents
移植片−対−宿主疾患を抑制するサイトカイン、細胞およびマイトジェンの使用 Download PDFInfo
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Description
臓器移植はいまヒトの生活の質を高めるため大成功裏に利用されている。実質的な進歩は非近縁個体からの腎臓、心臓および肝臓を用いてなされてきた。しかし、非近縁(あるいは同種異型)のドナーから造血幹細胞の移植はより複雑な努力が必要である。あらゆる造血要素と免疫系を再生する能力をもつ多能性幹細胞が、ひとつの個体由来の骨髄や末梢血液から採取され、別の個体に移植される。しかし、ドナーとレシピエント間の組織適合性の相違が高頻度で移植関連の合併症を来たし、さらに臓器移植法の利用を制限してきた(Forman et al., Blackwell Scientific Publications 1994)。
ここに概略する目的のように、本発明は、生体外の末梢血単核細胞 (PBMC)サンプル中のT細胞寛容を誘発する方法であって、細胞に阻害誘発組成物を添加することを含む方法を提供する。阻害誘発組成物は、IL−2、IL−10、TGF−βまたはそれらの混合物であり得る。
図1Aおよび1Bは、TGF−βがT細胞上でCD40リガンド(CD40L)の発現を上方調節し得ることを示す。精製T細胞をPMA(20ng/ml)およびイオノマイシン(5μM)でTGF−βの存在または不存在下に刺激した。6時間後に細胞を抗CD40L抗体で染色した。TGF−βの不存在で30%の陽性細胞があった(実線、パネルA)。100pg/mlのTGF−βでもって、66%の細胞が陽性であった(実線、パネルB)。両パネルの破線は対照抗体の活性を示す。
本発明は、生命に危険性のある移植片−対−宿主疾患を防ぐ方法を用いて、種々の悪性または遺伝性疾患のヒトに、組織不適合性幹細胞を移転することを可能にする。これは、ドナー細胞を同種異型抗原および/またはサイトカインの併用で生体外で処置することを伴う。この方法の特に優れた点は、幹細胞移植を容易にし、かついかなる残存の悪性細胞を攻撃する力を有するドナーT細胞を除去しないでよいことである。ドナーと宿主間の寛容状態が達成されると、非処置ドナーT細胞を移転して、好ましい移植片−対−腫瘍の免疫応答を最大にできる。
好ましい実施態様において、阻害誘発組成物はTGF−βを含むサイトカインの混合物を含有する。
などのマイトジェンをサイトカイン受容体発現の促進に用いるとき、既知方法で知られているように、その濃度範囲は1μg/mlから約10μg/mlである。さらに、既知方法のように、マイトジェンを離す成分、例えばα−メチルマンノシッドと共に細胞を洗うのが望ましい。
好ましい実施態様において、移植の前に全または活性TGF−βの量を検査する。本明細書で述べるように、TGF−βは、翻訳後に活性化される潜在性前駆体としてつくられている。
処置は必要に応じて繰り返し得る。ある期間後に、白血病性細胞が再び現れることがある。ドナー白血球がすでにレシピエント細胞に寛容であるので、白血病性細胞を異物として認識して殺す非処理ドナーリンパ球の注入を、患者は受けることになる。
ある実施態様において、キットはその使用に際しての説明書を追加的に含む。
個体の血液細胞に対する免疫攻撃についてのドナーCD8+細胞の処置
ドナーから血液サンプルを得て、密度勾配遠心法によりリンパ球を得た。T細胞は通常の陰性選別法を用いて調整した。該T細胞はレシピエント細胞を攻撃しないよう調整した。この調整のため、レシピエント由来の照射スティムレーター細胞にCD8+T細胞を混合した。該スティムレーター細胞はレシピエント由来のT細胞依存性血液細胞から誘導した。ドナーT細胞とレシピエントのスティムレーター細胞との混合物を異なる濃度で一種以上のサイトカインと48時間培養した。実施例で用いたサイトカインはTGF−βおよびIL−10であった。この方法は、レシピエント細胞を殺すドナーT細胞の能力を無くした(図4B)。
他のドナーT細胞が非近縁個体由来の血液細胞に対して免疫攻撃するのを防ぐための、生体外ドナーCD8+T細胞の処置(すなわちGVHDの阻止)
CD8+細胞は、非近縁のドナー細胞に対する個体の細胞毒性免疫応答を抑制するためTGF−βによって調整できる。この方法でドナーBの組織適合性不適合の血液単核細胞に対するドナーAの細胞毒性活性を評価できる。抑制細胞を生起させるため、ドナーA由来の精製CD8+細胞は、加えたTGF−βとドナー細胞由来の照射T細胞除去の単核細胞と培養した。別にドナーB細胞に対するドナーAのT細胞の細胞毒性活性を文献的に立証した。図5は、ドナーA由来のTGF−βで調整したCD8+T細胞の添加が細胞毒性活性を減弱させたことを示す。対照のCD8+細胞の添加では最少の作用であった。これらの実験で、ドナーA由来のCD8+T細胞は、ドナーBによって表示される外来抗原により活性化した。追加のIL−2の必要は無かった。これらの実験で明らかになったことは、TGF−βはCD8+T細胞を誘発して抗体の生産を抑制するのみならず、CD8+細胞も誘発して細胞仲介の免疫応答を抑制することである。
慢性骨髄性白血病患者の組織不適合性ドナー由来幹細胞による処置:マイトジェンによる寛容化
実施例1と同様に、採取したドナーの末梢血単核細胞(PBMC)を滅菌容器中のハンクス緩衝塩類溶液(HBBS)に入れる。ついで該細胞をマイトジェンとインキュベートしてレシピエントの組織適合性抗原に不応答となるようリンパ球を誘発させる。この場合、細胞は標準のインキュベーション技術を用いて4ないし72時間、生理的濃度のコンカナバリンA(ConA)と培養する。用いるConAの濃度は、好ましくは1μg/mlであるが、約0.01から約10μg/mlの範囲で変え得る。また別に、0.001から100ng/mlの濃度でブドウ球菌性エンテロトキシンB(SEB)をマイトジェンとして用いてもよい。
慢性骨髄性白血病患者の組織不適合性ドナー由来幹細胞による処置:TGF−βの生産を誘発するための抗CD2モノクロナール抗体の使用
ドナー由来の、採取した幹細胞の豊富な調製物を実施例1と同様に滅菌容器中のHBBSに入れる。ついで該細胞を抗CD2モノクローナル抗体とインキュベートしてレシピエントの組織適合性抗原に不応答となるようリンパ球を誘発させる。この場合、細胞は標準の培養技術を用いて4ないし72時間、抗CD2モノクロナール抗体とインキュベートする。抗CD2モノクロナール抗体の濃度は10ng/mlないし10μg/mlである。IL−2の1−1000単位を随意に加えることができる。
慢性骨髄性白血病患者の組織不適合性ドナー由来幹細胞による処置:マイトジェンおよびサイトカインによる寛容化
採取したドナーのPBMCを、実施例1と同様に滅菌容器中のHBBSに入れる。ついで該細胞をサイトカインおよびマイトジェンとインキュベートしてレシピエントの組織適合性抗原に不応答となるようリンパ球を誘発する。この場合、細胞は標準のインキュベーション技術を用いて、生理的濃度のConAまたはSEB、TGE−β、および/またはIL−2、IL−4またはIL−15と4時間ないし72時間インキュベートする。
慢性骨髄性白血病患者の組織不適合性ドナー由来幹細胞による処置:マイトジェンおよびサイトカインによる寛容化
精製CD8+細胞に対するTGF−βの作用
CD8+のTGF−βよる処置は、少なくとも三様にCD8+細胞に作用する。まず、TGF−βの存在下、T細胞のPMA(20ng/ml)およびイオノマイシン(5μM)による処置は、CD40リガンドの発現を上方調節する(図1)。第2に、IL−2発現はTGF−βの存在下にConAで刺激されたT細胞で高い(図3)。第3に、精製CD8+細胞をConA(5μg/ml)±TGF−β(10pg/ml)±IL−2(10U)で24時間刺激すると、TGF−βはCD8+細胞によるTNF−α発現を増加する(図2)。
免疫攻撃を阻止するための生体外CD4+細胞の処置
調節性T細胞を誘発するマイトジェンの代わりに、同種異型の混合リンパ球反応を当目的に用いる。該反応において、ドナーA由来のT細胞は、ドナーB由来のPBMCにより表示された外来の組織適合性抗原を確認し、それに応答する。この応答T細胞は、ドナーB細胞を殺す能力を増殖し発展さす。
CD4+T細胞を刺激して、TGF−βの免疫抑制レベルをつくり得る
TGF−βの免疫抑制レベルをつくるCD4+T細胞はTh3細胞と名づけられているが、その生起に関わるメカニズムはほとんど知られていない。我々は、スーパー抗原、ブドウ球菌性エンテロトキシンB(SEB)によるCD4+細胞の強い刺激、または低濃度のSEBによるCD4+細胞の反復刺激がこれらの細胞を誘発してTGF−βの免疫抑制レベルをつくるとの確証を得た。
幹細胞の移植後にGVHDを引き起こした慢性骨髄性白血病患者の処置
幹細胞の移植に伴う初期または後期GVHDを予防する最初の方法が成功しなかった場合に、サプレッサー細胞になるよう調整したドナーT細胞を大量移転することにより、GVHDを処置できる。白血球除去法により得た約1×109のPBMCを、滅菌したロイコパック、すなわちハンクス緩衝塩類溶液(HBBS)中で濃縮する。PBMCは、適当なモノクロナール抗体で被膜した磁性ビーズによってCD4+とCD8+に分離する。細胞を望ましいT細胞アクチベーターおよび阻害誘発組成物と最適時間処置し、最大の調節性活性を発揮させる。該細胞を増量し、レシピエントに移転する。調整したこのT細胞はリンパ器官に移行しGVHDを抑制する。
Claims (10)
- 末梢血単球細胞(PBMC)中のT細胞の寛容を誘導するための生体外の方法であって、ドナーPBMCと、TGF−βおよびIL−2を含む抑制組成物ならびに照射したレシピエントPBMCとを十分な時間接触させて、ドナーPBMCにおいてレシピエント組織に対するT細胞の寛容を誘導させることを含み、ドナーとレシピエントが別個体である、方法。
- 該ドナー細胞がCD8+細胞に富む、請求項1の方法。
- 該ドナー細胞がCD4+細胞に富む、請求項1の方法。
- 該方法が、医薬組成物として、T細胞の寛容を獲得したドナーPBMCを製剤することをさらに含む、請求項1−3のいずれかに記載の方法。
- ドナー幹細胞が、医薬組成物の使用前に該医薬組成物に添加される、請求項4記載の方法。
- 照射したレシピエントPBMCおよび該抑制組成物の接触後のドナーPBMCを、レシピエントへ移植することにより、該ドナー由来の移植片によりレシピエント組織の寛容を生じさせるものである、請求項1記載の方法。
- ドナーPBMCにおけるレシピエント組織に対するT細胞の寛容を誘導するためのキットであって、該ドナーとレシピエントが別個体であり、
a)ドナー由来の細胞を受容するのに適した細胞処置容器、
b)TGF−βおよびIL−2を含む、少なくとも1用量の抑制組成物;
c)少なくとも1つのT細胞アクチベーター、ここで該T細胞アクチベーターが照射したレシピエントPBMCである;および
d)ドナー細胞にCD4+またはCD8+T細胞を富化せしめるための少なくとも1つのモノクローナル抗体、
を含むキット。 - 該用量が該細胞処置容器中に含まれている、請求項7のキット。
- 該キットが、複数用量の抑制組成物をさらに含む、請求項7−8いずれかに記載のキット。
- 該細胞処理容器が少なくとも1つの出入口を含む、請求項7−9いずれかに記載のキット。
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