JP2005514054A - プロフェッショナルおよびサイトカイン産生制御t細胞の誘導のための方法 - Google Patents
プロフェッショナルおよびサイトカイン産生制御t細胞の誘導のための方法 Download PDFInfo
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Abstract
Description
本発明の分野は、一般的に、抑制活性を有するT細胞の誘導に使用される方法に関する。より具体的には、該方法は、強い抑制活性を持つプロフェッショナル制御T細胞およびサイトカイン産生T細胞を生成するために使用される。
上記の目的に従って、本発明は、ex vivo 末梢血液単球細胞(PBMC)の試料において制御T細胞を生成させるのに使用され得る組成物および方法を提供する。そのように生成された制御T細胞は、プロフェッショナルCD4+CD25+制御細胞またはサイトカイン産生制御細胞であり得る。好ましくは、制御細胞の数および抑制活性の両方が増加される。
図1A−Cは、大部分の通常のT細胞(conventional T cell)(2)およびバージンプロフェッショナル(professional)制御T細胞(3)を含むT細胞集団(1)で開始する制御T細胞を生成するための好ましい実施態様を示す。制御組成物を用いる、バージンCD4+CD25+細胞の標的化は、増強された抑制活性を持つ >50%活性化されたプロフェッショナル調節CD4+CD25+T細胞(4)を含む処理されたT細胞集団(6)を生成する。これらの細胞は、強い接触依存性の抑制活性(図1A)を発達させるために誘導されたバージン制御細胞または他のT細胞の子孫であり得る。
本発明は、ex vivoで制御T細胞を生成する方法を目的とする。該方法は、ナイーブT細胞を単離すること、それらを制御組成物で処理することを包含する。制御組成物による処理は、生成された制御T細胞の数および抑制活性を増加させる。この増強された抑制活性は、T細胞の増殖および分化に非常に重要な細胞表面の受容体の誘導により媒介されると考えられる。
成人のヒト免疫系、末梢T細胞において、CD4+およびCD8+の両方は、(a)活性化要件;(b)エフェクター機能(例えば、サイトカイン合成);(c)回帰挙動(homing behavior);(d)接着機能;および(e)細胞表面表現型を含む、多くの相関する機能的および表現型の特徴によって、2つの主なサブセット、ナイーブ対メモリー - エフェクターに分離し得る。未成熟(すなわち、新生児)免疫系において優性であり、大部分の成熟胸腺細胞に類似する推定ナイーブサブセットは、下記態様を示す:(a)リコール抗原にほとんどもしくは全く応答しない;(b)エフェクターシリン(cylines)、例えばインターフェロン-γを産生する能力をほとんどもたないか、もしくは全くもたない;(c)TCR媒介活性化のための高い共刺激要件;(D)MHCに制限された細胞毒性のT細胞中の不十分な成熟;(e)3次部位でなく2次リンパ様組織におけるin vivo局在化に有効;(f)アポトーシスおよび対応するこれらの機能的特徴に対する相対的に低い感受性;(g)高分子量の優性、CD45タンパク質チロシンホスファターゼの低活性RAアイソフォーム;(h)多くの一般的な接着分子、例えば、CD11a/CD18(LFA−1)、CD54(ICAM−1)、CD2、CD58(LFA−3)およびCD44、アポトーシス-トリガー分子のCD95/Faxおよび第3次皮膚選択性回帰受容体CLAの均一な低い発現;(i)末梢リンパ球ヌード回帰受容体L−セレクチンおよび共刺激性分子CD27の均一な高い発現;および(j)パイエル板回帰受容体α4β7インテグリンの均一な穏やかな発現 (Picker and Siegelman, (1999) "Lymphoid Tissue and Organs"in W. E. Paul, ed., Fundamental Immunology, 4th ed., chapter 14, pp 479-531)。
末梢血液単球細胞(PBMC)を、標準技術を用いて、個体の静脈血液をヘパリン化して採取した(参照、Zheng, et al., (2002) J. Immunol., 169: 4183-4189)。本明細書中の「末梢血液単核細胞」または「PBMC」は、リンパ球(T細胞、B細胞、NK細胞などを包含する)および単球を意味する。好ましくは、赤血球を残すか、または患者に戻してPBMCのみを取り出す。当業者には既知のように、例えば、白血球処理(leukophoresis)技術を用いて行う。一般的には、5〜7リットルの白血球処理過程をなし、主にPBMCを患者から除き、残っている血液成分を戻す。細胞試料の回収は、当業者には既知の抗凝集剤、例えばヘパリンの存在下でなすのが好ましい。
一旦単離されたT細胞を、制御組成物で処理し、増強された抑制活性を持った活性化された制御T細胞を生成する。本明細書中の「制御T細胞」は、他のT細胞における細胞毒性のT細胞活性を防止し、抗体産生を阻害し、遅延型高感受性応答を抑制し、単球または樹状細胞または抗原提示細胞としてのB細胞機能を阻害する能力を発展させるCD8+またはCD4+T細胞サブセットを意味する。上記で検討したように、いくつかの制御T細胞サブセットが存在する。これらのT細胞サブセットは、2つのカテゴリーに広く分けられる:(1)プロフェッショナル制御T細胞;および(2)サイトカイン産生制御細胞。
抑制活性を持つT細胞が生成されたらすぐに、患者において免疫応答を緩和するために投与し得る。本明細書中で「免疫応答」は、外来または自己の抗原に対する宿主応答を意味する。好ましくは、抑制活性を持つT細胞は、外来抗原への異常型免疫応答または望ましくない免疫応答を防止するのに使用し得る。本明細書中「異常型免疫応答」は、自己と非自己を区別する免疫系の機能不全、または外来抗原への応答に対する機能不全を意味する。言い換えると、異常型免疫応答は、患者の症候に導く不適当に制御された免疫応答である。本明細書中の「不適当な制御」は、不適当な誘導、不適当な抑制および/または応答性がないことを意味する。異常型免疫応答には、下記に限定するものではないが、組織損傷および生物自身の組織についての抗体産生によって生じる炎症、IL−2、TNF−αおよびIFN−γの産生の阻害および細胞毒性または非細胞毒性作用のメカニズムによって生じる組織損傷が含まれる。本明細書中で「望ましくない免疫応答」は、移植患者において観察される外来抗原に対する応答を意味する。すなわち、望ましくない免疫応答には、GVHDおよび移植拒絶反応と関連した応答を包含する。
ある態様において、抗体媒介不全は処理されない。
好ましい実施態様において、本発明は、本発明の方法、すなわち制御組成物と細胞とのインキュベーションを実施するためのキットをさらに提供する。該キットは、多数の成分を有している。例えば、該キットは、抗体媒介または細胞媒介の自己免疫疾患を有する患者からの受容細胞に適応する細胞処理容器を含んでもよい。容器は、滅菌であるべきである。ある実施態様において、細胞処理容器は、細胞の回収に用いる。例えば、入り口部分を用いて白血球処理機までつなげられるように用いうる。別の態様において、分離細胞回収容器を用い得る。
CD4+およびCD8+T細胞に対するTGF-βの共刺激の効果
CD4+およびCD8+細胞の増殖に対する効果
図1に示すように、TGF-βによる共刺激は、全CD4+CD25+およびCD4+CD25−細胞のパーセンテージおよび絶対数を著しく増加する。しかし、CD4+CD25−細胞の増加は、CD4+CD25+サブセットに依存し、CD4+CD25+サブセットの枯渇はTGF-βの成長促進効果を消失させる。同様に、小さい効果をCD8+細胞で観察した。
図2Aおよび2Bは、CD4+サブセットに対する同種(異型)混合リンパ球反応におけるTGF-βによる刺激後の細胞表面マーカーの発現を示す。全CD4+細胞、CD25枯渇のCD4+細胞、およびナイーブCD45RA+CD45RO−細胞を試験した。全CD4+細胞およびナイーブ細胞上の発現CD25に対するTGF-βの用量依存効果を観察した。開始集団におけるCD25の枯渇はこの効果を消滅させた。すなわち、TGF-βが、CD4+細胞のCD4+CD25+サブセットを増殖することがわかった。
図3A−Dは、様々なCD4+T細胞サブセットによって抑制活性を誘導する際にTGF-βの効果を示す。これらの実験において、精製されたCD4+T細胞サブセットを、細胞選別によって得、上記の混合リンパ球反応(MLR)においてTGF-β(1ng/ml)で調節した。次いで、精製されたCD4+サブセットを、T細胞の細胞毒性の生成を阻害し得る能力について試験した。図3AおよびBは、精製したCD4+CD25+T細胞が、顕著な抑制活性を持ち、この活性は顕著に増加するということ、すなわちTGF-βによる調節によって増強することを示す。図3Cおよび3Dは、TGF-βが同様の効果を有すること、すなわち他のT細胞サブセット:CD45RA+CD45RO−CD25-およびCD45RA−CD45RO+CD4+細胞のサブセットに対する抑制活性を顕著に増加すること示す。IL−2の添加は、抑制活性に関するこの増強を必要としなかった。
Claims (15)
- 通常のT細胞およびプロフェッショナル制御T細胞を含むCD4+T細胞の集団を、
CD4+T細胞の該集団において、抑制活性を有するプロフェッショナル制御T細胞の数を増やすのに十分な時間、
(i)少なくとも1つのサイトカイン;
(ii)少なくとも1つのT細胞アクチベーター;および
(iii)少なくとも1つの非Tアクセサリー細胞集団、
を含む制御組成物で処理することを含む、制御T細胞を生成する方法。 - CD4+T細胞の該集団がナイーブCD4+T細胞集団である、請求項1記載の方法。
- 増強された抑制活性を有する活性化された制御T細胞を生成する、請求項1記載の方法。
- a)通常のT細胞を、
サイトカイン産生制御T細胞の集団を生成するのに十分な時間、
(i)少なくとも1つのサイトカイン;
(ii)少なくとも1つのT細胞アクチベーター;および
(iii)少なくとも1つの非TアクセサリーT細胞集団
を含む制御組成物で処理すること、
を含む、制御T細胞を生成する方法。 - CD4+T細胞の該集団がナイーブCD4+T細胞集団である、請求項4記載の方法。
- 増強された抑制活性を有する活性化された制御T細胞を生成する、請求項4記載の方法。
- 制御T細胞の表面上のCD122の発現を誘導するための方法であって、通常のT細胞およびプロフェッショナル制御T細胞を含むCD4+T細胞集団を、それらの表面上のCD122マーカーを発現する制御T細胞を生成するのに十分な時間、
(i)少なくとも1つのサイトカイン;
(ii)少なくとも1つのT細胞アクチベーター;および
(iii)少なくとも1つの非Tアクセサリー細胞集団、
を含む制御組成物で、処理することを含む方法。 - a)活性化されたプロフェッショナル制御T細胞および通常のT細胞を含むCD4+T細胞集団をつくること;そして、
b)少なくとも1つのT細胞アクチベーターを、プロフェッショナル制御T細胞およびサイトカイン産生制御T細胞を含む制御細胞集団を生成するのに十分な時間、該CD4+T細胞集団に加えること、
を含む、制御T細胞を生成する方法。 - CD4+T細胞の該集団がナイーブCD4+T細胞集団である、請求項8の方法。
- 増強された抑制活性を持つ活性化された制御T細胞を生成する、請求項8記載の方法。
- 該サイトカインがTGF-β、IL−2、IL−15およびTNFαからなる群から選択される、請求項1−7のいずれかに記載の方法。
- 該T細胞アクチベーターが、可溶性抗原、抗原のペプチドフラグメント、アロ抗原、抗CD2、抗CD3、抗CD28およびLFA-3およびブドウ状球菌エンテロトキシンB(SEB)からなる群から選択される、請求項1−10に記載の方法。
- 該制御組成物が、B細胞、マクロファージ、単球および樹状細胞からなる群から選択される非Tアクセサリー細胞の少なくとも1つの集団をさらに含む、請求項1−7記載の方法。
- 望ましくない免疫応答を示すレシピエントに、該制御T細胞を投与することをさらに含む、請求項1−13に記載の方法。
- 該制御T細胞を、異常型免疫応答を示すレシピエントに投与することをさらに含む、請求項1−13のいずれかに記載の方法。
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