JP2022535881A - 精製されたダブルネガティブt細胞およびその調製と応用 - Google Patents
精製されたダブルネガティブt細胞およびその調製と応用 Download PDFInfo
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Abstract
Description
(a)単核細胞集団(PBMCs)を提供し、選別によってDNT細胞を主とする第1の細胞亜集団を得る段階と、
(b)第1の細胞亜集団からIL-17を分泌するDNT細胞を除去した後、それらを増殖および培養することにより、第2の細胞亜集団を得る段階、または
第1の細胞亜集団を増殖および培養した後、IL-17を分泌するDNT細胞を除去することにより、第2の細胞亜集団を得る段階と、
(c)選択可能に、第2の細胞亜集団内のDNT細胞をさらに選別することにより、第3の細胞亜集団を得る段階と、
(d)第2または第3の細胞亜集団を適切なベクターと混合することにより、本発明の第1の態様に記載の細胞製剤を得る段階とを含む。
好ましくは、グループAは、S100a6、CXCR6、ICOS、CCR2、CD82、CD127、Ltb4rまたはその組み合わせである。
好ましくは、グループBは、Lgals1、Ly6a、CXCR6、S100a6、Lgals3、Lta、ICOS、S100a10、Tnfrsf4、またはその組み合わせである。
コンカナバリンA(ConA)、フィトヘマグルチニン(PHA)、PMA、カルシウムイオノフォア(ionomycin)、IPP、パミドロネート(Pamidronate)、ゾレドロネート(Zoledronate)、CD2抗体または磁気ビーズ標識抗体、CD3抗体または磁気ビーズ標識抗体、CD28抗体または磁気ビーズ標識抗体、またはその組み合わせからなる群から選択される。
(i)喘息に関するアレルゲンポリペプチド、
(ii)1型糖尿病に関するGAD65抗原ペプチドおよびインスリン抗原ペプチド、
(iii)リウマチ性免疫疾患に関するENAポリペプチド、核タンパク質抗原ポリペプチド、細胞質タンパク質抗原ポリペプチド、および
(iv)自己免疫性肝疾患に関するミトコンドリア抗原ペプチドおよび肝抗原ペプチドからなる群から選択される。
DNT細胞、即ち、ダブルネガティブT細胞(Double negative T cells)は、独特の表現型を有するTCRαβ+Tリンパ球の一つであり、CD4、CD8、NK等の細胞の特徴的な表面マーカーを発現せず、免疫系において核心かつ多様な調節的役割を果たす。
本発明において、DNT細胞の精製は、培養および増殖前に、または培養および増殖後に行うことができ、前者は後者よりも抗体の使用量が大幅に少ないため、DNT細胞を培養および増殖させる前に、IL-17分泌DNT細胞を事前に除去することが好ましい。具体的には、二つの精製方法は、次のとおりである。
本発明は、T細胞の増殖を阻害し、および/またはT細胞のアポトーシスを誘導し、腫瘍、感染性疾患、メタボリックシンドローム(肥満、インスリン抵抗、糖尿病、脂肪性肝炎、冠状動脈アテローム性動脈硬化症)、脳卒中、またはその組み合わせからなる群から選択される疾患の治療に使用されることができる、本発明の第1の態様に記載の細胞製剤を含む本発明の第4の態様に記載の医薬組成物をさらに提供する。前記疾患は、アレルギー性喘息、1型糖尿病、紅斑性狼瘡、関節リウマチ、シェーグレン症候群、乾癬、多発性硬化症、自己免疫性肝炎、原発性胆汁性肝硬変和硬化性胆管炎、橋本甲状腺炎、自己免疫性腎症、器官移植拒絶反応、移植片対宿主病、またはその組み合わせをさらに含む。
単細胞シーケンシング
単細胞トランスクリプトームシーケンシング技術により、マウス脾臓のDNT細胞に対して、単細胞レベルの分析を行う。まず、蛍光活性化細胞選別技術(図1を参照する)を使用して、TCRαβ+CD4-CD8-NK1.1-のダブルネガティブT細胞を取得し、CD1dテトラマー抗体染色技術を使用して、1型NKT(αGalcer-CD1dテトラマー抗体陽性)および2型NKT(LPC-CD1dテトラマー抗体陽性)細胞をさらに除去し、次に精製されたnaive DNTに対して、単細胞トランスクリプトームシーケンシング分析を実行して、IL-17を分泌するDNT細胞亜集団が存在するかどうかを検出する。
DNT細胞の精製および有効性の検証
上記発見をさらに証明するために、まずマウスnaive DNTを精製し、即ち、無菌条件下でマウス脾臓を取得し、赤血球を粉砕および溶解した後、単一の脾臓細胞の懸濁液を取得する。CD19、CD4、CD8、TCR-γδ、NK1.1、aGalcer-CD1dおよびLPC-CD1dテトラマー抗体(またはTCRVα24-Jα18抗体)を使用して、マウスの脾臓細胞を標識し、磁気ビーズネガティブ選別によってDNT細胞を主とする細胞亜集団を取得し、同時にS100a6、CXCR6、ICOS、CCR2、CD82、CD127、Ltb4r等の抗体のいずれかを使用して、IL-17を分泌するDNT細胞亜集団を標識する。
精製後のDNT細胞の機能検証
精製後のDNT細胞のインビトロ免疫阻害機能を検証するためである。精製および増殖したDNT細胞を、樹状細胞によって刺激および増殖された同じマウスのTリンパ球と混合および培養する。
抗原特異性を有するDNT細胞の培養
DNTの抗原特異的免疫阻害を研究するために、まずOVAによって誘導されたマウスアレルギー性喘息モデルを初めて構築される。続いて、成熟したマウス樹状細胞および精製されたnaive DNT細胞をインビトロで混合培養する。刺激および増殖したDNT細胞の抗原特異的阻害効果をカンサスするために、培養中にOVA特異的OVA323-339抗原ペプチドを加えるか、またはOVAとは関係の内MOG33-55抗原ペプチドを加える。
ヒトDNT細胞の機能検証
精製されたヒトDNT細胞のインビトロ免疫阻害機能をさらに検証するために、実施例2の方法を使用してヒトDNT細胞を精製および増殖し、それらを樹状細胞(DC)によって刺激および増殖されたTリンパ球を混合培養する。
Claims (10)
- 細胞製剤であって、
前記細胞製剤は、DNT細胞集団を含み、前記DNT細胞集団において、総細胞数の95%以上、好ましくは、98%以上、より好ましくは、99%以上、最も好ましくは、99.9%以上を占める細胞は、IL-17を分泌および発現しないことを特徴とする、前記細胞製剤。 - 前記DNT細胞集団において、総細胞数の95%以上を占める細胞は、表面抗原CD3+およびTCRαβを有することを特徴とする
請求項1に記載の細胞製剤。 - 前記DNT細胞集団において、総細胞数の50%以上を占める細胞は、LAG3遺伝子を高発現することを特徴とする
請求項1に記載の細胞製剤。 - 請求項1に記載の細胞製剤を調製するための方法であって、
前記方法は、
(a)単核細胞集団(PBMCs)を提供し、選別によってDNT細胞を主とする第1の細胞亜集団を得る段階と、
(b)第1の細胞亜集団からIL-17を分泌するDNT細胞を除去した後、それらを増殖および培養することにより、第2の細胞亜集団を得る段階、または
第1の細胞亜集団を増殖および培養した後、IL-17を分泌するDNT細胞を除去することにより、第2の細胞亜集団を得る段階と、
(c)選択可能に、第2の細胞亜集団内のDNT細胞をさらに選別することにより、第3の細胞亜集団を得る段階と、
(d)第2のまたは第3の細胞亜集団を適切なベクターと混合することにより、請求項1に記載の細胞製剤を得る段階とを含むことを特徴とする、前記方法。 - 段階(a)において、単核細胞集団内のB細胞、CD4とCD8 T細胞、γδ T細胞、1型NKTおよび2型NKT細胞を除去することにより、DNT細胞を主とする第1の細胞亜集団を得ることを特徴とする
請求項4に記載の方法。 - 段階(b)において、グループAの発現タンパク質から選択される一つまたは複数の抗体を使用して、培養前にIL-17を分泌するDNT細胞を除去し、ここで、グループAは、S100a6、Tmem176b、CXCR6、Ramp1、Tmem176a、Lgals1、Lgals3、ACTN2、ICOS、CCR2、CD82、CD127(IL7r)、Ltb4r1、Hk2、TNFRSF25、Ly6a、BLK、Lsp1、Ly6e、Itgb7、Itm2b、S100a10、Ly6g5b、Thy1、CD40Ig、Ramp3、Gm2aまたはその組み合わせを含み、
好ましくは、グループAは、S100a6、CXCR6、ICOS、CCR2、CD82、CD127、Ltb4rまたはその組み合わせであることを特徴とする
請求項4に記載の方法。 - 段階(b)において、グループBの発現タンパク質から選択される一つまたは複数の抗体を使用して、培養後にシステムからIL-17を分泌するDNT細胞を除去し、ここで、グループBは、IL-17a、Lgals1、Ly6a、CXCR6、S100a6、Lgals3、Lta、IL-4、IL-3、ICOS、S100a10、Ramp1、Tmem176b、Tnfrsf4、AA467197、Itm2b、Thy1、Igtp、Arl6ip1、Serpine2、Ltb、Tnfrsf25、Furin、Tmem176a、Ifi27l2a、Gbp2、Emp3、Ltb4r1、Tspo、Cst3、Vim、CD200またはその組み合わせを含み、
好ましくは、グループBは、Lgals1、Ly6a、CXCR6、S100a6、Lgals3、Lta、ICOS、S100a10、Tnfrsf4、またはその組み合わせであることを特徴とする
請求項4に記載の方法。 - 段階(b)において、抗原提示細胞および/または抗原ペプチドの存在条件下で増殖培養することを特徴とする
請求項4に記載の方法。 - 請求項1に記載の細胞製剤の用途であって、
医薬組成物の調製に使用され、前記医薬組成物は、
腫瘍、感染性疾患、移植拒絶反応、移植片対宿主病、アレルギー性喘息、自己免疫疾患、メタボリックシンドローム、脳卒中、またはその組み合わせからなる群から選択される疾患の治療に使用されることを特徴とする、前記用途。 - 医薬組成物であって、
前記医薬組成物は、請求項4に記載の方法によって調製された細胞製剤、および薬学的に許容されるベクター、希釈剤または賦形剤を含むことを特徴とする、前記医薬組成物。
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