JP6732987B2 - ヒト化m−csfマウス - Google Patents
ヒト化m−csfマウス Download PDFInfo
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- JP6732987B2 JP6732987B2 JP2019059688A JP2019059688A JP6732987B2 JP 6732987 B2 JP6732987 B2 JP 6732987B2 JP 2019059688 A JP2019059688 A JP 2019059688A JP 2019059688 A JP2019059688 A JP 2019059688A JP 6732987 B2 JP6732987 B2 JP 6732987B2
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Description
本発明は、ヒトM-CSFタンパク質をコードする遺伝子を含む遺伝子改変マウス、およびヒト造血細胞の生着を支持するさらなる改変を含むマウスに関する。
ヒト疾患を調べるための動物モデルの開発により、癌を含むいくつかの疾患の基礎となる機序の理解は有意に前進した。今日まで、動物モデル、特にマウスは、薬物および治療選択肢の有効性および効能の評価のための優れた候補であることが証明されている。ヒトの生物学および疾患を研究するためにこれらの代用モデルを利用することは、十分に正当化することができるが(ヒトにおける実験的治療の実施に対する倫理的および技術的制約により)、マウスのデータをヒトに外挿する場合には限度がありうることが研究により強調されている(Mestas J, Hughes CC. (2004) Of mice and not men: differences between mouse and human immunology. J Immunol. 172:2731-2738(非特許文献1))。
ヒトM-CSFタンパク質をコードする核酸配列を含む遺伝子改変マウスを提供する。同様に、ヒト造血細胞等のヒト細胞が生着しているヒトM-CSFタンパク質をコードする核酸配列を含む遺伝子改変マウス、およびそのような生着マウスを作製する方法を提供する。これらのマウスは、ヒト免疫疾患および病原体感染症のモデルの作製;たとえば健康な状態または疾患状態で造血細胞の発達および/または活性を調整する物質に関するインビボスクリーニング;造血細胞に対して毒性である物質に関するインビボスクリーニング;造血細胞に対する毒性物質の毒性効果を防ぐ、緩和する、または逆転させる物質に関するインビボスクリーニング;疾患の治療に対する個体の反応性を予測するための個体のヒト造血細胞のインビボスクリーニング等の多数の応用において有用である。
[本発明1001]
ヒトM-CSFタンパク質をコードし、かつマウスM-CSF遺伝子のプロモーターに機能的に連結されている核酸配列を含む、ヒト化M-CSFマウス。
[本発明1002]
前記核酸配列を2コピー含む、本発明1001のヒト化M-CSFマウス。
[本発明1003]
前記核酸配列が、マウスM-CSF座で内因性のマウスM-CSFプロモーターに機能的に連結されている、本発明1001のヒト化M-CSFマウス。
[本発明1004]
少なくとも1つのマウスM-CSF対立遺伝子においてヌル変異を含む、本発明1001のヒト化M-CSFマウス。
[本発明1005]
ヌル変異がマウスM-CSFエキソン2〜9の欠失である、本発明1004のヒト化M-CSFマウス。
[本発明1006]
Rag2に関してホモ接合ヌルである、本発明1001のヒト化M-CSFマウス。
[本発明1007]
IL2rgに関してホモ接合ヌルである、本発明1006のヒト化M-CSFマウス。
[本発明1008]
ヒト細胞を含む、本発明1001のヒト化M-CSFマウス。
[本発明1009]
前記ヒト細胞が造血細胞である、本発明1008のヒト化M-CSFマウス。
[本発明1010]
ヒト病原体による感染症を含む、本発明1009のヒト化M-CSFマウス。
[本発明1011]
Rag2における2個のヌル変異;
IL2rgにおける2個のヌル変異;
マウスM-CSF遺伝子のプロモーターに機能的に連結された、ヒトM-CSFタンパク質をコードする核酸配列;および
ヒト造血細胞
を含む、ヒト造血系のマウスモデル。
[本発明1012]
前記核酸配列が、マウスM-CSF座で内因性のマウスM-CSFプロモーターに機能的に連結されている、本発明1011のマウスモデル。
[本発明1013]
マウスM-CSFに関してヌル欠失を含む、本発明1011のマウスモデル。
[本発明1014]
a.野生型マウスにおけるマウスM-CSFの発現と同等のレベルで、骨髄、脾臓、血液、肝臓、脳、肺、精巣、および腎臓においてヒトM-CSFを発現すること;
b.hM-CSFを発現しない細胞生着マウスにおけるhCD14+CD33+より2倍から6倍高い脾臓のhCD14+CD33+細胞の出現率を示すこと;
c.hM-CSFを発現しない細胞生着マウスにおけるhCD14+CD33+より2倍から8倍高い末梢血のhCD14+CD33+細胞の出現率を示すこと;
d.約15%から約40%のhCD14+CD33+単球/マクロファージ系列細胞の血中レベルを示すこと;
e.約20週齢で約5%から約15%のhCD14+CD33+単球/マクロファージ系列細胞の血中レベルを示すこと;
f.ヒトM-CSFを欠如しているマウスより肝臓においてhCD14+CD33+細胞のパーセンテージに関して約1.5倍から約6倍大きい、LPS注射に対する反応を示すこと;
g.LPS注射後約48時間で脾臓においてhCD14+CD33+hCD45+細胞の産生の増強を示し、ここで、増強が、hM-CSFを欠如している細胞生着マウスに対して約2倍から約5倍である、こと;
h.LPSに反応して血清中ヒトIL-6の産生の増強を示し、ここで、LPS注射後約6時間でのhIL-6のレベルが、hM-CSFを欠如している細胞生着マウスに対して約2倍から約5倍増強される、こと;
i.hM-CSF遺伝子を欠如している細胞生着マウスよりhTNFαに関して約2倍から3倍高い、LPS刺激時の単球および/またはマクロファージによるインビトロ分泌を示すこと;
j.hM-CSF遺伝子を欠如している細胞生着マウスよりhIL-6に関して約2倍から4倍高い、LPS刺激時の単球および/またはマクロファージによるインビトロ分泌を示すこと;
k.hM-CSF遺伝子を欠如している細胞生着マウスよりhIFNαに関して約3倍から6倍高い、poly I:C刺激時の単球および/またはマクロファージによるインビトロ分泌を示すこと;
l.hM-CSF遺伝子を欠如している細胞生着マウスよりhIFNβに関して約2倍から3倍高い、poly I:C刺激時の単球および/またはマクロファージによるインビトロ分泌を示すこと;
m.hM-CSF遺伝子を欠如している遺伝子改変細胞生着マウスと比較して増強された貪食を示すこと;
n.hM-CSF遺伝子を欠如している遺伝子改変細胞生着マウスと比較してMip3βに反応してインビトロで増強された走化性を示すこと;ならびに
o.LPS刺激に反応した共刺激分子のインビトロでのアップレギュレーションを示し、ここで、共刺激分子がヒトCD40、ヒトCD80、ヒトCD86、ヒトHLA-DRおよびそれらの組み合わせから選択される、こと
から選択される1つまたは複数の特徴を示す、本発明1011のマウスモデル。
[本発明1015]
マウスが、前記特徴の2つまたはそれより多くを示す、本発明1014のマウスモデル。
[本発明1016]
マウスが、前記特徴の3つまたはそれより多くを示す、本発明1014のマウスモデル。
[本発明1017]
Rag2における2個のヌル変異;
IL2RGにおける2個のヌル変異;
マウスM-CSF遺伝子のプロモーターに機能的に連結された、ヒトM-CSFタンパク質をコードする核酸配列;
ヒト造血細胞;および
ヒト病原体による感染症
を含む、ヒト病原体のマウスモデル。
[本発明1018]
前記病原体がウイルス、真菌、および細菌から選択される、本発明1017のマウスモデル。
[本発明1019]
前記細菌がマイコバクテリウム(mycobacterium)または腸内細菌である、本発明1018のマウスモデル。
本発明の方法および組成物を説明する前に、記述される特定の方法または組成物は当然変化しうることから、本発明は、それらに限定されないと理解すべきである。同様に、本明細書において用いられる用語は、特定の態様を説明する目的に限られ、本発明の範囲は添付の特許請求の範囲によってのみ制限されることから、制限的であると意図されないと理解すべきである。
本発明のいくつかの局面において、ヒト化M-CSFマウスが提供される。ヒト化M-CSFマウスまたは「hM-CSFマウス」とは、ヒトM-CSFタンパク質をコードする核酸配列を含むマウスを意味する。ヒトM-CSFタンパク質とは、ヒトM-CSFであるタンパク質、またはヒトM-CSFと実質的に同一である、たとえばヒトM-CSFと80%もしくはそれ以上同一である、85%もしくはそれ以上同一である、90%もしくはそれ以上同一である、または95%もしくはそれ以上同一である、たとえばヒトM-CSFと97%、98%、または99%同一であるタンパク質を意味する。それゆえ、ヒトM-CSFタンパク質をコードする核酸配列は、ヒトM-CSFタンパク質、すなわちヒトM-CSFまたはヒトM-CSFと実質的に同一であるタンパク質のコード配列を含むポリヌクレオチドである。M-CSF(同様にCSF-1、「コロニー刺激因子1」としても知られる)は、マクロファージの産生、分化、および機能を制御するサイトカインである。ヒトM-CSFのポリペプチド配列およびヒトM-CSFをコードする核酸配列は、Genbankアクセッション番号NM_000757.5(変種1)、NM_172210.2(変種2)、およびNM_172212.2(変種4)において見いだされうる。ヒトM-CSFタンパク質をコードするゲノム座は、ヒトゲノムにおいて1番染色体;NC_000001 .10(110453233-110472355)において見いだされうる。タンパク質配列は、この座でエキソン1から8によってコードされるが、エキソン9は、非翻訳配列を含む。そのため、ヒトM-CSFのコード配列を含む核酸配列は、ヒトM-CSF遺伝子のエキソン1〜8の1つまたは複数を含む。いくつかの例において、核酸配列はまた、ヒトM-CSFのゲノム座の局面、たとえばイントロン、3'および/または5'非翻訳配列(UTR)を含む。いくつかの例において、核酸配列は、ヒトM-CSFゲノム座の全領域を含む。いくつかの例において、核酸配列は、ヒトM-CSFゲノム座のエキソン2から非コードエキソン9の633ヌクレオチド下流までを含む。
ヒト化M-CSFマウスおよびヒト造血細胞を生着させたヒト化M-CSFマウス、たとえば細胞生着Rag2-/-IL2rg-/-hM-CSFマウス、および任意で他の遺伝子改変を有するマウスは、多くの応用において有用である。たとえば、これらのマウスは、ヒト免疫疾患およびヒト病原体のモデルを作製するために有用な系を提供する。たとえば、対象マウスは、初期ヒト造血細胞、たとえばヒト造血幹細胞または前駆細胞を起源とするヒト造血細胞悪性疾患のモデルを作製するために有用である。もう1つの例として、対象マウスは、通常はマウスに感染しないヒト病原体、たとえばウイルス、真菌、および細菌を研究するために有用である。
同様に、上記の方法の1つまたは複数を実践するための試薬、装置、およびキットが提供される。その対象試薬、装置、およびキットは、極めて多様でありうる。
CD34+細胞の単離および移植。ヒト胎児肝臓試料を、Albert Einstein College of Medicine, Bronx, NYのヒト胎児肝臓組織貯蔵所からおよびAdvance Biosciences Resources, Inc., Alameda, CAから得た。ヒト組織を伴う実験は全て、エール大学ヒト治験委員会の承認を受けて行った。
マウスの長骨を単離して、BM細胞を押し出した。骨を小片に切断して、コラゲナーゼDおよびP(25 ng/mL)の混合物によって37℃で45分間消化した。浮遊細胞を単離して、MSC培養培地(Stem Cell Technologies)の存在下で平板培養した。培養2週間後、CD45+Sca1+CD90+細胞を単離して培養した。
単細胞浮遊液をFACS CaliburまたはLSRIIおよびCELLQUEST(商標)ソフトウェア、FACS DIVA(商標)ソフトウェア(BD Biosciences, San Jose, CA)、またはFLOWJO(商標)ソフトウェア(Tree Star, Inc., Ashland, OR)をそれぞれ用いて、フローサイトメトリーによって分析した。定義された亜集団の細胞のソーティングは、FACS ARIA(商標)セルソーター(BD Biosciences, San Jose, CA)を用いて行った。
マウスマクロファージの分化に関して、BM細胞を、10%FCSおよび必要な補助物質(2 mM L-グルタミン、1%ペニシリン-ストレプトマイシン、および1 mM非必須アミノ酸)を添加したDMEMの存在下で6ウェルプレートにおいて平板培養した。細胞を、組み換え型マウスM-CSF(10 ng/mL)または組み換え型ヒトM-CSF(10 ng/mL)のいずれかによって7日間処置した。細胞培養上清を3日毎に採取して、培養物を新鮮な培地およびサイトカインに交換した。
インビボでのLPS刺激に関して、マウスにLPS(100 ng/g体重)をi.p.注射した。インビトロでのLPS刺激に関して、LPS(10 ng/mL)を細胞に添加して、1日または2日培養した。インビトロでのpoly I:C刺激に関して、細胞をpoly I:C(10μg/mL)の存在下で6時間または12時間培養した。
総RNAを市販のキットシステム(RNEASY(商標)ミニキット、Qiagen)を用いて単離した。オリゴdTプライマーを用いてcDNAを合成し、逆転写酵素(Roche)によって伸長させた。PCR反応は、7500リアルタイムPCRシステムおよびPower SYBR(商標)Green PCRマスターミックス(Applied Biosystems)を用いて製造元の説明書に従って、以下の遺伝子特異的プライマー対を用いて 1試料当たり2個ずつ行った:ヒトCSF1(センス:
およびアンチセンス:
、マウスcsf1(センス:
およびアンチセンス:
、ヒトIFNa(センス:
およびアンチセンス:
、ヒトIFNb(センス:
およびアンチセンス:
、マウスhprtプライマー(センス:
およびアンチセンス:
、ならびにヒトHPRTプライマー(センス:
およびアンチセンス:
)。通常のPCRに関して、標的細胞のDNAを、市販のキット(DNEASY(商標)血液および組織キット、Qiagen)を用いて抽出して、遺伝子特異的プライマー対を用いてPCR分析を行った。
サイトカイン定量試験に関して、血清または細胞培養上清のいずれかを採取して、市販のヒトIL6およびヒトTNF ELISAキット(Ray Biotech, Inc., GA)を用いて製造元の説明書に従ってELISAに供した。
固形臓器を4%PFA中で固定した。固定した臓器をパラフィン(Blue RiBbon; Surgipath Medical Industries)に包埋した。ブロックを切片にして、5μm切片をH&E染色によって染色した後、ルーチンの方法によってカバーガラスを載せた。切片はいかなる培地も加えずに維持した。Zeiss Axio Imager、A1顕微鏡(2倍および10倍の対物レンズ)、AxioCam MRc5カメラ、およびAxioVision 4.7.1イメージングソフトウェア(Carl Zeiss Microimaging LLC)を用いて、デジタル光学顕微鏡画像を室温で記録した。
データは平均値±SEMとして表記する。統計学的有意性は、両側のStudent t検定を用いて評価した。P値>0.05は、有意ではないと見なされ、P値<0.05は*で表記した。
ヒトM-CSFノックイン戦略
1回のターゲティング段階でマウスM-CSF核酸配列をヒトM-CSF核酸配列(VELOCIGENE(登録商標)、対立遺伝子識別番号5093)に交換するためのターゲティング構築物を、既に記述されたように(Valenzuela et al. (2003) High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nat. Biotechnol. 21 :652-659)、VELOCIGENE(登録商標)技術を用いて構築した。マウスおよびヒトM-CSF DNAをそれぞれ、細菌人工染色体(BAC)RPCI-23、クローン373B18およびBAC RPCI-11、クローン101 M23から得た。簡単に説明すると、エキソン2から非コードエキソン9の633 nt下流まで伸長する17.5 kbヒトM-CSF配列に隣接するマウスM-CSF上流および下流相同性アーム、およびfloxed薬物選択カセットを含む、ギャップ修復クローニングによって作製された線状化ターゲティング構築物を、市販のV17 ES細胞株(BALB/c×129F1)から作製したRAG2+/-γc-/-マウス胚幹(ES)細胞に電気穿孔した。M-CSF遺伝子のヘテロ接合欠失を有するマウスES細胞を、マウスCsf1遺伝子のイントロン2(TUFプライマー、
;TUPプローブ、
;TURプライマー、
および3'隣接配列(TDFプライマー、
;TDPプローブ、
;TDRプライマー、
)における配列を認識する2つのTaqMan qPCRアッセイによるLoss-of-Alleleスクリーニングによって同定した。マウス遺伝子とヒトCSF1遺伝子との同時の交換を、CSF1のイントロン2における配列(フォワードプライマー、
;プローブ、
;リバースプライマー、
)の1コピー、およびネオマイシン耐性(neor)カセット(フォワードプライマー、
;プローブ、
;リバースプライマー、
)の1コピーを検出するGain-of Allele TaqManアッセイによって確認した;図8を参照されたい。CSF1配列を認識するqPCRアッセイは、マウスゲノムからのDNAを増幅しない。同じアッセイを用いて、標的化ES細胞に由来するマウスの遺伝子型を確認した。薬物選択カセットのCreによる切除を、neor TaqManアッセイによって確認した。全てのプライマー-プローブセットは、Biosearch Technologiesによって供給された。プローブは、その5'末端で6-カルボキシ-フルオレセイン(FAM)およびその3'末端でBHQ-1によって標識された。
Balb/c Rag2-/-γc-/-M-CSFm/m、Balb/c Rag2-/-γc-/-M-CSFh/m、およびBalb/c Rag2-/-γc-/-M-CSFh/hマウスを、エール大学の動物飼育施設において特異的病原体を含まない条件下で維持した。マウスの実験は全て、エール大学の学内動物飼育使用委員会によって承認された。
マウスにおけるヒトM-CSFの生理的発現によって、ヒト化マウスにおいてヒトマクロファージの分化の改善が起こるか否かを確認するために、Balb/c Rag2-/-γc-/-マウスをヒトM-CSFを発現するように操作した。Rag2-/-γc-/-欠損を有するBalb/c系統は、マウスにおけるヒト免疫系の研究に関して成功したモデル系として役立つ(Traggiai E et al. (2004) Development of a human adaptive immune system in cord blood cell- transplanted mice, Science 304:104-107)。これらのマウスにおけるヒトM-CSFの生理的レベルを超える発現を回避するために、マウスM-CSFコード配列をヒト相対物に交換する戦略を採用した。一段階ターゲティングにおいてM-CSFオープンリーディングフレームの大部分をヒトM-CSFコード配列(VELOCIGENE(登録商標)対立遺伝子識別番号5093)に交換するための構築物(図8)を、既に記述されたようにVELOCIGENE(登録商標)技術を用いて構築した(Valenzuela et al.(2003))。注意すべきことに、プロモーターおよびマウスの他の調節エレメント(5' UTR等の)は、このベクターにおいて保存された。線状化ターゲティングベクターを、Balb/c×129 Rag2+/-γc-/-胚幹細胞に電気穿孔した。正確に標的化されたES細胞に、薬物選択カセットを除去するために一過性のCre発現ベクターをさらに電気穿孔した。薬物カセットを有しない標的化ES細胞クローンを、VELOCIMOUSE(登録商標)法によって8細胞期マウス胚に導入した(Poueymirou et al. (2007))。ヒト化M-CSF遺伝子(VG 5093)を有するVELOCIMICE(登録商標)(ドナーES細胞に完全に由来するF0マウス)を、修正を加えた対立遺伝子アッセイを用いて、マウス対立遺伝子の喪失およびヒト対立遺伝子の獲得に関して遺伝子タイピングすることによって同定した(Valenzuela et al.(2003))。子孫の連続的異種交配を通して、Balb/c Rag2-/-γc-/-マウスキメラマウス、ならびにマウスおよびヒトM-CSF(M-CSFm/h、ヘテロ接合ノックイン)、およびヒトM-CSFのみ(M-CSFh/h、ホモ接合ノックイン)を有するジャームライントランスミットマウスを作製した。
ヒト化M-CSFマウスにおけるヒトM-CSFの発現を評価した。M-CSFm/mまたはM-CSFh/hマウスのいずれかからの臓器を採取して、種特異的であるプライマーを用いて、マウスおよびヒトM-CSF mRNA発現に関して分析した。図1Aおよび1Bに示されるように、M-CSFは、BM、脾臓、血液、肝臓、脳、肺、精巣、および腎臓を含む分析された臓器の大部分において発現される。しかし、胸腺および皮膚は、M-CSFの検出可能な発現を示さなかった。注目すべきことに、マウスおよびヒトM-CSFの発現パターンはそれぞれ、M-CSFm/mおよびM-CSFh/hマウスのあいだで同等であった。次に、M-CSFm/m、M-CSFm/h、およびM-CSFh/hマウスにおけるマウスおよびヒトM-CSFの発現レベルを定量した。骨髄間葉間質細胞(MSC)を単離して、M-CSF mRNAの発現レベルを、リアルタイムPCRを用いて定量し(図1C)、M-CSFタンパク質(分泌型)を、ELISAを用いて定量した(図1D)。M-CSFm/mマウスは、マウスM-CSFのみを発現したが、M-CSFm/hマウスはマウスおよびヒトM-CSFの両方を発現し、ならびにM-CSFh/hマウスは、ヒトM-CSFのみを発現した。ヒトM-CSFの発現レベルは、マウスM-CSFと同等であった。これらのデータと一致して、血清中のCSF-1の分析から、m/m、h/m、およびh/hマウスにおけるCSF-1タンパク質の発現レベルが同等であることが判明した(図1E)。ヘミ接合性によって、遺伝子およびタンパク質発現レベルの減少は起こらず、遺伝子-用量レベルが、このサイトカインにとって制限的ではないように思われることを示している。
M-CSFヒト化の影響を評価するために、致死下量の放射線を照射した新生仔Rag2-/-γc-/-M-CSFm/m、Rag2-/-γc-/-M-CSFh/m、およびRag2-/-γc-/-M-CSFh/hの肝臓内(i.h.)に精製ヒト胎児肝CD34+細胞〜2×105個を移植した。次に移植後8週目にレシピエントから採血して、ドナー(ヒトCD45発現に基づく)起源の細胞を確認した。移植後12週目で、レシピエントを屠殺して、そのBM、SP、およびPBを採取した。分析から、M-CSFm/mマウスと比較して、M-CSFh/mマウスおよびM-CSFh/hマウスの両方のBM、SP、およびPBにおいてCD14+CD33+単球/マクロファージ系列細胞の相対出現率および絶対出現率の増強が明らかとなった(図3A〜C)。M-CSFh/mマウスは、CD14+CD33+細胞の出現率の増加を示したが、CD14+CD33+細胞の最大の出現率は、M-CSFh/hマウスにおいて見いだされた。興味深いことに、この増加に加えて、CD14+CD33+細胞の出現率は、M-CSFh/mおよびM-CSFh/hマウスのBM、SP、およびPBにおいても増加した(図3A)。
ヒト化M-CSFマウスにおけるヒトCD14+CD33+単球/マクロファージが通常に機能するか否かを調べるために、インビボおよびインビトロ機能試験を行った。致死下量の放射線を照射したM-CSFm/mおよびM-CSFm/h仔に胎児肝臓CD34+細胞を注射して、移植後12週目でドナー由来の造血を評価して、レシピエントマウスにLPSまたはPBSのいずれかを注射した。LPS注射の2日後、レシピエントを、脾臓におけるヒトCD14+CD33+細胞の出現率に関して分析した。LPS注射は、M-CSFm/mマウスにおいて単球/マクロファージ系列細胞の中等度の増加を誘導したが、PBS注射群と比較して、LPSを注射したM-CSFm/hマウスは、脾臓においてヒトCD14+CD33+細胞の数倍の増加を示した(図6A)。次に、これらの細胞がインビボでLPS刺激に反応して炎症誘発性サイトカインを産生できるか否かを調べた。
Claims (15)
- (a)ヒト造血細胞を生着させた第1のヒト化M-CSFマウスに候補物質を接触させる段階;および
(b)該物質を接触させた第1のヒト化M-CSFマウスにおけるヒト造血細胞の生存率および/または機能を、該物質を接触させていないヒト造血細胞を生着させた第2のヒト化M-CSFマウスにおけるヒト造血細胞の生存率および/または機能と比較する段階
を含み、
該第1および第2のヒト化M-CSFマウスがそれぞれ、
ヒト化M-CSFマウスのゲノムに組み込まれた、ヒトM-CSFタンパク質をコードしかつマウスM-CSF座でマウスM-CSF遺伝子の内因性プロモーターに機能的に連結されている核酸配列を含み、かつ
Rag2遺伝子ノックアウトおよびIL2rg遺伝子ノックアウトを含むかまたはNOD-scidγc-/-マウス、NOD/Shi-scidγc-/-マウス、およびBalb/c Rag2-/-γc-/-マウスからなる群より選択され、
該第1および第2のヒト化M-CSFマウスがそれぞれ、該核酸配列によってコードされるM-CSF RNAを骨髄、脾臓、血液、肝臓、脳、肺、精巣、および腎臓において発現し、かつ
候補物質を接触させた該第1のマウスにおける造血細胞の生存率および/または機能の減少により、該候補物質が造血細胞に対して毒性であることが示される、
ヒト造血細胞に対する毒性に関して候補物質をスクリーニングする方法。 - 前記第1および第2のヒト化M-CSFマウスがそれぞれ、前記核酸配列を2コピー含む、請求項1に記載の方法。
- 前記第1および第2のヒト化M-CSFマウスがそれぞれ、少なくとも1つのマウスM-CSF対立遺伝子において同じヌル変異を含む、請求項2に記載の方法。
- 前記ヌル変異が、マウスM-CSFエキソン2〜9の欠失である、請求項3に記載の方法。
- 前記第1および第2のヒト化M-CSFマウスがそれぞれ、少なくとも1つのマウスM-CSF対立遺伝子において同じヌル変異を含む、請求項1に記載の方法。
- 前記ヌル変異が、マウスM-CSFエキソン2〜9の欠失である、請求項5に記載の方法。
- (a)ヒト造血細胞を生着させた第1のヒト化M-CSFマウスに毒性物質を接触させる段階;
(b)ヒト造血細胞を生着させた第2のヒト化M-CSFマウスに毒性物質を接触させる段階;
(c)該第1のヒト化M-CSFマウスに候補物質を接触させる段階;および
(d)該候補物質を接触させた第1のヒト化M-CSFマウスにおけるヒト造血細胞の生存率および/または機能を、該候補物質を接触させていない第2のヒト化M-CSFマウスにおけるヒト造血細胞の生存率および/または機能と比較する段階
を含み、
該第1および第2のヒト化M-CSFマウスがそれぞれ、
ヒト化M-CSFマウスのゲノムに組み込まれた、ヒトM-CSFタンパク質をコードしかつマウスM-CSF座でマウスM-CSF遺伝子の内因性プロモーターに機能的に連結されている核酸配列を含み、かつ
Rag2遺伝子ノックアウトおよびIL2rg遺伝子ノックアウトを含むかまたはNOD-scidγc-/-マウス、NOD/Shi-scidγc-/-マウス、およびBalb/c Rag2-/-γc-/-マウスからなる群より選択され、
該第1および第2のヒト化M-CSFマウスがそれぞれ、該核酸配列によってコードされるM-CSF RNAを骨髄、脾臓、血液、肝臓、脳、肺、精巣、および腎臓において発現し、かつ
候補物質を接触させた該第1のマウスにおける造血細胞の生存率および/または機能の増強により、該候補物質が、造血細胞を毒性物質から保護するか、ヒト造血細胞に対する毒性物質の効果を軽減するか、またはヒト造血細胞に対する毒性物質の効果を逆転させることが示される、
ヒト造血細胞を毒性物質から保護する能力に関して候補物質をスクリーニングする方法。 - 前記第1および第2のヒト化M-CSFマウスがそれぞれ、前記核酸配列を2コピー含む、請求項7に記載の方法。
- 前記第1および第2のヒト化M-CSFマウスがそれぞれ、少なくとも1つのマウスM-CSF対立遺伝子において同じヌル変異を含む、請求項8に記載の方法。
- 前記ヌル変異が、マウスM-CSFエキソン2〜9の欠失である、請求項9に記載の方法。
- 前記第1および第2のヒト化M-CSFマウスがそれぞれ、少なくとも1つのマウスM-CSF対立遺伝子において同じヌル変異を含む、請求項7に記載の方法。
- 前記ヌル変異が、マウスM-CSFエキソン2〜9の欠失である、請求項11に記載の方法。
- 前記第1のマウスと毒性物質との接触が、該第1のマウスと候補物質との接触の後に起こる、請求項7〜12のいずれか一項に記載の方法。
- 前記第1のマウスと毒性物質との接触が、該第1のマウスと候補物質との接触の前に起こる、請求項7〜12のいずれか一項に記載の方法。
- 前記第1のマウスと毒性物質との接触が、該第1のマウスと候補物質との接触と同時に起こる、請求項7〜12のいずれか一項に記載の方法。
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