JP4403200B2 - ヒト免疫システムの動物モデルおよびそれを作出する方法 - Google Patents
ヒト免疫システムの動物モデルおよびそれを作出する方法 Download PDFInfo
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- 230000001988 toxicity Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0381—Animal model for diseases of the hematopoietic system
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Description
より複雑な第2の方針は、異種移植によるキメラの作製である(3)。これは、通常は免疫不全の動物における、ヒト細胞またはヒト組織の投与を包含する。ヒト免疫システムを作製するための優れた宿主動物は、適応免疫にいくつかの欠陥を持つマウス系統、例えばRag2−/−/γ−/−(4)、BNXまたはNOD/SCID B2mnullなどである(5)。さまざまな系統のNOD/SCID(非肥満糖尿病/重症複合型免疫不全症)マウスが、ヒト化のための標準モデルとして役立つ。それらは、基本的に、以下の免疫不全性によって特徴づけられる:Bリンパ球およびTリンパ球の完全な喪失、NK細胞数の減少、抗原提示細胞の分化および機能に関する欠陥、ならびに循環補体の不在。これらのマウスは、野生型よりも電離放射線の影響を受けやすく、DNA修復システムに欠陥を持っている。免疫不全動物では、ヒト造血幹細胞、分化した造血細胞ならびにリンパ器官の移植後に、ヒトの個々の造血系列またはいくつかの造血系列を形成させることが可能である。利用するマウス系統およびそのコンディショニングならびに造血幹細胞の数および供給源の関数として、動物の末梢血または脾臓および骨髄に0.1〜90%のヒトCD45+細胞を発生させることが可能である。
a)造血能を持つヒト幹細胞を非ヒト哺乳動物に移植するステップ;および
b)ヒト細胞株、ヒト細胞および/またはヒト組織の培養物の細胞培養上清で、非ヒト哺乳動物をコンディショニングするステップ;および随意に
c)それ自体は造血能を持たない支持細胞を投与するステップ
を含む、非ヒト哺乳動物におけるヒト免疫システムの動物モデルを作出する方法によって、解決される。
ヒト肺細胞癌細胞株(ここではライプツィヒ大学動物学研究所から入手したII型肺細胞株358/8サブクローン[NCI−H358由来])または肉腫細胞株(VA−ES−BL、Deutsche Sammlung fuer Mikroorganismen und Zellkulturen GmbH、ドイツ・ブラウンシュワイク、ACC328)を、5%ウシ胎仔血清を添加したRPMI 1640中、滅菌条件下で、対数増殖期に到達するまで増殖させる。調整培地を調製するために、2〜4×105細胞/mlを播種する。培養培地を3日後に回収して集め、滅菌条件下で濾過し(孔径0.2μm)、さらに使用するまで、少なくとも−20℃で、分割保存した。
少なくとも6週齢の雄および雌NOD/SCIDマウス(Jackson Laboratories, 米国)を、特定病原体不在条件下で飼育し、レシピエントとした。x線治療装置を使って動物の全身照射を350cGyで実行し、照射の3〜5時間後に、ヒト臍帯血から単離した1〜10×106個の単核球を、エーテル麻酔した動物の尾静脈に投与した。個別のドナー血に由来する細胞およびいくつかの混合血試料に由来する細胞を利用した。Boyum(1976)の方法に従い、リンパ球分離培地LSM 1077(PAA Laboratories、オーストリア・パッシング)を使った密度勾配遠心分離によって、単核球を単離した。単核球画分を移植に先だって少なくとも24時間は−196℃で保存し、移植日に、間に合うように融解した。移植を行うまで、細胞を培地またはPBS中に4℃で保存した。細胞の投与後、直ちに、上述のようにして得たヒト肺細胞株の調整細胞培地の初回用量200μlを、腹腔内投与した。さらに、移植後14日目まで二日ごとに、動物を鎮静させずに上清を追加投与した。
マウスのヒト造血再構成の照査として、移植後14日目から開始して二週間毎に、約75μlの血液試料を、尾静脈穿刺によって、またはメスで尾静脈をわずかに傷つけることによって、各マウスから採取した。凝固を防ぐために、ヘパリンナトリウムを試料に加えた後、試料を良く混合した。移植の8週間後に、ヒト長期生着を決定するためにマウスを屠殺し、その動物の末梢血、脾臓、骨髄および肝臓を単離した。固形臓器から単細胞懸濁液を機械的に調製した。必要に応じて、それらの細胞から結合組織を分離するために、ナイロンフィルターで濾過を行った。赤血球は蒸留水で溶解するか、塩化アンモニウム含有緩衝液を使って溶解した。生着を特徴づけるために、マウス抗原との考えうる交差反応性に関して分析前に試験しておいた直接コンジュゲートヒト特異的抗体を利用した。以下のヒト特異的抗体を利用した:CD45、CD3、CD19、CD56、CD14、CD16、CD34、HLA−DR、抗lineageカクテル、CD11c、CD123(Becton Dickinson、ドイツ・ハイデルベルク)。さらにまた、特異性対照として、マウス特異的CD45抗体(IQ Products、ドイツ・オルデンブルク)によるマーキングも行った。個々の系列に関するデータは、ヒトCD45陽性細胞に対する相対比率に基づく。マーキングした試料をFACS Calibur(Becton Dickinson)で分析した。ヒトCD45陽性細胞の含有量が≧0.1%であった場合に、そのレシピエントはヒトキメラ状態を示したとする。
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本発明の説明および図面では、以下の略号を使用する。
ANG :アンギオゲニン
APC:アロフィコシアニン
bFGF:塩基性線維芽細胞増殖因子
CD:分化クラスター
CFSE:カルボキシフルオレシンスクシンイミジルエステル
DSZM:Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH(ドイツ微生物細胞培養収集機関)
EBV:エプシュタイン・バーウイルス
ELISA:酵素結合免疫吸着アッセイ
HLA:ヒト白血球抗原
HIV:ヒト免疫不全ウイルス
HSV:ヒト口内炎ウイルス
hu:ヒト
IGF:インスリン様成長因子
IL:インターロイキン
IP−10:インターフェロン−γ誘導タンパク質10
KM:骨髄
LPS:リポ多糖
MCP−1:単球化学誘引タンパク質−1
MIG:インターフェロンγ誘導モノカイン
MNC:単核球
NOD:非肥満糖尿病性
NK:ナチュラルキラー
PC7:フィコシアニン7
PE:フィコエリトリン
PerCP:ペリジニンクロロフィルタンパク質
RANTES:ランテス(regulated upon activation, normal T−cell expressed and secretedの頭字語)
sCD40L:可溶性CD40リガンド
SCID:重症複合免疫不全症
sPセレクチン:可溶性血小板セレクチン
sVCAM−1:血管細胞接着分子−1
TNF−α:腫瘍壊死因子−アルファ
tPA:組織型プラスミノゲン活性化因子
VEGF:血管内皮増殖因子
Claims (14)
- a)造血能を持つヒト幹細胞を非ヒト哺乳動物に移植するステップ、および
b)細胞株、細胞および/または組織の培養物の細胞培養上清で、非ヒト哺乳動物をコンディショニングするステップであって、前記細胞培養上清が、ヒト因子インターロイキン−8、インターロイキン−6、および血管内皮増殖因子(VEGF)、インターフェロン−γ誘導タンパク質10(IP−10)、単球化学誘引タンパク質−1(MCP−1)、アンギオゲニン、および組織型プラスミノゲン活性化因子(tPA)を含有する、前記ステップ
を含む、非ヒト哺乳動物におけるヒト免疫システムの動物モデルを作出する方法。 - 細胞培養上清がサイトカインおよび他の分子媒介因子(機能分子)を産生する細胞株から得られることを特徴とする、請求項1に記載の方法。
- 非ヒト哺乳動物がマウスであることを特徴とする、請求項1または2に記載の方法。
- 造血能を持つヒト幹細胞がヒト骨髄、動員もしくは非動員末梢血、臍帯血、または臍帯組織に由来することを特徴とする、請求項1から3のいずれか一項に記載の方法。
- 移植が非ヒト哺乳動物の照射の3〜24時間後に行われることを特徴とする、請求項1から4のいずれか一項に記載の方法。
- コンディショニングが細胞培養上清の静脈内投与または腹腔内投与によって達成されることを特徴とする、請求項1から5のいずれか一項に記載の方法。
- コンディショニングが、移植日から開始して、移植後4週間行われることを特徴とする、請求項1から6のいずれか一項に記載の方法。
- 細胞培養上清によるコンディショニングに加えて、それ自体は造血能を持たない支持細胞を、非ヒト哺乳動物に投与することを特徴とする、請求項1から7のいずれか一項に記載の方法。
- 請求項1から8のいずれか一項に記載の方法によって得られる、造血システムのヒト免疫担当細胞を含む非ヒト哺乳動物におけるヒト免疫システムの動物モデルであって、前記細胞がT細胞およびB細胞、単球、樹状細胞、NK細胞、顆粒球ならびにCD34+幹細胞を含む動物モデル。
- ヒト免疫担当細胞が人体と同等な機能性を持つことを特徴とする、請求項9に記載の動物モデル。
- 動物モデル中のヒト樹状細胞が、ヒトインターロイキン−8を構成的に産生する能力ならびにヒトインターロイキン−6、ヒトインターロイキン−1β、およびヒト腫瘍壊死因子−アルファ(TNF−α)を免疫刺激後に産生する能力を持つことを特徴とする、請求項9または10に記載の動物モデル。
- 作成した動物モデルにおいて、ヒト免疫システムが安定であり、移植後3ヶ月をはるかに越えても依然として機能的であることを特徴とする、請求項9から11のいずれか一項に記載の動物モデル。
- 製品開発、ヒト抗体の製造を目的とする、または薬理学的研究、免疫学的研究、微生物学的研究、および医学的研究のためのモデル系としての、請求項9から12のいずれか一項に記載の動物モデルの使用。
- 動物実験疾患モデルを、病原研究のために、そして/または新しい診断戦略および/もしくは治療戦略を開発するために、作出し利用するための、請求項9から12のいずれか一項に記載の動物モデルの使用。
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