JP6109740B2 - Il33のn末端ドメインが欠失している炎症マウスモデル - Google Patents
Il33のn末端ドメインが欠失している炎症マウスモデル Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
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- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
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- G—PHYSICS
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
- G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
- A01K2217/077—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out heterozygous knock out animals displaying phenotype
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; 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
- A01K2267/0306—Animal model for genetic diseases
- A01K2267/0325—Animal model for autoimmune diseases
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; 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
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; 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
- A01K2267/0368—Animal model for inflammation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Description
[本発明1001]
IL-33遺伝子のN末端が欠失している、非ヒト動物。
[本発明1002]
IL-33遺伝子のN末端のDNA結合ドメイン全体が欠失している、本発明1001の非ヒト動物。
[本発明1003]
哺乳動物である、本発明1001または1002の非ヒト動物。
[本発明1004]
齧歯動物である、本発明1003の非ヒト動物。
[本発明1005]
非ヒト動物がマウスであり、かつ、IL-33遺伝子のN末端の欠失が、IL-33遺伝子の発現産物のアミノ酸1-67の欠失を含む、本発明1004の非ヒト動物。
[本発明1006]
同一または別の遺伝子型の動物と繁殖させることにより得られる、本発明1001〜1005のいずれかの非ヒト動物の子孫。
[本発明1007]
本発明1001〜1005のいずれかの非ヒト動物または本発明1006の子孫に由来する、細胞株または初代細胞培養物。
[本発明1008]
本発明1001〜1005のいずれかの非ヒト動物または本発明1006の子孫に由来する、組織もしくは器官外植片またはそれらの培養物。
[本発明1009]
炎症性疾患のモデルとしての、本発明1001〜1005のいずれかの非ヒト動物、本発明1006の子孫、本発明1007の細胞株もしくは初代細胞培養物、または本発明1008の組織もしくは器官外植片の使用。
[本発明1010]
抗炎症性化合物のスクリーニングのための、本発明1009の炎症性疾患のモデルの使用。
[本発明1011]
抗炎症性化合物の薬理学的効果の評価のための、本発明1009の炎症性疾患のモデルの使用。
[本発明1012]
本発明1001〜1005のいずれかの非ヒト動物または本発明1006のその子孫に候補化合物を投与する段階を含む、抗炎症性化合物のスクリーニングのための方法。
[本発明1013]
本発明1001〜1005のいずれかの非ヒト動物または本発明1006のその子孫に抗炎症性化合物を投与する段階を含む、該抗炎症性化合物の薬理学的効果の評価のための方法。
[本発明1014]
本質的に明細書において記載されるような、非ヒト動物、使用、および方法。
ターゲティングベクター(SEQ ID. NO. 2)を、Gene Bridges GmbH, Heidelbergにより供給されるようなリコンビニアリング(recombineering)技術を用いて作製した。ベクターは、以下の要素を含有する。
1-70 IL-33エクソン1b
71-3871 イントロン
3872-3882 IL-33エクソン2
3883-4557 dsRedモノマーCDS
4558-4579 IL-33エクソン3
4580-4590 イントロン配列
4591-4626 lox部位
4625-6040 ネオマイシン選択カセット
6041-6074 lox部位
6075-6571 イントロン配列
6572-6682 IL-33エクソン4
6683-7285 イントロン
7286-7603 pBluescript SKII+
7604-8463 ジフテリア毒素選択カセット
8464-10697 pBluescript SKII+
オリゴヌクレオチド
2種のBalb/cバックグラウンドに遺伝子改変したノックインマウスモデルを作製した。第1の変異体は、N末端の細胞内転写因子様活性を標的として蛍光色素DsRdモノマーでインフレーム置換し(DsRed-IL33/COOH)、機能的なサイトカインドメインは完全に保持する(図1)。第2の変異体は、炎症誘発性サイトカインドメインを蛍光色素DsRedでのインフレームノックインにより置換し、DNA結合ドメインは無傷のまま保持する(NH2/L33-DsRed)。
予想外に、IL-33N末端ドメインを失っているが細胞質中の有効な炎症誘発性サイトカイン活性を維持している、遺伝子操作したヘテロ接合性変異体マウス(DsRed-IL33/COOH)は、生後4か月ごろに死亡した。それらは、出生時明らかに正常であり、進行的に病気になり、4〜5か月後に約60%の推定表現型浸透率で最終的に瀕死状態になる。生後3〜4か月で、これらの変異体は、耳における血性病変および肥大した腹部を示し始める。剖検時には、大量の脾腫、腸炎症を示唆する回腸(ilion)の肥厚、胸腔における大きな凝塊の存在、および腎萎縮症が、繰り返し観察される(図2〜5)。FACS解析における様々な器官のより精密な検査により、肺、脾臓、リンパ球、パイエル板、および末梢血における強度の好酸球増加が示された(図6)。血清IL-33レベルは、DsRed-IL33/COOHノックアウトマウスにおいて上昇している(図7)。
本発明者らは、最近、IL-33の鼻腔内投与が、間質におけるマクロファージ起源の多核巨細胞を伴う重度の肺炎症を誘発することを見出した(準備中のHicksらの原稿)。同様に、IL-33はまた、組織病理学により示されるように、骨髄性/顆粒球性細胞の大きなクラスターを伴う骨髄過形成も誘発した(準備中のHicksらの原稿)。さらに、高レベルの可溶性IL-33が、これらのマウスの末梢血の血漿中に見出され、本発明者らのDsRed-IL33/COOH変異体動物において見られる免疫病理学的効果が、細胞質中の完全に活性を有するDsRed-IL33/COOHサイトカインの連続的な存在および細胞外区画中へのその可能性のある放出の結果であり、従って仮定されているように強力な内因性DAMPシグナルとして挙動することを、強く示唆する。
Claims (7)
- IL-33遺伝子の発現産物のアミノ酸1-67を欠失している、炎症性疾患モデルマウス。
- 請求項1記載のマウスに由来する、組織もしくは器官外植片またはそれらの培養物。
- 炎症性疾患のモデルとしての、請求項1記載のマウス、請求項1記載のマウスに由来する細胞株もしくは初代細胞培養物、または請求項2記載の組織もしくは器官外植片の使用。
- 抗炎症性化合物のスクリーニングのための、請求項3記載の炎症性疾患のモデルの使用。
- 抗炎症性化合物の薬理学的効果の評価のための、請求項3記載の炎症性疾患のモデルの使用。
- 請求項1記載のマウスに候補化合物を投与する段階を含む、抗炎症性化合物のスクリーニングのための方法。
- 請求項1記載のマウスに抗炎症性化合物を投与する段階を含む、該抗炎症性化合物の薬理学的効果の評価のための方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10189446 | 2010-10-29 | ||
EP10189446.7 | 2010-10-29 | ||
PCT/EP2011/068696 WO2012055891A1 (en) | 2010-10-29 | 2011-10-26 | Murine model of inflammation with il33 n-terminal domain deletion |
Publications (2)
Publication Number | Publication Date |
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JP2013544075A JP2013544075A (ja) | 2013-12-12 |
JP6109740B2 true JP6109740B2 (ja) | 2017-04-05 |
Family
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Application Number | Title | Priority Date | Filing Date |
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JP2013533243A Expired - Fee Related JP6109740B2 (ja) | 2010-10-29 | 2011-10-26 | Il33のn末端ドメインが欠失している炎症マウスモデル |
Country Status (10)
Country | Link |
---|---|
US (2) | US20130318641A1 (ja) |
EP (1) | EP2632250A1 (ja) |
JP (1) | JP6109740B2 (ja) |
KR (2) | KR101755965B1 (ja) |
CN (1) | CN103179851B (ja) |
BR (1) | BR112013007041A2 (ja) |
CA (1) | CA2815112A1 (ja) |
MX (1) | MX2013004239A (ja) |
RU (1) | RU2577988C2 (ja) |
WO (1) | WO2012055891A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11708608B2 (en) | 2014-11-10 | 2023-07-25 | Genentech, Inc. | Therapeutic and diagnostic methods for IL-33-mediated disorders |
JP6929771B2 (ja) | 2014-11-10 | 2021-09-01 | ジェネンテック, インコーポレイテッド | 抗インターロイキン−33抗体及びその使用 |
US10143187B2 (en) | 2017-02-17 | 2018-12-04 | Denali Therapeutics Inc. | Transferrin receptor transgenic models |
US10457717B2 (en) | 2017-02-17 | 2019-10-29 | Denali Therapeutics Inc. | Engineered polypeptides |
IL307373A (en) | 2017-02-17 | 2023-11-01 | Denali Therapeutics Inc | Polypeptides that bind to a transgenic transferrin receptor |
WO2021018198A1 (en) * | 2019-07-29 | 2021-02-04 | Beijing Biocytogen Co., Ltd | Genetically modified non-human animal with human or chimeric il33 |
WO2021183849A1 (en) | 2020-03-13 | 2021-09-16 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10258885A1 (de) * | 2002-12-17 | 2004-07-15 | Aventis Pharma Deutschland Gmbh | Verfahren zur Generierung eines gentechnisch veränderten Organismus |
-
2011
- 2011-10-26 WO PCT/EP2011/068696 patent/WO2012055891A1/en active Application Filing
- 2011-10-26 EP EP11776153.6A patent/EP2632250A1/en not_active Withdrawn
- 2011-10-26 CN CN201180051772.2A patent/CN103179851B/zh not_active Expired - Fee Related
- 2011-10-26 KR KR1020157023121A patent/KR101755965B1/ko active IP Right Grant
- 2011-10-26 MX MX2013004239A patent/MX2013004239A/es unknown
- 2011-10-26 JP JP2013533243A patent/JP6109740B2/ja not_active Expired - Fee Related
- 2011-10-26 BR BR112013007041A patent/BR112013007041A2/pt not_active Application Discontinuation
- 2011-10-26 KR KR1020137010445A patent/KR20130092589A/ko not_active Application Discontinuation
- 2011-10-26 CA CA2815112A patent/CA2815112A1/en not_active Abandoned
- 2011-10-26 RU RU2013123512/10A patent/RU2577988C2/ru not_active IP Right Cessation
-
2013
- 2013-04-22 US US13/867,263 patent/US20130318641A1/en not_active Abandoned
-
2014
- 2014-09-03 US US14/476,626 patent/US9271479B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
KR101755965B1 (ko) | 2017-07-07 |
JP2013544075A (ja) | 2013-12-12 |
US20130318641A1 (en) | 2013-11-28 |
RU2577988C2 (ru) | 2016-03-20 |
CN103179851A (zh) | 2013-06-26 |
KR20150103332A (ko) | 2015-09-09 |
EP2632250A1 (en) | 2013-09-04 |
US20150026832A1 (en) | 2015-01-22 |
RU2013123512A (ru) | 2014-12-10 |
BR112013007041A2 (pt) | 2016-09-13 |
CA2815112A1 (en) | 2012-05-03 |
KR20130092589A (ko) | 2013-08-20 |
US9271479B2 (en) | 2016-03-01 |
CN103179851B (zh) | 2016-08-03 |
WO2012055891A1 (en) | 2012-05-03 |
MX2013004239A (es) | 2013-05-30 |
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