TNF-αヒト化マウス

品系バックグラウンド:C57BL/6J

 

品系構築策略:

遺伝子の置き換えを通じてTNF-αヒト化を実現する:マウスのTNF-αはヒトのTNF-αで置き換える。hTNF-αの発現はマウスの内因性プロモーターによって調節される。

 

品系説明:

  • hTNF−αはマウスの体内で正常な生理発現と調節モードを持っている。
  • マウスの標的遺伝子を発現しない。

 

研究の応用:

  • このモデルはhTNF−α標的医薬の体内での有効性と安全性を評価するのに用いられる。
  • 自己免疫性疾患と炎症分野によく使用されている。 

 

モデル検証:

  • TNF−αの発現検査  

Figure1. Mean plasmatic concentrations of murine TNF-α and human TNF-α following LPS injection

Figure1. Mean plasmatic concentrations of murine TNF-α and human TNF-α following LPS injection. Mean concentrations of murine TNF-α (A) and human TNF-α (B) measured by ELISA from plasma samples collected from WT(n=2) and KI (n=2) mice treated with saline solution vs. LPS.

  

Figure2. The Analysis of secretion of humanized (red) and murine (blue) TNF-α by ELISA

Figure 2. ELISA analysis of humanized (red) and murine (blue) TNF-α expression.
(Left) αCD3/αCD28 stimulated human peripheral blood mononuclear cells (hPMBC0 and (Right) wild-type or humanized TNF-α (hTNF-α) mouse spleen cells activated with αCD3/αCD28 (Act) or untreated (NA). After stimulated by αCD3/αCD28, humanized mouse peripheral blood mononuclear cells secrete humanized TNF-α (hTNF-α) instead of murine TNF-α (mTNF-α).

 

TNF−αの機能検査  

Figure3. Humanized TNF-α mouse hTNF-α anti-proliferative activity

Figure 3. Humanized TNF-α (hTNF-α) and mouse TNF-α (mTNF-α) anti-proliferative activity. (Left) The supernatant of wild-type (mTNF-α) and hTNF-α mouse spleen cells activated by αCD3/αCD28 was collected to treat L929 cells. Compared with the supernatant of WT spleen cells, the supernatant of hTNF-α mice spleen cells used to treat L929 cells showed a concentration-dependent anti-proliferative phenotype of TNF-α. (Right) Pretreatment of wild-type mouse and hTNF-α mouse supernatants with murine and human TNF-α antibodies can relieve the inhibitory effect on L929 proliferation.

 

Figure 4. Human TNF-a induces the expression of several cytokines, including mMCP1, in homozygous TNF-a humanized mice (TNF-a HO)

Figure 4. Human TNF-a induces the expression of several cytokines, including mMCP1, in homozygous TNF-a humanized mice (TNF-a HO).


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