Human IL-15-secreting immunodeficient mouse for NK cell maintenance
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Solution Overview
Problem
Current humanized immunodeficient mice models, such as NOG mice, have limitations in maintaining human NK cells for extended periods and efficiently differentiating transplanted human NK cells, which hampers long-term in vivo studies and tumor suppression capabilities.
Innovation Solution
Generation of NOD-scid, IL-2rγnull-hIL-15 Tg mice by inserting a DNA sequence encoding human IL-15 operably ligated with a human IL-2 signal peptide into immunodeficient mice, enabling the secretion of human IL-15 and supporting the long-term engraftment and function of human NK cells, including their ability to suppress tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunodeficient mice (NOG mice) are used, then engraftment of human cells is improved, but the lifespan of human NK cells is shortened
Solution Approach 1:
The patent introduces a transgenic human IL-15 gene into the mouse genome, fundamentally changing the cytokine environment parameter. This allows continuous production of human IL-15, which is the specific growth factor required for human NK cell survival and proliferation, thereby extending their lifespan in the mouse model while maintaining high engraftment efficiency
Solution Approach 2:
Human IL-15 acts as an intermediary substance that mediates between the mouse host environment and human NK cells. The transgenic mouse produces human IL-15 endogenously, creating a supportive niche that enables long-term persistence and function of transplanted human NK cells without requiring continuous external administration
2Ease of operation
If conventional immunodeficient mice are used, then human cell transplantation is facilitated, but differentiation efficiency of human NK cells is reduced
Solution Approach 1:
By changing the cytokine milieu parameter through transgenic expression of human IL-15, the patent creates optimal conditions for human NK cell differentiation. The constitutive presence of this critical differentiation factor significantly enhances the efficiency with which transplanted human cells differentiate into functional NK cells
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The NOD-scid, IL-2rγnull-hIL-15 Tg mice maintain human NK cells for at least 6 months, allowing for prolonged in vivo studies and effective tumor suppression, both in vitro and in vivo, due to the sustained expression of human IL-15 and enhanced NK cell engraftment and function.
Implementation Method 1
a DNA in which a cDNA sequence encoding interleukin 15 (hIL-15) is operably ligated to a cDNA sequence encoding a human interleukin 2 (hIL-2) signal peptide
Data Source
AI summary
An object of the present invention is to provide a mouse that enables the functions of human NK cell to be studied. A DNA consisting of a nucleotide sequence represented by SEQ ID NO: 1, which is a gene region comprising a DNA in which a cDNA sequence encoding interleukin 15 (IL-15) is operably ligated to a cDNA sequence encoding the signal peptide of human interleukin (IL-2), is inserted to immunodeficient mouse cDNA. In NOD-scid, IL-2rγnull-hIL-15 Tg mice thus generated, hCD56+ cell having a concentration sufficient for conducting in vivo study on human mature NK cell are detected for at least 6 months after transplantation.