Humanized Immunodeficient Mouse Model for Conditioning-Free Engraftment
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Solution Overview
Problem
Existing humanized mouse models face challenges such as graft-versus-host disease (GvHD), high costs, and insufficient engraftment of human immune cells, limiting their use in evaluating human cell therapy products and clinical applications.
Innovation Solution
Development of a humanized immunodeficient mouse model with a robust human immune system, using NOD mice genetically modified to express human cytokines and engrafted with unfractionated human cells without myeloablation, supporting long-term engraftment and function of human T cells, NK cells, and innate immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If myeloablatve conditioning is used to facilitate human HSC engraftment, then engraftment efficiency is improved, but mouse survival and human cell function are compromised
Solution Approach 1:
The patent changes the genetic parameters of the immunodeficient mouse by introducing specific transgenes (human IL-7, human IL-15, human IL-3, human GM-CSF, human SCF) that modify the mouse cytokine environment. This allows human HSCs to engraft without myeloablatve conditioning, as the transgenic cytokines provide the necessary growth and survival signals, thereby improving both engraftment efficiency and mouse survival simultaneously
Solution Approach 2:
The patent uses transgenic cytokines as intermediary substances that mediate between the mouse host and human HSCs. These cytokines (IL-7, IL-15, IL-3, GM-CSF, SCF) act as bridging molecules that support human cell survival and proliferation in the mouse environment without requiring destructive conditioning therapies
2Adaptability or versatility
If human PBMC engraftment is used to replicate human adaptive and innate immunity, then immune system representation is improved, but GvHD develops
Solution Approach 1:
The patent modifies the immunodeficient mouse background by introducing specific transgenes that alter the cytokine environment. This creates a permissive environment where human PBMCs can engraft without triggering GvHD, as the transgenic cytokines (particularly IL-7 and IL-15) support human T cell and NK cell survival without activating harmful immune responses against the mouse host
3Adaptability or versatility
If multiple individual mouse models are used to evaluate different immune biology aspects, then evaluation comprehensiveness is improved, but project cost and timeline are increased
Solution Approach 1:
The patent creates a universal mouse model platform by combining multiple transgenes (human IL-7, IL-15, IL-3, GM-CSF, SCF) into a single immunodeficient background. This multi-functional model can simultaneously support engraftment of human HSCs, PBMCs, and various immune cell types, allowing researchers to evaluate multiple aspects of human immune cell biology in a single model system rather than requiring multiple separate models
Data Source
AI summary
The present disclosure provides, in some aspects, humanized immunodeficient mouse models that support long-term engraftment and function of human T cells, natural killer cells, and myeloid cells, without the need for conditioning.