Primatized Mouse Model Enhances Primate Stem Cell Engraftment
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Solution Overview
Problem
Current methods for hematopoietic stem cell transplantation, such as hematopoietic stem and progenitor cell (HSPC) engraftment in immune-deficient mice, face challenges with suboptimal engraftment and immune cell reconstitution, limiting the effectiveness of therapies and requiring costly and time-consuming non-human primate studies.
Innovation Solution
A primatized mouse model is developed by injecting HSPCs from non-human primates into immune-deficient mice, along with co-transplantation of a fetal thymus fragment, to enhance engraftment and immune cell reconstitution, utilizing transgenic mice expressing human cytokines for improved cross-reactivity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HSPCs from non-human primates are engrafted into immune-deficient mice using conventional methods, then engraftment can be achieved, but the engraftment level is suboptimal and immune cell reconstitution is insufficient
Solution Approach 1:
The patent modifies the cytokine environment by introducing transgenic mice expressing human cytokines (IL-3, GM-CSF, or M-CSF) to change the biochemical parameters of the host system. This parameter change enables better compatibility and support for non-human primate HSPC engraftment, resolving the contradiction between achieving engraftment and maintaining effective immune cell reconstitution.
Solution Approach 2:
The patent uses fetal thymus tissue as an intermediary component to facilitate the engraftment process. The thymus serves as a bridging structure that supports the development and maturation of engrafted HSPCs, enabling both successful engraftment and effective immune cell reconstitution simultaneously.
2Reliability
If non-human primate HSPCs are engrafted into mice with wild-type murine cytokines, then engraftment can occur, but cross-reactivity is insufficient leading to poor engraftment persistence
Solution Approach 1:
The patent changes the cytokine parameter by using transgenic mice that express human cytokines instead of wild-type murine cytokines. This parameter change creates a biochemical environment with better cross-reactivity to non-human primate HSPCs, enabling persistent engraftment while maintaining adaptability to the donor cells.
3Reliability
If fetal thymus co-transplantation is performed with HSPCs, then multilineage immune cell engraftment is achieved, but the procedure complexity increases
Solution Approach 1:
The patent merges two transplantation operations (HSPC injection and fetal thymus implantation) into a single coordinated procedure. This merging approach achieves multilineage engraftment through the synergistic effect of both components while managing the overall procedural complexity as a unified process rather than separate steps.
4Ease of manufacture
If adult mobilized blood HSPCs are used for engraftment, then the procedure is simpler, but engraftment levels remain low
Solution Approach 1:
The patent changes the host environment parameters by using transgenic mice expressing human cytokines, which compensates for the limited engraftment potential of adult mobilized blood HSPCs. This parameter change in the host system enables simpler HSPC preparation to achieve reliable engraftment levels that would otherwise require more complex cell processing.
Data Source
AI summary
A primatized rodent or swine, and methods of making and using the primatized rodent or swine, are provided.