Flk2 Deficient Rag-/-γc-/- Mice for Human Dendritic Cell Development
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Solution Overview
Problem
Current small animal models for studying human dendritic cells in vivo have suboptimal development and homeostasis due to competition with endogenous mouse dendritic cells, leading to immune responses primarily of mouse origin, which does not accurately mimic human immune responses.
Innovation Solution
Development of Flk2 deficient Rag-/-γc-/- mice engrafted with human hematopoietic stem cells and treated with exogenous Flk2L, which compromises mouse DC development and enhances human DC development, resulting in a murine model with increased numbers of functional human dendritic cells and associated immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If human hematopoietic stem cells are transferred into conventional mice to generate HIS mice, then human B, T, and NK cells can be developed, but endogenous mouse dendritic cells compete with human DC development, resulting in suboptimal human DC numbers and function
Solution Approach 1:
The patent removes the harmful element (endogenous mouse DC development capability) by using Flk2 deficient Rag -/-γc-/- mice that lack the ability to develop mouse DCs. This extraction eliminates the competition for cytokine resources, allowing human DCs to develop optimally without being outcompeted by mouse DCs.
Solution Approach 2:
The patent changes the biological parameter of the mouse model by introducing Flk2 deficiency and γc chain deficiency. These genetic modifications alter the cytokine environment and cell development capabilities, creating a permissive environment for human DC development while preventing mouse DC development.
2Quantity of substance
If exogenous cytokine protocols are used to boost human DC development, then human DC numbers increase, but the model complexity and cytokine administration requirements increase
Solution Approach 1:
The patent enables the system to self-regulate human DC development through the engineered mouse's own cytokine environment. The Flk2 deficient Rag -/-γc-/- mouse background naturally creates conditions favorable for human DC development without requiring complex external cytokine administration protocols, reducing experimental complexity.
3Reliability
If conventional HIS mice are used for vaccine evaluation, then some immune responses can be measured, but the responses are primarily of mouse origin rather than human, reducing translational relevance
Solution Approach 1:
The patent converts the potential harm of having a mixed immune system into a benefit by selectively eliminating mouse DC development while preserving human lymphocyte development. The Flk2 deficient Rag -/-γc-/- background specifically prevents mouse DC formation (the harmful element) while allowing human DCs to thrive, thereby improving the translational relevance of immune response measurements.
Data Source
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Figure 2
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AI summary
The present invention relates to a transgenic animal mode! system based on the development of transgenic mice bearing components of the human immune system. Specifically, the Invention relates to a Flk2 deficient Rag "?c" transgenic mouse and the engraftment of said mouse with human hematopoietic stem cells. The present invention further presides methods for increasing the numbers of functionally competent human dendritic cells is and the hematopoietic targets celis that they interact with in said transgenic mouse through the administration of Flk2L. The transgenic animal model system of the invention may be used for testing human vaccine candidates, for screening potential Immune adjuvants and for developing novel therapeutics.