Immunodeficient Mouse Expressing Human IL-15 for NK Cell Studies
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for mouse models that effectively support the study of human natural killer (NK) cells and interleukin 15 (IL-15)-dependent cell populations for research in human immunity, cancer, and infectious diseases, as mouse IL-15 cannot support the development of human NK cells, and existing models require additional factors like IL-15 receptor alpha.
Innovation Solution
An immunodeficient mouse genetically modified to express human interleukin 15 (hu-IL-15), lacking functional endogenous mouse NK cells, is engrafted with human hematopoietic stem cells or peripheral blood mononuclear cells, providing a model for assessing NK-cell mediated antibody-dependent cellular toxicity and IL-15-dependent processes without the need for additional factors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If mouse IL-15 is used in the mouse model, then the model is simple to maintain, but human NK cells cannot develop or survive
Solution Approach 1:
The patent changes the cytokine parameter from mouse IL-15 to human IL-15 in the mouse model system. This parameter change enables human NK cells to receive appropriate signaling for development and survival, resolving the incompatibility between mouse model simplicity and human cell functionality.
Solution Approach 2:
Human IL-15 acts as an intermediary substance that bridges the gap between the mouse model environment and human NK cell requirements. By introducing this intermediary cytokine, the model supports human cell development without requiring complex humanized immune system components.
2Adaptability or versatility
If additional factors like IL-15 receptor alpha are supplied, then human NK cell development is supported, but the model complexity increases
Solution Approach 1:
The patent extracts the essential requirement from the complex system of multiple factors (IL-15, IL-15Rα, etc.) and identifies that human IL-15 alone is sufficient to support human NK cell development. This extraction simplifies the model by removing unnecessary complexity while maintaining functionality.
Solution Approach 2:
Human IL-15 serves multiple functions in the model: it acts as both the cytokine signal and the sole essential factor for human NK cell development and survival. This multi-functionality eliminates the need for additional factors like IL-15 receptor alpha supplementation.
3Adaptability or versatility
If in vitro culture with human IL-15 is used, then human NK cells can be maintained, but repeated injections of recombinant IL-15 are required
Solution Approach 1:
The mouse model expresses human IL-15 endogenously, enabling it to self-produce the necessary cytokine for human NK cell maintenance. This self-service capability eliminates the need for external supplementation through repeated injections, as the model sustains itself autonomously.
Solution Approach 2:
The model is pre-configured with human IL-15 expression capability before human NK cells are introduced. This preliminary action ensures that the cytokine is already available in the model environment, eliminating the need for subsequent repeated injections to maintain human NK cells.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
An immunodeficient mouse is provided which is useful as a model of functions and regulation of human natural killer (NK) cells and other interleukin 15 (IL-15)-dependent cell populations and processes in studies of human immunity, cancer, infectious diseases, and other areas. According to specific aspects, an immunodeficient mouse is provided which is genetically modified to express human interleukin 15, wherein the mouse does not have or produce functional mouse natural killer cells, and wherein the mouse is modified to include human natural killer cells. Methods of identifying anti-tumor activity of a test substance using a mouse of the present invention are described along with methods of making the mouse.