Transgenic Mouse Model for Human Immune System Reconstitution
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Solution Overview
Problem
Current humanized mouse models fail to adequately reconstitute functional human T and B cells, serum levels of human IgM and IgG, and elicit immune responses comparable to humans, due to the lack of expression of Human Leukocyte Antigens (HLA) molecules, limiting their effectiveness in testing immunogenicity and protective efficacy of human vaccines.
Innovation Solution
A transgenic mouse model is developed by expressing human leukocyte antigen DR4 and costimulatory molecules (CD80) upon infusion of human HLA-matched hematopoietic stem cells, creating a multi-transgenic animal capable of reconstituting a functional human immune system, including high levels of human T cell reconstitution, development of human regulatory T cells, and production of human immunoglobulins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current humanized mouse models are used, then long-term hematopoiesis of human B cells is permitted, but poor development of functional human T cells and insufficient serum levels of human IgM and IgG occur
Solution Approach 1:
The patent changes the genetic parameters of the mouse model by knocking out multiple genes (Rag1, Il2rg, HLA-A2) and introducing transgenic expression of HLA-DR4 and CD80. This multi-parameter genetic modification enables both human B cell long-term hematopoiesis and functional human T cell development, resolving the contradiction between B cell reconstitution and T cell functionality.
2Duration of action of stationary object
If current humanized mouse models are used, then long lifespan is achieved, but lack of appropriate MHC molecules for T-cell selection occurs
Solution Approach 1:
The patent modifies the MHC molecule parameter by eliminating mouse MHC class I (through Il2rg knockout) and class II (through Rag1 knockout), and introducing human MHC class II (HLA-DR4) transgenic expression. This parameter change enables proper human T-cell selection while maintaining long mouse lifespan.
3Quantity of substance
If transgenic expression of human HLA-A2 is introduced, then higher level of engraftment of human cells is achieved, but low and variable level of T cell-dependant antibody responses occurs
Solution Approach 1:
The patent changes the HLA molecule parameter from HLA-A2 (class I) to HLA-DR4 (class II), and adds CD80 costimulatory molecule expression. This parameter change improves both human cell engraftment levels and T cell-dependant antibody responses, overcoming the limitations of HLA-A2 transgenic models.
4Quantity of substance
If complete absence of IL2rg gene is introduced, then higher level of engraftment of human cells is achieved, but many innate-immune defects occur
Solution Approach 1:
The patent changes the immune system parameter by combining Il2rg knockout (for high engraftment) with HLA-DR4 and CD80 transgenic expression. This compensatory parameter change allows high human cell engraftment while the human MHC and costimulatory molecules provide functional compensation for the lost innate immunity.
Data Source
AI summary
Provided is a transgenic animal model for testing immunogenicity and protective efficacy of human vaccines and the method for generating such a multitransgenic animal. Also disclosed are methods for screening compositions for human vaccine development. More specifically, a mouse model capable of expressing human leukocyte antigen DR4, and human costimulatory molecules (CD80) upon infusion of human HLA-matched hematopoietic stem cells, which can develop into a functional human immune system is provided.