Chimeric MHC I Animals for Human CTL Identification
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Solution Overview
Problem
Current systems lack effective methods to mimic the human cellular immune response for identifying disease-associated antigens and enhancing the activity of CTL populations, particularly for therapeutic applications such as vaccines and combating infections.
Innovation Solution
Genetically modified non-human animals, like rodents, are engineered to express human or humanized MHC class I and β2 microglobulin proteins, allowing for the generation and identification of peptides that associate with human MHC class I proteins and bind to CD8+ T cells, thereby mimicking aspects of the human immune system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified non-human animals are engineered to express human MHC class I and β2 microglobulin proteins, then the ability to mimic human cellular immune response is improved, but the complexity of the biological system increases
Solution Approach 1:
The patent uses genetically modified non-human animals as an intermediary system to bridge the gap between simple animal models and complex human immune system studies. These animals express human MHC class I and β2 microglobulin proteins, enabling them to present human peptides to human CD8+ T cells while maintaining the simpler biology of non-human animals for experimental manipulation.
2Measurement precision
If chimeric human/non-human MHC I polypeptides are expressed in non-human animals, then the ability to identify therapeutically useful CTL populations is improved, but the manufacturing precision of the genetic modification process becomes more challenging
Solution Approach 1:
The patent applies local quality by creating chimeric MHC I polypeptides that have human extracellular domains (for peptide binding and T cell recognition) combined with non-human transmembrane and cytoplasmic domains (for cellular integration and signaling). This localized humanization approach allows the system to mimic human immune responses where needed while maintaining compatibility with the host animal's cellular machinery.
3Reliability
If humanized MHC class I molecules are expressed on cell surfaces, then the ability to present human peptides to CD8+ T cells is improved, but the stability of the biological system may be compromised
Solution Approach 1:
The patent creates composite MHC class I molecules that combine human and non-human protein domains. The human extracellular domains provide the necessary function for peptide binding and T cell recognition, while the non-human transmembrane and cytoplasmic domains ensure proper integration into the cell membrane and compatibility with the host cell's signaling pathways, thereby maintaining system stability.
Data Source
AI summary
The invention provides genetically modified non-human animals that express chimeric human/non-human MHC I polypeptide and/or human or humanized β2 microglobulin polypeptide, as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same. Methods of using the genetically modified animals to study various aspects of human immune system are provided.