Humanized BAFF Mouse Model for Human Lymphocyte Survival
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Solution Overview
Problem
Current in vivo systems for testing and developing therapeutics for autoimmune diseases are inadequate, lacking effective models for human lymphocyte activation and survival post-immunization and engraftment of human hematopoietic stem cells.
Innovation Solution
Engineering non-human animals, such as mice or rats, to express a humanized Baff gene that encodes the extracellular portion of a human BAFF protein linked to the intracellular portion of a mouse Baff protein, enabling improved activation and survival of human lymphocytes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a mouse Baff gene is used in the in vivo system, then the system is simple to establish, but it fails to support effective human lymphocyte activation and survival post-immunization and engraftment
Solution Approach 1:
The Baff protein is divided into two functional domains: the extracellular portion (amino acids 1-285) which is replaced with human sequence to enable human lymphocyte interaction, and the intracellular portion (amino acids 286-339) which retains the mouse sequence for proper signaling and membrane anchoring. This segmentation allows the protein to function in both human and mouse biological contexts.
Solution Approach 2:
The chimeric Baff protein acts as an intermediary between human and mouse biological systems. The human extracellular domain serves as the mediator for human lymphocyte recognition and binding, while the mouse intracellular domain serves as the mediator for mouse cell signaling pathways, enabling cross-species compatibility.
2Reliability
If exons 3 to 6 of human BAFF gene are introduced to encode the extracellular portion, then human lymphocyte recognition is improved, but the genetic modification complexity increases
Solution Approach 1:
The genetic modification is segmented into specific exon replacements (exons 3-6) rather than complete gene replacement. This allows precise introduction of human BAFF coding sequence for the extracellular domain while preserving mouse regulatory elements and intracellular signaling sequences, reducing overall complexity.
Solution Approach 2:
The genetic modification applies local quality change by replacing only the specific region encoding the extracellular domain (exons 3-6) with human sequence, while maintaining mouse sequence in other regions. This localized modification achieves the necessary human lymphocyte recognition without requiring complete gene replacement.
Data Source
AI summary
Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.