Human antibodies from transgenic mice

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• B cells are crucial for adaptive immunity, producing antibodies through immunoglobulin gene rearrangement, somatic mutation, and class switching.
• Engineering mice with targeted gene knockouts is a key method for studying immune cell development and function.

Purpose of the Study:

• To develop a mouse model capable of producing human monoclonal antibodies.
• To investigate the processes of immunoglobulin gene expression, including heavy chain class switching, using human transgenes.

Main Methods:

• Homologous recombination in embryonic stem (ES) cells to create B cell-deficient mice lacking endogenous immunoglobulin heavy and kappa light chain genes.
• Introduction of human germline-configuration heavy- and kappa light-chain minilocus transgenes to rescue B cell development.
• Immunization of engineered mice and subsequent antibody production using hybridoma technology.

Main Results:

• B cell development was successfully rescued in mutant mice by human immunoglobulin transgenes.
• Transgenes underwent rearrangement, class switching, and somatic mutation upon antigen stimulation, mirroring the humoral immune response.
• Human sequence, antigen-specific monoclonal antibodies were generated from immunized mice.
• Heavy chain class switching was observed within an autonomous transgene, a previously unrecorded phenomenon.

Conclusions:

• The engineered mice serve as a valuable model for studying human immunoglobulin gene expression and the humoral immune response.
• This model facilitates the generation of human monoclonal antibodies for therapeutic and research applications.
• The study provides novel insights into the mechanisms of immunoglobulin heavy chain class switching in a transgenic context.