Gene-targeted mice with a simplified immune system. Even in inbred strains, the magnitude and variable region diversity of an immune response to a simple antigen varies enormously. This fact has hampered the precise prediction of the outcome of an immune response a major challenge for vaccine development. Many questions of antibody production can be attacked in mice with a simplified immune system, i.e., with B-cells that start out with genes encoding only one or a few specificities. The quasi-monoclonal (QM) mouse and its derivatives will be used to study the mechanism of allelic exclusion, generation of antibody diversity, serum immunoglobulin production, and the immune response to cognate antigen. The QM mouse is a gene-targeted mouse that is homozygous for a rearranged VDJ segment at the immunoglobulin heavy-chain locus, the other allele being non-functional. The mouse also has no functional kappa light chain allele. The heavy chain, when paired with any lambda light chain, is specific for the hapten NP. Derivatives of the QM mouse, with a variety of hemizygous and homozygous genotypes will be generated by breeding: (I) mice homozygous for the VDJ heavy -chain transgene; (ii) heterozygous mice with one transgenic VDJ allele and one normal heavy-chain locus in the germline configuration; (iii) QM and heterozygous mice with a rearranged lambda transgene; and (iv) QM mice with a rearranged lambda transgene that are V(D)J recombinase-negative. The degree of allelic exclusion in B-cells and the level of serum immunoglobulins in QM mice as well as the QM-derivatives from it will be compared before and after immunization, with and without adoptive transfer. Furthermore, RAG and T-cell independent mechanisms of repertoire diversifications will be studied. In the absence of allelic exclusion, receptors to self-antigens might be triggered along with receptors to non-self, which would lead to autoimmunity, or cells displaying two receptors might be taken out of the functional pool, which would diminish the repertoire available for protection against disease.
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