Naïve HIS mice display an extensive human IgM-expressing B cell repertoire. Based on the analysis of the length of the CDR3 regions, this IgM B cell repertoire is similar to the repertoire of healthy individuals. Thus, HIS mice have no obvious limitations for the generation of human IgM mAbs against any possible antigen. Upon intramuscular vaccinations with either TT or HBsAg, approximately 40% of the HIS mice were able to mount an antigen-specific antibody response. Human IgM-producing B cell lines against both antigens were obtained after isolation of memory B cells followed by ex vivo differentiation into plasmablastlike cells. It is important to highlight that the selection of the antigen-specific human B cell clones relied on relevant bioassays (e.g., ELISA or neutralization test). In contrast to EBV-based approaches, human B cell immortalization using transduction with BCL-6 and BCL-XL preserves the expression of the BCR at the surface and antigen-specific B cell clones can also be selected by binding of labeled antigen to the BCR of immortalized memory B cells (e.g. by using a labeled antigen).