AbstractThe rat is a species frequently used in immunological studies but, until now, there were no models with introduced gene‐specific mutations. In a recent study, we described for the first time the generation of novel rat lines with targeted mutations using zinc‐finger nucleases. In this study, we compare immune development in two Ig heavy‐chain KO lines; one with truncated Cμ and a new line with removed JH segments. Rats homozygous for IgM mutation generate truncated Cμ mRNA with a de novo stop codon and no Cγ mRNA. JH‐deletion rats showed undetectable mRNA for all H‐chain transcripts. No serum IgM, IgG, IgA and IgE were detected in these rat lines. In both lines, lymphoid B‐cell numbers were reduced >95% versus WT animals. In rats homozygous for IgM mutation, no Ab‐mediated hyperacute allograft rejection was encountered. Similarities in B‐cell differentiation seen in Ig KO rats and ES cell‐derived Ig KO mice are discussed. These Ig and B‐cell‐deficient rats obtained using zinc‐finger nucleases‐technology should be useful as biomedical research models and a powerful platform for transgenic animals expressing a human Ab repertoire.