HUMAN-IMMUNOGLOBULIN TRANSGENES UNDERGO REARRANGEMENT, SOMATIC MUTATION AND CLASS SWITCHING IN MICE THAT LACK ENDOGENOUS IGM

We have generated transgenic mice that contain human-sequence Ig minil oci and, because they are also homozygous for a targeted disruption of their endogenous heavy chain genes, must rely on the transgene sequen ces for B cell receptor expression. Although the human transgenes cont ain only a fraction of the intact human heavy chain locus, these defin ed sequences are able to at least partially restore the humoral immune system in the mouse. B cells expressing human heavy chains develop in the bone marrow, populate peripheral lymphoid tissue and respond spec ifically to antigen. Furthermore, the heavy chain transgenes contain b oth human mu and gamma 1 coding exons as well as the respective mu and gamma 1 switch regions. The sequences included within the transgene a re sufficient to direct class switch recombination. Transgene sequence s are also sufficient to direct somatic mutation of the class-switched heavy chain genes. These observations define the upper limit of the c is-acting sequences necessary to direct heavy chain class switching an d somatic mutation.