Immortalization of B cells from immune humans seems to be the logical strategy to avoid these problems. However, the methods to achieve this goal have showed low efficiencies, although some progress has recently been reported [8, 9] . Nevertheless, the major disadvantage of human B cells immortalization is the need for cells from either vaccinated individuals or patients who had recovered from an infection. Thus, to fully exploit the Ig repertoire of human B cells in an in vivo setting, we explored the possibility to raise mAbs following de novo induction of human B cell responses in mice carrying elements of the human immune system (HIS). HIS mice are generated by engrafting immunodeficient mice with human hematopoietic stem cells (HSC) with or without human lymphoid tissues from fetal origin [10, 11, 12] . In particular, mice deficient for the recombinase activating gene-2 (Rag2) and the common gamma chain of the IL-2 receptor (Il2rg) on a BALB/c or a non-obese diabetic (NOD) background are permissive for human HSC xenografts. Inoculation of newborn mice from these strains with human HSC of fetal or umbilical cord blood origin gives rise to robust engraftment of a number of immune cells, including T, B, NK and dendritic cells. In this work, we describe a convenient approach to generate fully human mAbs based on the immunization of BALB/c Rag2 2/2 IL-2Rcc 2/2 engrafted with human CD34 + CD38 2 HSC [13, 14] . To this end, HIS mice were immunized with commercial vaccines against hepatitis B virus (HBV) and tetanus. Following immunization, human CD19 + B cells were sorted based on surface CD27 expression, as a marker of memory phenotype, and the isotype of surface Igs. The sorted B cell populations were immortalized in vitro by retroviral transduction with human B cell lymphoma (BCL)-6 and BCL-XL genes and antigen-specific B cell clones were established and characterized.