The potential of monoclonal antibodies, (mAbs), for use in therapeutic and diagnostic applications has not been fully realized in part due to counter-immune responses that often arise in patient recipients of mAb. A growing research effort to "humanize" mAb has focused primarily on the structure or sequence of the antibody variable (V) region domains. However, these approaches may ultimately suffer, as they overlook the requirement of T cell help for the immune counter-reaction and the potential of somatic hypermutation and V-D-J recombination to generate target T cell epitopes within mAb V regions. My approach focuses on this issue. In order to understand some basic principals concerning anti-immunoglobulin immune responses, I have developed a panal of T cell hybridomas and new transgenic mice. Studies with these tools strongly support our basic hypothesis that T cells are tolerant of endogenous immunoglobulin-derived diversity.