BOTH RESTING AND ACTIVATED B-LYMPHOCYTES EXPRESSING ENGINEERED PEPTIDE-IG MOLECULES SERVE AS HIGHLY EFFICIENT TOLEROGENIC VEHICLES IN IMMUNOCOMPETENT ADULT RECIPIENTS

To test the potential for genetically transferring foreign sequences i nto autologous cells for specific modulation of immunity, we have gene rated transgenic mice that express an engineered peptide-IgG construct in the peripheral B cell compartment. B cells from these mice express and can be stimulated to secrete a murine IgG1 chain grafted with res idues 12-26 from bacteriophage lambda cl repressor protein in-frame at the heavy chain N terminus. As expected, 12-26-IgG transgenic mice ar e profoundly tolerant to the peptide at both the T and B cell levels. Importantly, the injection of transgenic whole spleen, purified B cell s, or even bone marrow cells into normal, immunocompetent adults resul ts in profound peptide-specific T cell tolerance, as well as partial B cell tolerance, Injection of LPS-activated peptide-Ig-expressing B ce lls was uniquely effective at diminishing an ongoing humoral immune re sponse typical of both Th1 and Th2 help. Since fixed transgenic B cell s were tolerogenic, this suggests that secretion of the fusion protein is not required for tolerogenicity. These results show that an engine ered self Ig, as well as B lymphocytes expressing epitopes from such a fusion protein, can regulate both cellular and humoral immune respons es. Moreover, these studies provide the basis for expressing foreign e pitopes on engineered IgG for the induction of gene-transferred tolero genesis in autoimmune states.