title: Both resting and activated B lymphocytes expressing engineered peptide-Ig molecules serve as highly efficient tolerogenic vehicles in immunocompetent adult recipients.
abstract: To test the potential for genetically transferring foreign sequences into autologous cells for specific modulation of immunity, we have generated 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 residues 12-26 from bacteriophage A cI repressor protein in-frame at the heavy chain N terminus. As expected, 12-26-IgG transgenic mice are profoundly tolerant to the peptide at both the T and B cell levels. Importantly, the injection of transgenic whole spleen, purified B cells, or even bone marrow cells into normal, immunocompetent adults results in profound peptide-specific T cell tolerance, as well as partial B cell tolerance. Injection of LPS-activated peptide-Ig-expressing B cells was uniquely effective at diminishing an ongoing humoral immune response typical of both Th1 and Th2 help. Since fixed transgenic B cells were tolerogenic, this suggests that secretion of the fusion protein is not required for tolerogenicity. These results show that an engineered self Ig, as well as B lymphocytes expressing epitopes from such a fusion protein, can regulate both cellular and humoral immune responses. Moreover, these studies provide the basis for expressing foreign epitopes on engineered IgG for the induction of gene-transferred tolerogenesis in autoimmune states.
authors.affiliation: Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Zambidis
authors.forename: R K
authors.initials: RK
authors.lastname: Barth
authors.forename: D W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D001853:Bone Marrow / Q000528:radiation effects; D000939:Epitopes / Q000032:analysis; D005260:Female; D007108:Immune Tolerance; D007111:Immunity, Cellular / Q000235:genetics; D007114:Immunization; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000637:transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015202:Protein Engineering; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis
chemical_list: D000939:Epitopes; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins