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 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.
Zambidis
E T
ET
Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Barth
R K
RK
Scott
D W
DW
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
D000939:Epitopes; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins