Both Resting and Activated B Lymphocytes Expressing Engineered peptide-Ig Molecules Serve as Highly Efficient Tolerogenic Vehicles in Immunocompetent Adult Recipients

J Immunol. 1997 Mar 1;158(5):2174-82.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Amino Acid Sequence
  • Animals
  • Antigen-Presenting Cells / immunology
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow / radiation effects
  • Epitopes / analysis
  • Female
  • Immune Tolerance*
  • Immunity, Cellular / genetics
  • Immunization
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / genetics*
  • Interphase / immunology
  • Lymphocyte Activation*
  • Lymphoid Tissue / transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics*
  • Peptide Fragments / immunology
  • Protein Engineering
  • Radiation Chimera
  • Recombinant Fusion Proteins / biosynthesis

Substances

  • Epitopes
  • Immunoglobulin G
  • Peptide Fragments
  • Recombinant Fusion Proteins