Genetically transferred central and peripheral immune tolerance via retroviral-mediated expression of immunogenic epitopes in hematopoietic progenitors or peripheral B lymphocytes

Mol Med. 1997 Mar;3(3):212-24.

Abstract

Background: Based on the hypothesis that IgGs are potent tolerogens and that immature lymphohematopoietic antigen-presenting cells (APC), and even mature peripheral B cells, may be effective APC for tolerance induction, we designed an immunoglobulin fusion protein retroviral expression vector to test the role of B cells in a novel gene therapy strategy for the transfer of immune tolerance.

Methods: An immunodominant epitope (residues 12-26 of the lambda repressor cI protein) was fused in frame to an IgG heavy chain in a retroviral vector, which was used to infect either bone marrow cells or activated peripheral B lymphocytes. These cells were transferred into syngeneic recipients, who were subsequently challenged with the 12-26 peptide in adjuvant.

Results: Bone marrow (BM) chimeras generated with retrovirally transduced bone marrow were shown to be profoundly unresponsive to the 12-26 peptide at both the humoral and cellular levels, but were competent to respond to an unrelated protein (lysozyme or PPD). Importantly, we also show that immunocompetent adult recipients infused with transduced mature, activated B lymphocytes, are rendered unresponsive by this treatment. Surprisingly, lymphoid-deficient BM progenitors from syngeneic SCID donors could also be transduced to produce tolerogenic APC.

Conclusions: Our data suggest that activated B cells are sufficient to be effective tolerogenic APC in immunocompetent adult mice, but that nonlymphoid cells may also induce tolerance in reconstituted hosts. This approach for gene-transferred tolerogenesis has the potential to be maintained indefinitely, and it requires only knowledge of cDNA sequences of target antigens.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibody Formation
  • Antigen-Presenting Cells / immunology
  • B-Lymphocytes / immunology*
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / immunology*
  • Gene Transfer Techniques
  • Hematopoietic Stem Cells / immunology*
  • Immune Tolerance / genetics
  • Immune Tolerance / immunology*
  • Immunity, Cellular
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Immunosuppression / methods*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Retroviridae

Substances

  • Epitopes, B-Lymphocyte
  • Immunodominant Epitopes
  • Immunoglobulin Heavy Chains
  • Recombinant Fusion Proteins