Epitope-specific tolerance induction with an engineered immunoglobulin

Elias Zambidis, D. W. Scott

Research output: Contribution to journalArticle

Abstract

Isologous and heterologous immunoglobulins have been shown to be extremely effective as tolerogenic carriers for nearly 30 years. The efficacy of these proteins is due in part to their long half-life in vivo, as well as their ability to crosslink surface IgM with Fc receptors. The concept of using IgG as a carrier molecule to induce unresponsiveness in the adult immune system has been exploited for simple haptens, such as nucleosides, as well as for peptides. To further evaluate the in vivo potential of these molecules for inducing tolerance to a defined epitope, we have engineered a fusion protein of mouse IgG1 with the immunodominant epitope 12-26 from bacteriophage λ cI repressor protein. This 15-mer, which contains both a B-cell and T-cell epitope, has been fused in-frame to the N terminus of a mouse heavy chain IgG1 construct, thus creating a 'genetic hapten-carrier' system. We describe a novel in vitro and in vivo experimental system for studying the feasibility of engineered tolerogens, consisting of a recombinant flagellin challenge antigen and a murine IgG1 tolerogen, both expressing the λ repressor epitope 12-26. Herein, we show that peptide-grafted IgG molecules injected i.v., or expressed by transfected, autologous B cells, can efficiently modulate the cellular and humoral immune responses to immunodominant epitopes. This model displays the feasibility of 'tailor-designing' immune responses to whole antigens by selecting epitopes for either tolerance or immunity.

Original languageEnglish (US)
Pages (from-to)5019-5024
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number10
DOIs
Publication statusPublished - May 14 1996
Externally publishedYes

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Keywords

  • antigen presentation
  • gene therapy
  • immune self-tolerance
  • protein engineering

ASJC Scopus subject areas

  • Genetics
  • General

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