EPITOPE-SPECIFIC TOLERANCE INDUCTION WITH AN ENGINEERED IMMUNOGLOBULIN

Isologous and heterologous immunoglobulins have been shown to be extre mely effective as tolerogenic carriers for nearly 30 years. The effica cy of these proteins is due in part to their long half-life in vivo, a s well as their ability to crosslink surface IgM with Fc receptors. Th e concept of using IgG as a carrier molecule to induce unresponsivenes s in the adult immune system has been exploited for simple haptens, su ch 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 i mmunodominant epitope 12-26 from bacteriophage lambda cI repressor pro tein. This 15-mer, which contains both a B-cell and T-cell epitope, ha s been fused in-frame to the N terminus of a mouse heavy chain IgG1 co nstruct, thus creating a ''genetic hapten-carrier'' system. We describ e a novel in vitro and in vivo experimental system for studying the fe asibility of engineered tolerogens, consisting of a recombinant flagel lin challenge antigen and a murine IgG1 tolerogen, both expressing the lambda 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 respo nses to immunodominant epitopes. This model displays the feasibility o f ''tailor-designing'' immune responses to whole antigens by selecting epitopes for either tolerance or immunity.