Dynamics of Tolerance induction by B‐cell delivered Gene Therapy

Abstract

B cells, functioning as APC's, can provide signals to T cells either activating immunity or inducing a specific hyporesponsive state (tolerance). Our laboratory has shown that B cells, when retrovirally transduced with peptide‐IgG, are highly tolerogenic for epitopes fused with the IgG. In this system, a DNA sequence encoding a full‐length protein or an immunodominant epitope is inserted into the N‐terminus of the murine IgG1 heavy chain. After injection into immunocompetent mice, peptide‐IgG transduced B cells are able to induce specific tolerance to the IgG associated antigen. This gene therapy approach has been applied to several animal models of autoimmune diseases, including EAU, EAE, and diabetes, as well as in hemophilia. In these disease models, specific tolerance was observed in both Th1 and Th2 responses. Moreover, our data indicate that the IgG heavy chain is critical for efficient tolerance induction and trafficking to endosomal processing pathways. We recently reported that activation with LPS, anti‐IgM or CD40L led to efficient tolerogenic presentation, but CpG‐activated B cells were not tolerogenic. While IL‐10 production by LPS‐activated B cells may play a role, analysis by two‐photon microscopy suggests that the LPS‐stimulated B cells interact with specific T cells longer, thus facilitating tolerogenic signals. We also propose that IgG promotes tolerance by co‐presentation of regulatory epitopes. (Supported by NIH grants AI035622 and GM41514)MM and YS contributed equally to this work