Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated gene expression: The IgG scaffold is important for induction and maintenance of immune hyporesponsiveness

IgG molecules can be highly tolerogenic carriers for associated antigens. P reviously, we reported that recipients of bone marrow or lipopolysaccharide -stimulated B-cell blasts, both of which were retrovirally gene-transferred with an immunodominant peptide in-frame with the variable region of a muri ne IgG heavy chain, were rendered profoundly unresponsive to that epitope. To further investigate whether tolerance to larger molecules can be achieve d via this approach and whether the IgG scaffold is important for induction and maintenance of immunological tolerance, we engineered two retroviral c onstructs encoding the cI lambda repressor (MBAE-1-102 and MBAE-1-102-IgG) for gene transfer. Our results show that recipients of bone marrow or perip heral B cells, transduced with the MBAE-1-102-IgG recombinant, are hyporesp onsive to p1-102. In addition, the self-IgG scaffold enhanced the induction and maintenance of such an immune hyporesponsiveness. Thus, our studies de monstrate that in vivo-expressed IgG heavy chain fusion protein can be proc essed and presented on the appropriate MHC class II, resulting in hyporespo nsiveness to that antigen and offering an additional therapeutic approach t o autoimmune diseases.