Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated gene expression: The IgG scaffold is important for induction and maintenance of immune hyporesponsiveness (gene therapyyimmune self-toleranceyretroviral vectoryantigen presentation)

IgG molecules can be highly tolerogenic car- riers for associated antigens. Previously, 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 murine IgG heavy chain, were rendered profoundly unresponsive to that epitope. To further investigate whether tolerance to larger molecules can be achieved via this ap- proach and whether the IgG scaffold is important for induc- tion and maintenance of immunological tolerance, we engi- neered two retroviral constructs encoding the cI l repressor (MBAE-1-102 and MBAE-1-102-IgG) for gene transfer. Our results show that recipients of bone marrow or peripheral B cells, transduced with the MBAE-1-102-IgG recombinant, are hyporesponsive to p1-102. In addition, the self-IgG scaffold enhanced the induction and maintenance of such an immune hyporesponsiveness. Thus, our studies demonstrate that in vivo-expressed IgG heavy chain fusion protein can be pro- cessed and presented on the appropriate MHC class II, resulting in hyporesponsiveness to that antigen and offering an additional therapeutic approach to autoimmune diseases.