Humoral immune response in mice against a circulating antigen induced by adenoviral transfer is strictly dependent on expression in antigen-presenting cells

Gutless adenovirus: last-generation adenovirus for gene therapy

“…70 Vectors that mediate transgene expression in APCs trigger antibody formation because they increase the probability of neoantigen presentation by APCs, 71 and, hence, careful selection of tissue-specific promoters may significantly improve adenovirus-associated toxicity profiles and diminish or abolish APC transduction and transgene expression. 72 In addition, systemic administration of gutless vectors in a clinical setting might be inefficient because of the presence of circulating neutralizing antibodies against the same or crossreactive serotype as a consequence of a natural infection or as a result of previous vector administration.…”

The impact of antigen expression in antigen-presenting cells on humoral immune responses against the transgene product

“…10 The distinction between both forms of immunological unresponsiveness can be made by challenging mice with subcutaneous administration of the neo-antigen formulated in complete Freund's adjuvant several weeks after gene transfer. 10,11 In the case of immunological tolerance, no antibodies appear after classical immunization, whereas in the case of immunological ignorance, classical immunization will break the immunological unresponsiveness.…”

“…10 The distinction between both forms of immunological unresponsiveness can be made by challenging mice with subcutaneous administration of the neo-antigen formulated in complete Freund's adjuvant several weeks after gene transfer. 10,11 In the case of immunological tolerance, no antibodies appear after classical immunization, whereas in the case of immunological ignorance, classical immunization will break the immunological unresponsiveness. The risk of antibody formation against the transgene product may be limited by hepatocyte-directed gene transfer [11][12][13] and even more pronounced by restricting transgene expression to hepatocytes using hepatocyte-specific expression cassettes.…”

“…The risk of antibody formation against the transgene product may be limited by hepatocyte-directed gene transfer [11][12][13] and even more pronounced by restricting transgene expression to hepatocytes using hepatocyte-specific expression cassettes. 10,14 Whether use of potent hepatocyte-specific expression cassettes consistently prevents the occurrence of a humoral immune response against the transgene product is currently unclear.…”

“…10 This suggests highly efficient class II presentation of peptides derived from endogenously synthesized proteins in antigen-presenting cells. To evaluate whether immunological unresponsiveness for human apo A-I after adenoviral hepatocyte-specific gene transfer 10,15 is independent of the H-2 complex haplotype, we performed gene transfer with 5 Â 10 10 particles of AdA-I in C57BL/6 mice (H-2 b ), 129 (H-2 b ) mice, Balb/c mice (H-2 d ), C3H/HeJ (H-2 k ) mice, Fvb (H-2 q ) mice and outbred Swiss Webster mice. AdA-I is an E1E3E4-deleted vector containing a potent hepatocytespecific expression cassette consisting of the 1.5 kb human a 1 -antitrypsin promoter upstream of the genomic human apo A-I sequence and four copies of the human apo E enhancer.…”