Immune Suppression

Both cellular and humoral immune responses have been implicated in the shortening of the time span of transgene expression. Transgene expression is limited by eradication of the transfected cells. Induction of anti-Ad neutralizing antibodies precludes the opportunity to readminister the gene therapy. Immunosuppressive drugs including cyclophosphamide [6], cyclosporine [7], and FK506 [8-10], have reduced the T-cell immune response. Lochmuller et al. [8] used FK506, resulting in prolonged expression of adenovirus-mediated dystrophin gene transfer in mdx adult mice for at least 2 months, even though the FK506 treatment was discontinued after 1 month. There was a marked reduction in inflammation and reduced levels of nitric oxide synthesase in macrophages in the muscles of such treated animals. Howell et al. [9] used the dystrophin-deficient golden retriever dog model and showed that cyclosporine significantly prolonged transgene expression after Ad-mediated expression of a truncated human dystrophin gene. Ilan et al. [10] showed that combined immunotherapy in humans resulted in prolonged transgene expression.

Combined therapy with cyclosporine, azathioprin, and prednisone has been shown to reduce the immune response to adenovirus-mediated gene therapy and prolonged transgene expression.

Other strategies reported to control the immune response include reduction of T-cell response by oral tolerance [11], thymic tolerance, anti-T-cell therapy, and anti-CD4 monoclonal antibody therapy [12-15]. Modulation of T-cell subset development after adenovirus therapy has successfully been attempted using recombinant interleukin 12 (IL-12). IL-12 activates Th-1 cells to secrete gamma interferon (IFNy) which diminishes Th-2 T-cell formation and reduces formation of neutralizing antibodies [16].

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