Gene transfer to the thymus: A means of abrogating the immune response to recombinant adenovirus
Objective: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vive and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. Summary Background Data: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long- lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. Methods: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. Results: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in vital clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. Conclusions: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.
DeMatteo, RP; Raper, SE; Ahn, M; Fisher, KJ; Burke, C; Radu, A; Widera, G; Claytor, BR; Barker, CF; Markmann, JF; Simmons, RL; Alexander, JW; Busuttil, RW; Lyerly, K; Flye, MW
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