Rooijen, N. (Nico) van

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    Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice
    (Wiley-Blackwell, 2006) Berraondo, P. (Pedro); González-Aseguinolaza, G. (Gloria); Rooijen, N. (Nico) van; Qian, C. (Cheng); Kochanek, S. (Stefan); Barajas, M. (Miguel); Shankar, V. (Vijay); Ochoa, L. (Laura); Crettaz, J. (Julien); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Mauleon, I. (Itsaso)
    Recombinant adenoviruses (Ad) are among the most extensively used vectors for liver gene transfer. One of the major limitations for the clinical application of these vectors is the inflammatory immune response associated with systemic administration of high dose of virus. We evaluated the effect of Ad administration route on the inflammatory immune response and liver transgene expression. We compared direct intrahepatic injection (IH) with the systemic administration via tail vein (IV). IH injection of Ad resulted in a lower inflammatory response and a higher transgene expression. When a relatively low dose of virus was used, IV administration resulted in no detectable protein expression but production of proinflammatory cytokines. In contrast, IH administration induced high levels of transgene expression and no inflammation, although we detected a transient hypertransaminemia, which fully resolved within days. Furthermore, IH injection resulted in a faster protein expression being more intense at the site of injection, whereas IV administration caused slower but diffuse liver expression. IH injection also reduced the spreading of the virus to other organs. Independently of the route, depletion of Kupffer cells significantly enhanced the transduction efficiency of Ad. This effect was stronger when using IV injection, indicating that IH injection partially overcomes Kupffer cell phagocytic activity. Moreover, the antitumor efficacy of high-capacity-Ad encoding murine interleukin-12 (IL-12) was significantly greater when the vector was administered by IH injection than when given IV. In conclusion, IH injection of adenovirus represents a safe and efficient administration route for clinical applications of gene therapy targeting the liver.
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    Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine-plasmid complex
    (Elsevier, 2005) Berraondo, P. (Pedro); González-Aseguinolaza, G. (Gloria); Vales, A. (África); Rooijen, N. (Nico) van; Garzon, M. (Manolo); Ochoa, L. (Laura); Crettaz, J. (Julien); Prieto, J. (Jesús); Vera, M. (María); Ruiz, J. (Juan); Zulueta, J. (Javier); Lasarte, J.J. (Juan José)
    The induction of IFN-gamma-secreting CD8+ T cells and neutralizing antibodies to HIV-1 are both key requirements for prevention of viral transmission and clearance of pathogenic HIV. Although DNA vaccination has been shown to induce both humoral and cellular immune responses against HIV antigens, the magnitude of the immune responses has always been disappointing. In this report, we analyze the ability of polyethylenimine (PEI)-DNA complex expressing an HIV-glycoprotein 120 (gp120) antigen (PEI-pgp120) to induce systemic CD8+ T cell and humoral responses to the gp120 antigen. The administration of PEI-plasmid complex resulted in rapid elevation of serum levels of IL-12 and IFN-gamma. Furthermore, a single administration of PEI-pgp120 complex elicits a number of gp120-specific CD8+ T cells 20 times higher than that elicited by three intramuscular injections of naked DNA. Interestingly, we found that systemic vaccination with PEI-pgp120 induced protective immune responses against both systemic and mucosal challenges with a recombinant vaccinia virus expressing a gp120 antigen. The data also demonstrated that the depletion of macrophages with liposome-encapsulated clodronate completely abolished gp120-specific cellular response. Overall, our results showed that a single administration of PEI-pgp120 complexes, eliciting strong immune responses, is an effective vaccination approach to generate protection against systemic and mucosal viral infections.