Characterization of the immune response after local delivery of recombinant adenovirus in murine pancreas and successful strategies for readministration

Human Gene Therapy
S J McClaneS E Raper

Abstract

The pancreas is an ideal organ for adenoviral gene therapy because of the high level of gene transfer that can be achieved and because of the many diseases that can potentially be treated using this technology. In this report, we characterize the immune response to direct pancreatic injection of adenovirus and we overcome some of the limitations it imposes by using immunosuppression. Direct injection of recombinant adenovirus into the pancreas leads to the production of neutralizing antibodies and to sensitized splenocytes which engage in increased cytotoxic, lymphoproliferative, and cytokine release activity when reexposed to adenovirus. Transgene expression is transient and the vector cannot be readministered. Deletion of CD4+ T helper cells improves expression over time (40% of pancreatic cells express transgene at day 28 vs. 5% in controls), and allows the vector to be readministered in the pancreas, albeit, inefficiently, when compared to naive animals. Similarly, blockade of CD40 ligand, which preserves the CD4+ T helper cell population, also improves expression over time (30% of pancreatic cells express transgene at day 28), and allows the vector to be readministered. With both approaches, neutralizing antibodies are dec...Continue Reading

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Citations

Mar 28, 2007·Journal of Biomedical Science·Henrique ChengY Clare Zhang
Feb 17, 2005·Pancreas·Alexander L ShifrinSteven E Raper
Jul 22, 2014·Human Gene Therapy·Meritxell MorróEduard Ayuso
Apr 28, 2005·Surgery·Alexander L ShifrinSteven E Raper
Apr 24, 2014·Liver International : Official Journal of the International Association for the Study of the Liver·Pilar AlzugurenRuben Hernandez-Alcoceba
Nov 28, 2013·Human Vaccines & Immunotherapeutics·Eric A Weaver
Sep 27, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Fabienne VernejoulGérard Tiraby
Dec 7, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Eduard AyusoFàtima Bosch
Mar 29, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·A I KuzminR C Eisensmith
Jun 30, 2019·International Journal of Molecular Sciences·Masahiro SatoSatoshi Watanabe

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