Interleukin-4 gene transfer into rat pancreas by recombinant adenovirus

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Abstract
Adenovirus-mediated gene transfer technology may provide a novel approach in the treatment of pancreatic diseases. In the rat model of chronic pancreatitis induced by dibutyltin dichloride (DBTC), Th1 lymphocytes are known to be involved in the mediation of inflammation. We therefore investigated whether local expression of the Th2 cytokine interleukin (IL)-4 might modulate the inflammatory response. To address this question, we have established a protocol of efficient gene transfer into rat pancreas.Recombinant adenovirus constructs carrying the Escherichia coli beta-galactosidase gene (Adbeta-gal) or the rat IL-4 gene (AdrIL-4) were injected into the left gastric artery of healthy LEW.1W rats. Expression of beta-Gal and IL-4 in pancreatic cells was analyzed by X-Gal staining and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. After optimization of the transduction protocol, effects of the IL-4 gene transfer on pancreatic inflammation and fibrosis were studied in DBTC-treated rats.Seven days after Adbeta-gal injection, beta-gal-positive cells were detectable in the rat pancreas. RT-PCR analysis using RNA from pancreata of AdrIL-4-treated rats indicated that IL-4 was expressed for at least 14 days after adenovirus application. Expression of the IL-4 transgene was accompanied by a transient increase of the IL-10 mRNA level in the pancreas. In DBTC-treated rats, adenovirus-mediated transfer of the IL-4 gene modified the pattern of infiltrating inflammatory cells in the pancreas. Importantly, a decrease of CD4+ helper cells was observed.Our data suggest that the injection of recombinant adenoviruses into the left gastric artery is a promising approach to achieving expression of therapeutic transgenes in the pancreas.