Methods for human skin gene therapy requires efficient and stable introduction of genes into skin cells. Transient\r\ncutaneous gene therapy is an attractive approach in the treatment of skin diseases. The ââ?¬Ë?Achilles heelââ?¬â?¢ of adenoviral\r\ngene therapy is its immunogenicity and many aspects of adenovirus induced cutaneous immune reaction still\r\nremain unanswered, particularly the role of keratinocytes. Therefore, human keratinocytes were transfected with\r\nadenoviral DNA and cytokine expression was analyzed. Moreover, adenoviral transduction of full-skin was\r\nperformed ex vivo and in vivo. We observed cytokine induction after cytoplasmatic internalization of adenoviral DNA\r\ninto epidermal cells. Inhibition of AIM2, NALP3, DAI or mda5 downregulated the cytokine response. Transduction of\r\nimmunocompetent mice led to a detectable transgene expression for 12 days. Re-application of the vector led to a\r\ndecrease in intensity and duration of transgene expression limited to 4 days and an increased cytokine expression.\r\nIn contrast, immunodeficient mice showed a reduced expression of cytokines after DNA internalization. AIM2,\r\nNALP3, DAI and mda5 are essential in the induction of an innate immune response towards adenoviral DNA. This\r\nimmune reaction leads to a decrease in transduction efficiency of the vector after re-application and modulation of\r\nthese receptor systems stabilizes transgene expression.
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