Adenovirus transduction induces expression of multiple chemokines and chemokine receptors in murine beta cells and pancreatic islets

Abstract

Adenoviral vectors are highly efficient for transferring genes to islets. However, the inflammatory and immune responses stimulated by adenovirus may be detrimental to islet survival. Given the role of chemokines and their receptors in inflammation, we analyzed their expression in isolated murine islets, in a murine beta cell line and in syngeneic islet grafts after adenovirus transduction (AdRSVLacZ). AdRSVLacZ transduction enhanced and induced the expression of a variety of chemokines. Transduced syngeneic transplanted islets showed significantly enhanced expression of multiple chemokines and receptors, including monocyte chemoattractant protein-1 (MCP-1), CC chemokine receptor 2 (CCR2) and regulated upon activation, normal T cell expressed and secreted (RANTES), compared with untransduced islet grafts. AdRSVLacZ-transduced islet grafts had significant mononuclear infiltrates, and in situ hybridization demonstrated intragraft expression of MCP-1, CCR2 and RANTES. Although adenovirus transduction did not impair in vitro insulin secretion, diabetes was reversed in only one of six recipients of a marginal mass of AdRSVLacZ-transduced islets, compared with six of six control recipients. In conclusion, multiple chemokines and chemokine receptors are expressed by murine islets constitutively and in response to adenovirus transduction. Adenovirus transduction impairs engraftment of marginal mass of transplanted islets. This is not because of direct vector toxicity of islet secretory capacity, but may be related to host innate immunity in response to adenovirus vector.