Zhang Nan, Schröppel Bernd, Chen Dongmei, Fu Shuang, Hudkins Kelly L, Zhang Haojiang, Murphy Barbara M, Sung Randall S, Bromberg Jonathan S
Recanati-Miller Transplantation Institute, Carl C Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Am J Transplant. 2003 Oct;3(10):1230-41. doi: 10.1046/j.1600-6143.2003.00215.x.
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.
腺病毒载体在将基因导入胰岛方面效率很高。然而，腺病毒刺激的炎症和免疫反应可能对胰岛存活不利。鉴于趋化因子及其受体在炎症中的作用，我们分析了它们在分离的小鼠胰岛、小鼠β细胞系以及腺病毒转导（AdRSVLacZ）后的同基因胰岛移植中的表达情况。AdRSVLacZ转导增强并诱导了多种趋化因子的表达。与未转导的胰岛移植相比，转导后的同基因移植胰岛显示出多种趋化因子和受体的表达显著增强，包括单核细胞趋化蛋白-1（MCP-1）、CC趋化因子受体2（CCR2）以及活化后正常T细胞表达和分泌的调节蛋白（RANTES）。AdRSVLacZ转导的胰岛移植有明显的单核细胞浸润，原位杂交显示移植体内有MCP-1、CCR2和RANTES的表达。虽然腺病毒转导不损害体外胰岛素分泌，但与六个对照受体中的六个相比，在接受边缘量AdRSVLacZ转导胰岛的六个受体中，只有一个受体的糖尿病得到了逆转。总之，小鼠胰岛组成性地表达多种趋化因子和趋化因子受体，并对腺病毒转导产生反应。腺病毒转导损害移植胰岛边缘量的植入。这并非由于对胰岛分泌能力的直接载体毒性，而是可能与宿主对腺病毒载体的固有免疫有关。
