Viral IL-10 gene transfer inhibits the expression of multiple chemokine and chemokine receptor genes induced by inflammatory or adaptive immune stimuli.
Previously we have shown that adenovirus-mediated gene transfer and expression of vIL-10 are able to prolong cardiac allograft survival, through the inhibition of the immune response to both alloantigen and adenoviral antigens. In the current study, we have defined further mechanisms of Ad.vIL-10-mediated prolongation of cardiac allograft survival. E1- and E3-deleted adenoviral vectors encoding beta-galactosidase or vIL-10 were transferred into grafts at the time of transplantation, chemokine and chemokine receptor expression were evaluated by a pathway-specific cDNA array, and the results were confirmed with real time RT-PCR on selected genes. Ischemic injury, alloantigen and adenovirus vector induced the expression of multiple pro-inflammatory chemokines in the grafts, which likely amplify allograft rejection. Most of these Th1-related chemokine genes were inhibited or down-regulated by Ad.vIL-10 administration, which may help to decrease leukocytic infiltration and improve graft survival. Among the potent Th1 type chemokines inhibited were the CXCR3 ligands CXCL9 and CXCL10, which could directly inhibit vector-mediated gene expression in myoblasts, although targeting CXCR3 or its ligands did not prolong allograft survival with vIL-10 gene transfer. Ad.vIL-10 administration also induced the expression of the Th2-associated chemokines eotaxin-2 and MIP-1 gamma, suggesting Th1 to Th2 immune deviation. These results demonstrated that the vIL-10 gene transfer inhibits chemokine expression, preventing stimulation of innate and adaptive immunity.
Chen
Dongmei
D
Carl C. Icahn Center for Gene Therapy and Molecular Medicine, and Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY, USA.
Ding
Yaozhong
Y
Zhang
Nan
N
Schröppel
Bernd
B
Fu
Shuang
S
Zang
Weiping
W
Zhang
Haojiang
H
Hancock
Wayne W
WW
Bromberg
Jonathan S
JS
D000818:Animals; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D017930:Genes, Reporter; D005822:Genetic Vectors; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*; D015427:Reperfusion Injury; D014161:Transduction, Genetic
D018925:Chemokines; D019707:Receptors, Chemokine; D016753:Interleukin-10