Intracoronary adenovirus-mediated transfer of immunosuppressive cytokine genes prolongs allograft survival

Abstract

Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts is efficient and effectively prolongs graft survival. Vectors that would induce long-term expression of such genes may make this approach clinically applicable.

Effects of local and systemic viral interleukin-10 gene transfer on corneal allograft survival

“…Local gene transfer of immunomodulatory cytokines, for example, IL-10 has been shown to prevent graft rejection in various transplant models including the cornea. 13,[15][16][17][18] However, the results presented here indicate that local expression of IL-10 is not sufficient to prevent corneal graft rejection in a full mismatched rat transplant model. Liposome-mediated gene transfer in corneal endothelial cells has been suggested as an interesting technology without inducing immune responses against the transfected cells.…”

“…13,14 Gene transfer and gene therapy leading to IL-10 expression in allogeneic transplants may therefore be a promising therapy to impair effective antigen presentation, reduce graft immunogenicity and inhibit inflammation. Indeed, it has been shown that gene transfer of IL-10 led to prolonged graft survival in different transplant models including the cornea, 13,[15][16][17][18] however, in the latter one, the mechanism of graft prolongation is not clear.…”

Liposome-Mediated Combinatorial Cytokine Gene Therapy Induces Localized Synergistic Immunosuppression and Promotes Long-Term Survival of Cardiac Allografts

“…The lower transcription of IL-4 vs IL-10 was further evidenced in the remarkable and proportional decrease at both mRNA and protein levels. Many investigators have reported the poor correlation in the gene transfer efficiency between a reporter gene and a therapeutic gene, or between two therapeutic genes (15,38). It seems that each gene has its own rate of transcription.…”

“…The pathologic characteristic of this mismatch acute rejection model has been described previously (4,15). Briefly, under general anesthesia, median sternotomy was performed on donor rabbits, both superior and inferior venae cavae were ligated, then cardiac arrest was induced by infusion of University of Wisconsin solution (4°C, 20 ml/kg, 120 ml/h) through an aortic cannula (4).…”

“…However, systemic administration of IL-10 after transplantation did not show any benefit in humans, which is mainly due to the significant pleiotropic effect (12). Localized IL-10 gene transfer mediated by adenovirus or liposome has been the most effective gene therapy, other than CTLA4Ig, for prolonging allograft survival in various animal models (4,13,14); however, true tolerance was never achieved (15,16). IL-4 shares many of its activities with IL-10, and some activities with IL-13; however, unexpectedly, the observations of its role as a mediator of allograft rejection are inconsistent (17,18).…”