title: Exogenous IL-10 overexpression reduces perforin production by activated allogenic CD8+ cells and prolongs cardiac allograft survival.
abstract: Perforin is a cytolytic mediator produced by cytotoxic T cells (CD8(+) cells) and natural killer cells. We previously reported that ex vivo IL-10 gene therapy induced apoptosis of allogenic infiltrative CD8(+) cells and significantly prolonged cardiac allograft survival. To further test the hypothesis that localized IL-10 overexpression in cardiac allografts may also effect the alloreactive CD8(+) T cell function by downregulating its perforin production, we used a rabbit functional heterotopic allograft heart transplant model. Human recombinant IL-10 gene complexed with liposome was intracoronary delivered into the cardiac allografts ex vivo. The percentage of apoptotic infiltrative CD8(+) cells in cardiac allografts was increased 6-fold in the gene therapy group vs. the control group, whereas the percentage of perforin-positive CD8(+) cells was decreased 2.9-fold (P < 0.01). Perforin expression level in the allograft myocardium of the gene therapy group was deceased 3.2-fold (P < 0.01). The amount of infiltrative perforin-positive CD8(+) cells and perforin expression level were inversely correlated with IL-10 transgene and protein expression level in the myocardium of cardiac allografts (P < 0.01), the percentage of apoptotic cardiac myocytes (P < 0.01), and the peak left ventricular systolic pressure of cardiac allografts (P < 0.01) but significantly correlated with the infiltrative T cell cytotoxicity (P < 0.01) and allograft rejection score (P < 0.01). These results suggest that localized IL-10 gene therapy prolongs cardiac allograft survival, at least in part, through downregulation of perforin production by activated allogenic CD8(+) T cells. Reduction of cytolytic function of cytotoxic effector cells prevents the apoptosis of cardiac myocytes.
authors.affiliation: Division of Cardiothoracic Surgery, Dept. of Surgery, UCLA Medical Center, David Geffen School of Medicine in UCLA, 10833 Le Conte Ave., 47-123 CHS, Los Angeles, CA 90095-1679, USA.
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Oshima
authors.forename: Guanggen
authors.initials: G
authors.lastname: Cui
authors.forename: Thomas
authors.initials: T
authors.lastname: Tung
authors.forename: Onisuru
authors.initials: O
authors.lastname: Okotie
authors.forename: Hillel
authors.initials: H
authors.lastname: Laks
authors.forename: Luyi
authors.initials: L
authors.lastname: Sen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation / Q000379:methods* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D011817:Rabbits; D014184:Transplantation, Homologous; D015854:Up-Regulation
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D016753:Interleukin-10