Localized interleukin-10 gene transfer induces apoptosis of alloreactive T cells via FAS/FASL pathway, improves function, and prolongs survival of cardiac allograft.
We hypothesized that localized IL-10 gene transfer can induce alloreactive T cell apoptosis and tested this hypothesis with liposome-mediated ex vivo intracoronary IL-10 gene transfer using a functional heterotopic allograft heart transplant model in rabbits. Localized IL-10 overexpression prolonged cardiac allograft survival over three folds. In parallel with the time-course of IL-10 overexpression, the percentage of apoptotic CD3+ cells among total CD3+ cells was significantly increased in the gene therapy group (36.5+/-3.9%) compared with that in the control group (6.2+/-2.6%, P<0.01) on postoperative day (POD) 3-6, and it was further increased (45.8+/-5.7%) on POD7-10. Apoptotic CD4+ and CD8+ cells were also significantly increased in the gene group (P<0.01). In contrast, the percentage of apoptotic myocytes significantly decreased from 10.1+/-0.8% in the control group to 3.5+/-0.4% in the gene group on POD7-10 (P<0.01). This reduction was inversely correlated with the increase in the percentages of apoptotic CD4+ and CD8+ cells (P<0.01). The percentage of caspase-3 positive myocytes was significantly reduced, although percentages of caspase-3 positive CD4+ and CD8+ cells were markedly increased in the gene group (P<0.01). Moreover, about 60-80% of apoptotic T lymphocytes expressed Fas in the gene group compared with less than 10% in the control group (P<0.01). These results suggest that localized IL-10 gene transfer induces alloreactive T cell apoptosis via the Fas/FasL pathway that may contribute to the alleviated acute rejection, improved cardiac function, and prolonged survival in the IL-10 gene-treated cardiac allografts.
Oshima
Kiyohiro
K
Division of Cardiothoracic Surgery, Department of Surgery, University of California Los Angeles, School of Medicine, Los Angeles, CA 90095-1679, USA.
Sen
Luyi
L
Cui
Guanggen
G
Tung
Thomas
T
Sacks
Benjamin M
BM
Arellano-Kruse
Anthony
A
Laks
Hillel
H
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D053222:Fas Ligand Protein; D015316:Genetic Therapy; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D020287:In Situ Nick-End Labeling; D016753:Interleukin-10 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000502:physiology*; D011817:Rabbits; D013601:T-Lymphocytes / Q000502:physiology*; D014162:Transfection; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000502:physiology*
D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D016753:Interleukin-10; D053148:Caspase 3; D020169:Caspases