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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/H277    most recent 00441.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Oshima, K. Articles by Sen, L. Search for Related Content PubMed PubMed Citation Articles by Oshima, K. Articles by Sen, L.

Exogenous IL-10 overexpression reduces perforin production by activated allogenic CD8⁺ cells and prolongs cardiac allograft survival

¹Division of Cardiothoracic Surgery, Department of Surgery, and ²Division of Cardiology, Department of Medicine, University of California, Los Angeles (UCLA) Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California

Submitted 2 May 2006 ; accepted in final form 30 August 2006

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.

gene therapy; cardiac allograft rejection; apoptosis; cytokine