Exogenous Il-10 Overexpression Reduces Perforin Production by Activated Allogenic Cd8+ Cells and Prolongs Cardiac Allograft Survival.
From: 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.
American journal of physiology. Heart and circulatory physiology
- Publish Date: Jan 2007
- ISSN: 0363-6135
- Volume: 292
- Issue: 1
- Pages: H277-84
- Medium: Print
- Language: English
- Citation (JAMA): Oshima Kiyohiro, Cui Guanggen, Tung Thomas, et al. Exogenous Il-10 Overexpression Reduces Perforin Production by Activated Allogenic Cd8+ Cells and Prolongs Cardiac Allograft Survival.. Am. J. Physiol. Heart Circ. Physiol. Jan 2007;292:H277-84
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.
Mesh Headings (Keywords): Animals, CD8-Positive T-Lymphocytes, Graft Survival, Heart Transplantation, Interleukin-10, Lymphocyte Activation, Membrane Glycoproteins, Myocardium, Perforin, Pore Forming Cytotoxic Proteins, Rabbits, Transplantation, Homologous, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 16951047
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