Overexpressed exogenous IL-4 And IL-10 paradoxically regulate allogenic T-cell and cardiac myocytes apoptosis through FAS/FASL pathway
The authors' previous study has shown that liposome-mediated ex vivo intracoronary interleukin (IL)-4 and IL-10 combined gene therapy suppressed the allo-immune responses and prolonged the cardiac allograft survival by 15 folds. However, the mechanism for promoting long-term allograft survival...
Saved in:
Published in | Transplantation Vol. 85; no. 3; p. 437 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
15.02.2008
|
Subjects | |
Online Access | Get more information |
Cover
Loading…
Summary: | The authors' previous study has shown that liposome-mediated ex vivo intracoronary interleukin (IL)-4 and IL-10 combined gene therapy suppressed the allo-immune responses and prolonged the cardiac allograft survival by 15 folds. However, the mechanism for promoting long-term allograft survival remains unknown.
This study tested the hypothesis that this combined cytokine gene targeting may promote alloreactive T-cell apoptosis or prevent apoptosis of cardiac allograft myocytes through Fas/Fas ligand (FasL) pathway. A rabbit functional cervical heterotopic heart transplantation model was used, and plasmid human recombinant IL-4 and IL-10 gene complexed with cationic liposome (GAP/DLRIE) was delivered into cardiac allografts by intracoronary infusion ex vivo.
This liposome-mediated IL-4 and IL-10 combined gene therapy significantly increased apoptotic T cells detected by TUNEL staining. The caspase-8 or caspase-3 expressing T cells were also significantly increased. The Fas+ apoptotic T cells dominated in the population of apoptotic CD4+ T cells, but FasL+ CD4+ T-cell population was less effected in the combined gene therapy group. The effect of combined gene therapy on the infiltrative Fas+ CD8+ T-cell population is much less than that on Fas+ CD4+ cells, and there was almost no effect on the FasL+ CD8+ T-cell population. Furthermore, localized IL-4 and IL-10 combined gene therapy protected cardiac allograft myocytes by down-regulating its FasL expression, but not Fas.
These results suggest that this combined gene targeting strategy which induced localized overexpression of exogenous IL-4 and IL-10 may promote alloreactive T-cell apoptosis and prevent myocytes apoptosis through Fas/FasL cell surface interaction, therefore inducing cardiac allograft tolerance. |
---|---|
ISSN: | 0041-1337 1534-6080 |
DOI: | 10.1097/TP.0b013e31816026e7 |