TY - JOUR
T1 - Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis
AU - Oberholzer, Caroline
AU - Oberholzer, Andreas
AU - Bahjat, Frances R.
AU - Minter, Rebecca M.
AU - Tannahill, Cynthia L.
AU - Abouhamze, Amer
AU - LaFace, Drake
AU - Hutchins, Beth
AU - Clare-Salzler, Michael J.
AU - Moldawer, Lyle L.
PY - 2001/9/25
Y1 - 2001/9/25
N2 - Sepsis remains a significant clinical conundrum, and recent clinical trials with anticytokine therapies have produced disappointing results. Animal studies have suggested that increased lymphocyte apoptosis may contribute to sepsis-induced mortality. We report here that inhibition of thymocyte apoptosis by targeted adenovirus-induced thymic expression of human IL-10 reduced blood bacteremia and prevented mortality in sepsis. In contrast, systemic administration of an adenovirus expressing IL-10 was without any protective effect. Improvements in survival were associated with increases in Bcl-2 expression and reductions in caspase-3 activity and thymocyte apoptosis. These studies demonstrate that thymic apoptosis plays a critical role in the pathogenesis of sepsis and identifies a gene therapy approach for its therapeutic intervention.
AB - Sepsis remains a significant clinical conundrum, and recent clinical trials with anticytokine therapies have produced disappointing results. Animal studies have suggested that increased lymphocyte apoptosis may contribute to sepsis-induced mortality. We report here that inhibition of thymocyte apoptosis by targeted adenovirus-induced thymic expression of human IL-10 reduced blood bacteremia and prevented mortality in sepsis. In contrast, systemic administration of an adenovirus expressing IL-10 was without any protective effect. Improvements in survival were associated with increases in Bcl-2 expression and reductions in caspase-3 activity and thymocyte apoptosis. These studies demonstrate that thymic apoptosis plays a critical role in the pathogenesis of sepsis and identifies a gene therapy approach for its therapeutic intervention.
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U2 - 10.1073/pnas.181338198
DO - 10.1073/pnas.181338198
M3 - Article
C2 - 11553765
AN - SCOPUS:0035949476
SN - 0027-8424
VL - 98
SP - 11503
EP - 11508
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -