Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis.
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.
Oberholzer
C
C
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Oberholzer
A
A
Bahjat
F R
FR
Minter
R M
RM
Tannahill
C L
CL
Abouhamze
A
A
LaFace
D
D
Hutchins
B
B
Clare-Salzler
M J
MJ
Moldawer
L L
LL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000276:immunology / Q000628:therapy*
D016753:Interleukin-10