The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia
Status:
Completed
Trial end date:
2011-11-01
Target enrollment:
Participant gender:
Summary
The human body knows a biphasic immunological reaction to sepsis. First, the pro-inflammatory
reaction takes place, marked by the release of pro-inflammatory cytokines like TNF-α, as a
reaction to the bacterial toxins. Secondly, the counter regulatory anti-inflammatory reaction
arises. This phase is acting as negative feedback on the inflammation by inhibition of the
pro-inflammatory cytokines. This is called "immunoparalysis", a pronounced immunosuppressive
state, which renders patients vulnerable to opportunistic infections. Most of the septic
patients survive the initial pro-inflammatory phase, but die during this second
stage.Research in the past has shown that immunostimulatory therapy with GM-CSF or IFN-γ has
promising effects on the pro-inflammatory reaction during immunoparalysis ex vivo. Both drugs
are known for their immunostimulatory effects. Recent pilot studies have showed in septic
patients, that long-lasting monocyte deactivation in sepsis ex vivo can be reversed by these
two immunostimulants. However, the mechanism and extent of immunoparalysis recovery may be
different between the two compounds. Previously it has been shown that human endotoxemia
(induced by LPS), leads to marked immunosuppression in healthy individuals, characterized by
a transient refractory state to a subsequent LPS challenge (endotoxin tolerance).
Consequently, human endotoxemia can serve as a standardized, controlled model for
sepsis-induced immunoparalysis. Until now, all studies have focused on the ex vivo tolerance.
However, we have recently proved, that the ex vivo condition is not completely representative
for the in vivo situation. Ex vivo, leukocyte tolerance to LPS resolves within one day, while
the in vivo immunoparalysis persists for two weeks. In this project, we will investigate the
effects of both GM-CSF and IFN-γ in a parallel double-blind placebo controlled randomized
manner on the immunoparalysis following human endotoxemia, both in-vitro and in vivo. As a
result, we hope to get more insight in the pathophysiology of sepsis-induced immunoparalysis
and thereby develop new immunostimulatory therapies that improve patient outcome