The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia

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

Conditions

• Endotoxemia
• Inflammation
• Multi Organ Dysfunction Syndrome
• Sepsis

Interventions

DRUG

GM-CSF

GM-CSF (4microgram/kg/day subcutaneously) on days 2, 4 and 6.

DRUG

IFN-Y

IFN-Y (100 microgram/day, subcutaneously) on days 2, 4 and 6.

OTHER

E.coli endotoxin

2 ng/kg E.coli reference endotoxin 11:H 10:K negative intravenously

Sponsors & Collaborators

• Radboud University Medical Center

  lead OTHER

Principal Investigators

• Peter Pickkers, Prof, MD, PhD · Radboud University Nijmegen Medical Centre, The Netherlands

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

35 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2011-05-31

Primary Completion

2011-11-30

Completion

2011-11-30

Countries

• Netherlands

Study Locations