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NCT Number: NCT01374711

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

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

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Key information

Conditions

Endotoxemia Bacteremia Infections Inflammation Multi Organ Dysfunction Syndrome Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Systemic Inflammatory Response Syndrome Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Healthy male volunteers

Exclusion criteria

  • seropositivity for markers of hepatitis B or HIV infection or medical history of any other obvious disease associated with immune deficiency
  • Use of any medication or drugs
  • a history of adverse reaction or hypersensitivity to GM-CSF/ IFN-γ
  • Smoking.
  • Previous spontaneous vagal collapse.
  • History, signs or symptoms of cardiovascular disease.
  • (Family) history of myocardial infarction or stroke under the age of 65 years.
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90) or hypotension (defined as RR systolic < 100 or RR diastolic < 50).
  • Renal impairment (defined as plasma creatinin >120 μmol/l).
  • Liver enzyme abnormalities or positive hepatitis serology.
  • Febrile illness during the week before the LPS challenge
  • Participation in a drug trial or donation of blood 3 months prior to the LPS challenge.
  • Chronic hiccups (defined as hiccups longer than 15 minutes in the past 6 months)
  • Pre-existent muscle disease (congenital or acquired) or diseases / disorders know to be associated with myopathy including diabetes and auto-immune diseases.
  • Pre-existent lung disease
  • Upper airway / esophageal pathology
  • Recent (< 1 month) nasal bleeding
  • Phrenic nerve lesions
  • Any metals in body (pacemaker, splinters, metal stitches)

Treatment and study plan

GM-CSF

Drug

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

IFN-Y

Drug

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

E.coli endotoxin

Other

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

Primary outcomes

  1. the effects of GM-CSF/IFN-γ on the development of in vivo immunoparalysis induced by experimental human endotoxemia

    Time frame: 1 week (day 1- day 8)

    This will be determined by measuring plasma levels of various pro and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response between day 1 and 7

Secondary outcomes

  1. The effects of GM-CSF/IFN-γ on the ex-vivo responsiveness of leukocytes to various inflammatory stimuli

    Time frame: 1 week (day 1- day 8)

  2. the effects of GM-CSF/IFN-γ on monocyte HLA-DR expression

    Time frame: 1 week (day 1- day 8)

  3. the effects of GM-CSF/IFN-γ on transcriptional pathways of leukocytes (qPCR and microarray)

    Time frame: 1 week (day 1- day 8)

  4. the effects of GM-CSF/IFN-γ on urine markers of tubular injury

    Time frame: 1 week (day 1- day 8)

  5. The effect of LPS on twitch transdiaphragmatic pressure

    Time frame: 1 day

  6. the effects of GM-CSF/IFN-γ on clinical symptoms (illness score, mean arterial pressure, heart rate and temperature)

    Time frame: 1 week (day 1- day 8)

  7. the effects of GM-CSF/IFN-γ on changes in phenotype and gene expression caused by mechanisms other than changes in the underlying DNA sequence

    Time frame: 1 week (day 1- day 8)

  8. Beta 2 Glycoprotein and platelet-monocyte interactions post-LPS

    Time frame: 1 day

  9. Macrophage differentiation

    Time frame: 1 day

  10. Immunosuppressive neutrophil populations

    Time frame: 1 week (day 1- day 8)

  11. Blood viscosity

    Time frame: 1 day

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Official study title

The Effects of Immunostimulation With GM-CSF or IFN-y on Immunoparalysis Following Human Endotoxemia. A Parallel Randomized Double-blind Placebo-controlled Study

Important dates

Study start
2011
Primary completion
2011
Study completion
2011
First posted
Jun 16, 2011
Registry last updated
Jun 27, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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