The goal of this clinical trial is to investigate the immunomodulatory effects of the drugs dexamethasone, tocilizumab and anakinra in healthy male subjects aged 18 to 35 undergoing experimental endotoxemia. The main questions it aims to answer are:
* What are the effects of these drugs on the development of immunoparalysis in a repeated human endotoxemia model? * What is the extent of the neuroinflammatory response and how do these drugs affect neuroinflammation in a repeated human endotoxemia model?
Researchers will compare these drugs to a placebo (a look-alike substance that contains no drug).
Participants will visit the Intensive Care research department on two or five occasions (screening included):
* The intervention group will receive an LPS challenge twice, with a week in between. Before the first LPS challenge, one of the described drugs will be administered. Blood, saliva and tear fluid will be collected regularly during the LPS challenge. Cerebrospinal fluid will also be collected through a catheter in the spinal cord. * The control group will not receive an LPS challenge or drug administration and will have only one study day. During this day, blood, saliva, tear fluid and cerebrospinal fluid will be collected as regularly as during the LPS challenge of the intervention group.
During an LPS challenge, the investigators mimic blood poisoning by giving an endotoxin, also called LPS. This is a small part of the cell wall of a bacteria. This will cause transient flu-like symptoms for 3-4 hours.
Male subjects aged ≥18 and ≤35 years
Body mass index (BMI) ≥18 and ≤30 kg/m2
Healthy (as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram and routine clinical laboratory parameters)
Able to comprehend and sign the Information letter and Informed Consent (IC) prior to enrolment in the study.
Use of any prescription medication or over-the-counter non-steroidal anti-inflammatory drugs
Known anaphylaxis or hypersensitivity to any (non-)investigational products or their excipients
History of chronic headache or previous post-dural puncture headache (PDPH)
History or signs of severe atopic syndrome (asthma, rhinitis with medication and/or eczema)
Parallel
Dexamethasone
DrugDexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
Tocilizumab
DrugTocilizumab 600mg in 100mL NaCl 0.9% i.v. in 1 hour + a bolus of 10mL NaCl 0.9% placebo infusion on the first LPS challenge.
Anakinra
DrugAnakinra 200mg in 100mL NaCl 0.9% i.v. in 1 hour + a bolus of 10mL NaCl 0.9% placebo infusion on the first LPS challenge.
Placebo
DrugBolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
LPS
Biological/VaccineThis is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state.
Between-group differences in plasma TNF concentrations upon the second LPS challenge
The effects of dexamethasone, tocilizumab and anakinra on the development of immunoparalysis in a repeated endotoxemia model in humans, reflected by between-group differences in plasma TNF concentrations upon the second LPS challenge.
Within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia
The extent of the neuroinflammatory response as well as the effects of dexamethasone, tocilizumab and anakinra on neuroinflammation, reflected by within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia
Between-group differences in plasma cytokine concentrations during the second LPS challenge (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by plasma concentrations of other mediators than TNF (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) during the second LPS challenge.
Between-group differences in the log2-fold change of the Area Under the Curves (AUCs) of plasma cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) during the first and second LPS challenges.
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by between-group differences in the log2-fold change of the Area Under the Curves (AUCs) of plasma concentrations of other mediators than TNF during the first and second LPS challenges.
Between-group differences in other plasma inflammatory proteins upon the second LPS challenge, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as measured by the Olink Target 96 inflammation panel (92 protein biomarkers) upon the second LPS challenge.
Between-group differences in the log2-fold change of peak plasma concentrations of other inflammatory proteins, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers), during the first and second LPS challenges
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as measured by the Olink Target 96 inflammation panel (92 protein biomarkers), during the first and second LPS challenges.
Within and between-group differences in cytokine concentrations in saliva and tear fluid during both LPS challenges (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10).
The effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on salivary and tear fluid cytokine levels, as reflected by within and between-group differences in cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10) during the first and second LPS challenges.
Correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation upon both LPS challenges.
The relationship between systemic, salivary and tear fluid cytokine responses as reflected by the correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation during the first and second LPS challenges.
Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in saliva, as reflected by within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells during the first and the second LPS challenges.
Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in tear fluid upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in tear fluid, as reflected by within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells during the first and the second LPS challenges.
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