Clinical trial NCT05570643: The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
Official title: The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sepsis, Endotoxemia, Immunosuppression
Keywords: Sepsis, immunosuppression, systemic inflammation, human endotoxemia, bone marrow stem and progenitor cells, myelopoiesis, monocytes, transciptomics
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: UMC Utrecht
First posted: 2022-10-06
Enrollment: 12
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An pilot study to explore the effects of a LPS-challenge on functional capacity and gene expression of human stem and hematopoietic progenitor cells and blood leukocytes. Subjects will be allocated to a LPS group (n=8 healthy volunteers) that will be challenged with endotoxin twice, or to a placebo group (n=4) who will undergo the same study procedures but receive a placebo challenge (NaCl 0.9%).
Primary purpose: OTHER

Brief summary: We will investigate whether human endotoxemia induces changes in human bone marrow cells and their downstream effector cells. To comprehensively investigate underlying mechanisms behind functional and transcriptional changes in these cell types, we will use state-of-the-art systems biology techniques, including single cell transcriptomics (epi)genetics, and metabolomics.

Detailed description: In the present study, we want to further elucidate the mechanisms behind systemic inflammation and endotoxin tolerance in vivo in humans by focusing on functional changes in hematopoietic stem and progenitor cells. Healthy male volunteers will be challenged with endotoxin to evoke a transient systemic inflammatory response. To evaluate the responses over time, blood and bone marrow aspirates will be collected at multiple timepoints. To comprehensively investigate underlying mechanisms behind functional changes, we will use state-of-the-art systems biology techniques, including single cell transcriptomics, epigenetics (e..g. scATACseq), and metabolomic. As such, this study will yield a comprehensive insight into inflammatory signaling in the different compartments of the body and will thereby improve our understanding of systemic inflammation, endotoxin tolerance,and sepsis, possibly revealing new therapeutic targets to improve sepsis outcome.

Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Age ≥18 and ≤35 yrs
* Male
* Healthy (as confirmed by medical history, examination, ECG, blood sampling)

Exclusion Criteria:

* Use of any medication
* Smoking
* History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema)
* Known anaphylaxis or hypersensitivity to the non-investigational products or their excipients.
* History or signs of hematological disease (bone marrow dysfunction):
* Thrombocytopenia (\<150\*10\^9/ml) or anemia (hemoglobin \< 8.0 mmol/L)
* Abnormalities in leukocyte differential counts
* History, signs or symptoms of cardiovascular disease, in particular:
* Previous spontaneous vagal collapse
* History of atrial or ventricular arrhythmia
* Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block
* Hypertension (defined as RR systolic \> 160 or RR diastolic \> 90)
* Hypotension (defined as RR systolic \< 100 or RR diastolic \< 50)
* Renal impairment (defined as plasma creatinine \>120 μmol/l)
* Liver enzyme abnormalities (above 2x the upper limit of normal)
* Medical history of any disease associated with immune deficiency
* CRP \> 20 mg/L, WBC \> 12x109/L or \< 4 x109/L, or clinically significant acute illness, including infections, within 3 weeks before labeling day
* Previous (participation in a study with) LPS administration
* Any vaccination within 3 months prior to labeling day
* Participation in a drug trial or donation of blood 3 months prior to labeling day
* Recent hospital admission or surgery with general anesthesia (\<3 months to labeling day)
* Use of recreational drugs within 21 days prior to labeling day
* Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Primary outcomes:
measure: Change in function and transcriptional pathways
timeFrame: 15 days
Secondary outcomes:
measure: Change in (Genome-wide) chromatin accessibility
timeFrame: 15 days
measure: Change in cellular metabolism
timeFrame: 15 days
measure: Change in macrophage activity in the brain
timeFrame: 15 days
measure: Life-span of blood leukocytes during homeostasis
timeFrame: 8 days
measure: Life-span of blood leukocytes during endotoxemia
timeFrame: 8 days
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Intensive Care Medicine, Radboud University Nijmegen Medical Centre
state: Gelderland
Study officials:
References: