The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells (LPS-BM)

Radboud University Medical Center

Status

Completed

Conditions

Sepsis, Endotoxemia, Immunosuppression

Treatments

Drug: Placebo

Drug: LPS

Study type

Interventional

Funder types

Other

Identifiers

NCT05570643

2017-3337 (Other Identifier)

NL61136.091.17

Details and patient eligibility

About

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.

Full 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.

Enrollment

12 patients

Sex

Male

Ages

18 to 35 years old

Volunteers

Accepts Healthy Volunteers

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.