The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in function and transcriptional pathways
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
盲法说明
LPS is a non-investigational product and will only be used as a challenge agent to induce systemic inflammation. Since the effects op LPS-induced systemic inflammation are profound, no masking will be required.
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Written informed consent
- •Age ≥18 and ≤35 yrs
- •Healthy (as confirmed by medical history, examination, ECG, blood sampling)
排除标准
- •Use of any medication
- •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.
研究组 & 干预措施
LPS group
Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.
干预措施: LPS (Drug)
Placebo group
Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%).
干预措施: Placebo (Drug)
结局指标
主要结局
Change in function and transcriptional pathways
时间窗: 15 days
The change in function and transcriptional pathways (gene expression) of hematopoietic progenitor cells and blood leukocytes (using various functional assays and single cell RNAseq) following human endotoxemia.
次要结局
- Change in (Genome-wide) chromatin accessibility(15 days)
- Change in cellular metabolism(15 days)
- Life-span of blood leukocytes during endotoxemia(8 days)
- Change in macrophage activity in the brain(15 days)
- Life-span of blood leukocytes during homeostasis(8 days)