Main objectiveComparison of:- circulating B cell subsets,- immunoglobulin subsets,- B cell functionality (by means of ex vivo challenges),- and other relevant immune cellsbetween young healthy donors (aged 18-25 years), elderly healthy donors (>…
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Circulating B cell subsets:
- B1 cells
- Naive B cells
- Transitional B cells
- Non-class-switched memory B cells
- Class-switched memory B cells
- Plasmablasts and plasma cells
- Regulatory B-cells
- Age associated B-cells
Immunoglobulin classes:
- total IgG, IgM, IgE. oxLDL IgG1, IgG2 + IgM.
- oxLDL specific IgM and IgG ELISpot
B cell functionality, by means of ex vivo challenges, evaluating:
- Pathways:
* TLR7 stimulation
* TLR9 stimulation
- Readouts:
* Cellular mRNA (isolated B-cells)
* Circulating cytokines (e.g. IL-10 and IL-35 + IL-12p70, IL-1*, TNF*, IL-6,
IL-17)
* Secreted cytokines after stimulation (e.g. IL-10, IL-35, TGF*,
pro-inflammatory cytokines)
* Intracellular cytokines (e.g. IL-10, IL-35)
* Surface markers on B-cells (non-lineage markers) (e.g. PD-1, PDL-1, PDL-2,
TIM-1)
- Other relevant immune cells including, but not limited to:
o CD4+ T cells (Th1/Th2/Th17/Treg), CD8+ T cells, inflammatory monocytes,
neutrophils, basophils
- Routine laboratory blood tests:
o Chemistry
o Hematology
- Immune cells in adipose tissue
Secondary outcome
N.A.
Background summary
Atherosclerosis is a chronic inflammatory disease of the artery wall. Treatment
of atherosclerosis has been based on lipid-lowering therapies for years,
reducing multiple risk factors. Adaptive immunity plays a key role in the
pathogenesis of atherosclerosis. Accumulating evidence supports the idea that
immunization with antigenic proteins or peptides may reduce atherosclerosis.
Modulation of the adaptive immune system may treat or prevent atherosclerosis,
and lead to the development of more selective and less harmful interventions,
while keeping host defense mechanisms against infections and tumors intact.
Aging is one of the major drivers of atherosclerosis and with a rapidly
increasing aging population, there is a huge need to enhance our understanding
of immune responses during cardiovascular disease to develop the most effective
therapeutic intervention for the patient.
Although the role of T cells in the development and progression of
atherosclerosis has been extensively studied for decades, only recently the
role of B cells has gained more attention. B cell subsets are found in human
and murine atherosclerotic plaques. B cells have long been thought to have a
general protective effect in atherosclerosis. However, recent studies have
identified differential effects of different B-cell subsets. B1 cells are
atheroprotective, mainly via the production of natural IgM antibodies that bind
oxidized low-density lipoprotein and apoptotic cells. B2 cells are suggested to
be proatherogenic, via production of IgG, secretion of TNF*, and activation of
CD4 T cells. Finally, there is a minor subset of splenic regulatory B cells
(Bregs) that protect against atherosclerotic inflammation by promoting the
generation of Tregs and production of anti-inflammatory cytokines IL-10 and
TGF-* and proapoptotic molecules. It is unknown whether Bregs are a permanently
existing cell subset, or derived from B cells upon specific stimulation.
Study objective
Main objective
Comparison of:
- circulating B cell subsets,
- immunoglobulin subsets,
- B cell functionality (by means of ex vivo challenges),
- and other relevant immune cells
between young healthy donors (aged 18-25 years), elderly healthy donors (>60
years), young smokers (aged 18-25 years), heavy smokers (>45 years) and
patients with stable coronary artery disease (>60 years).
Secondary objectives
- Development of optimal flow cytometry panels for identification of various B
cell subsets;
- Setup of ex vivo B cell challenges for evaluation of B cell functionality.
- Immune cells in adipose tissue.
Study design
Single-center observational study
Study burden and risks
Subjects will be subjected to a single blood draw and fat biopsy, no benefits
or risks are to be expected.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Healthy volunteers:
1. healthy male subjects (18-25 years or >60 years);
2. ability to participate, and willingness to give written informed consent and
to comply with the study restrictions.
3. BMI 18 - 28
4. non-smoking, elderly non-smoking for at least 15 years.
smokers:
1. male subjects (18-25 years or >45 years)
2. ability to participate, and willingness to give written informed consent and
to comply with the study restrictions.
3. BMI 18 - 28
4. volunteers >45 years: smoking for at least 15 packyears, volunteers 18- 25
years: at least * pack a day for 6 months. , CAD patients:
1. male patients (>60 years) with proven stable atherosclerotic coronary artery
disease defined as having undergone a revascularization procedure followed by a
period of at least one year without signs or symptoms of coronary artery
disease;
2. having one of the following risk factors: high cholesterol, smoking,
diabetes, hypertension, or familiar risk.
3. ability to participate, and willingness to give written informed consent and
to comply with the study restrictions.
4. BMI 18 - 28
Exclusion criteria
healthy volunteers:
1. evidence of any active or chronic disease or condition (based on medical
history, a physical examination, and vital signs) that could, in the opinion of
the investigator, interfere with the study objectives;
2. evidence of any active or chronic disease or condition that affects the
immune system.
3. having one of the following risk factors for CAD: high cholesterol, smoking,
diabetes, hypertension, or familiar risk.
4. the use of any medication or vitamin/mineral/herbal/dietary supplement
within less than 5 half-lives prior to study participation is prohibited, if
the Investigator judges that it may interfere with the study objectives. The
use of paracetamol (up to 4 g/day) is allowed;
5. body weight < 50 kg; BMI <18 or >28.
6. subject is pregnant or breast feeding;
7. smoking or current substance abuse, including alcohol and drugs;
8. loss or donation of blood over 500 mL within three months prior to
participation;
9. unwillingness or inability to comply with the study protocol for any other
reason., Smokers:
1. evidence of any active or chronic disease or condition (based on medical
history, a physical examination, and vital signs) that could, in the opinion of
the investigator, interfere with the study objectives;
2. body weight < 50 kg; or BMI <18 or >35;
3. substance abuse, including alcohol and drugs;
4. loss or donation of blood over 500 mL within three months prior to
participation;
5. unwillingness or inability to comply with the study protocol for any other
reason., CAD patients:
1. evidence of any active or chronic disease or condition other than stable CAD
(based on medical history, a physical examination, and vital signs) that could,
in the opinion of the investigator, interfere with the study objectives;
2. evidence of any active or chronic disease or condition other than stable CAD
that affects the immune system.
3. body weight < 50 kg; BMI <18 or >28.
4. substance abuse, including alcohol and drugs;
5. loss or donation of blood over 500 mL within three months (males) prior to
participation;
6. unwillingness or inability to comply with the study protocol for any other
reason.
7. use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL68390.056.19 |