Primary 1) Establish whether HTx induces a trained immunity phenotype of circulating mono-cytes in pediatric and adult HTx patients, and compared to healthy controls.2) Investigate whether trained immunity phenotypes in pediatric and adult HTx…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
a) Trained immunity: Functional testing of trained immunity is performed using
previously established protocols. Levels of the inflammatory cytokines IL1β,
IL6 and TNF are measured in culture supernatants upon ex vivo stimulation of
whole blood with trained immunity stimuli such as the TLR2 and TLR4 ligands
Pam3CysK4 and lipopolysaccharide (LPS), and NLRP3-inflammasome activating
cholesterol crystals. The cytokine levels are continuous variables.
b) CAV grading: CAV grading is performed using computed tomography (CT)
coronary angiograms, including fractional flow reserve measurement, according
to international society for heart and lung transplantation guidelines (ISHLT)
and established local protocols. CAV grade is an ordinal variable (grade 0-3).
Secondary outcome
a) Innate and adaptive immune cell phenotypes (secondary objectives):
Compre-hensive phenotyping of circulating immune cells will be performed using:
• Multi-color flow cytometry of circulating monocytes, dendritic cells, T-cells
and B-cells (naïve versus effector and memory). Phenotyping will include the
expression of activation markers, inflammatory factors and adhesion proteins
relevant for CAV development, using previously established protocols. Leukocyte
subset frequencies and expression levels of activation markers, inflammatory
factors and adhesion proteins are continuous varia-bles.
• Morphological phenotyping of circulating leukocytes, using DeepCell
technology. Morphological parameters are continuous variables.
b) Clinical determinants of CAV development: Routine clinical parameters with
rele-vance for CAV development and the study objectives will be included in the
study database. These parameters include: age, gender, underlying cardiac
dis-ease, HTx date, AB0 blood group and antibodies, HLA antibodies / mismatch,
re-jection episodes, viral reactivation episodes and immune status,
immunosup-pression, and cardiometabolic determinants (dyslipidemia, obesity,
dysglycemia, hypertension).
Background summary
Long-term survival of heart transplantation (HTx) in children and adults is
often limited due to cardiac allograft vasculopathy (CAV). CAV is caused by
monocytic and lymphocytic inflammation of the intimal layer of the coronary
arteries, which results in luminal narrowing of the coronaries, and ultimately
in cardiac ischemia. CAV is a leading cause of mortality ten years following
HTx, affecting approximately 50% of adolescent and adult HTx patients, with
slightly lower numbers in younger children. Here, we investigate whether
trained immunity of circulating monocytes is associated with CAV development.
Trained immunity is reflected by a hyperinflammatory phenotype of the
monocytes, caused by repetitive inflammatory stimulation leading to
pro-inflammatory epigenetic changes. If trained immunity is indeed associated
with CAV development, inhibition of trained immunity could provide novel
avenues to prevent CAV development in the near future.
Study objective
Primary 1) Establish whether HTx induces a trained immunity phenotype of
circulating mono-cytes in pediatric and adult HTx patients, and compared to
healthy controls.
2) Investigate whether trained immunity phenotypes in pediatric and adult HTx
patients are associated with the development of cardiac allograft vasculopathy.
Secondary 1) Explore differences between children and adults in the innate and
adaptive immune phenotypes following HTx. 2) Explore innate and adaptive immune
phenotypes associated with viral reactivations, CAV development, and graft
rejection.
Study design
Observational.
Study burden and risks
Burden: Whole blood sampling. Sampling will be combined with routine clinical
blood sampling whenever possible, to reduce study burden.
a) For pediatric subjects, total volume will be adjusted to circulating volume,
in accordance with international standards and EU directive No 536/2014 (2017).
Rule of thumb in sick children: blood sampling for research maximum 3% of
circulating volume (2.5ml/kg) over a period of 4 weeks, in addition to clinical
/ routine blood sampling.
b) For primary objective 1, 50 patients will undergo blood withdrawal at 4
timepoints, general-ly more than 4 weeks apart. Blood sampling for research
maximum 2.5ml/kg/timepoint for children (or 1.25ml/kg/timepoint if less than 4
weeks from previous blood sampling), and 40ml/timepoint for adolescents and
adults.
c) For primary objective 2 and the secondary objectives, patients and controls
will undergo one-time blood sampling. Blood withdrawal maximum 2.5ml/kg for
children, and 40ml for adolescents and adults.
Risks: addition of extra tubes to routine blood sampling is considered a
minimal risk. Benefits: no personal benefits for study participants. On a group
level, data from this study may open novel avenues to prevent CAV development
in the future.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
Patient groups:
- Children and adults undergoing HTx (Primary objective 1) or
- Pediatric and adult HTx patients 5-10 years post-HTx or * 10 years post-HTx
(Primary objective 2 and secondary objectives).
- Written informed consent.
Control group:
- Healthy adolescents enrolled in the Whistler birth cohort study.
- Written informed consent, including transfer of data and blood samples to the
Trained immunity in heart transplantation study team at the Erasmus MC.
Exclusion criteria
Acute infection (fever >38.5*C and/or clinical infectious symptoms).
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 | NL86533.078.24 |