Our primary objective is to identify which intrinsic defect in Tregs is crucial for sarcoidosis pathology. To this end we will examine the genetic and functional properties of Tregs in the peripheral blood and at the site of disease, i.e. the lung…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number, distribution and phenotype of Tregs in peripheral blood, lung (BAL and
EBBs) and lymph nodes (FNAs); the suppressive function of Tregs on allogenic T
cell proliferation in the peripheral blood; viability and apoptotic
susceptibility of Tregs in the peripheral blood; the cytokine and chemokine
environment of the Tregs in peripheral blood, lung and lymph nodes; the gene
expression profile of Tregs in the peripheral blood, lung and lymph nodes
(including apoptosis-related and survival genes).
Secondary outcome
Clinical parameters indicating disease progression or resolution after two
years.
Background summary
Sarcoidosis is a granulomatous disorder of unknown cause. Current therapy is
immunosuppressive, not curative and often ineffective as we do not thoroughly
understand the underlying pathogenesis of sarcoidosis. It is thought to arise
from an exaggerated Th1/Th17-response upon exposure to one or more
(unidentified) antigens in susceptible individuals. Failure of
immunosuppressive regulatory T cells (Tregs), could contribute to an ongoing
and uncontrolled Th1/Th17 response in sarcoidosis. Our preliminary data
suggests an impaired immunosuppressive function of peripheral blood Tregs of
sarcoidosis patients, possibly due to an intrinsic survival disadvantage.
Therefore, we hypothesize that in sarcoidosis, Tregs are critically involved in
the observed inflammatory response and that sarcoidosis originates from altered
intrinsic properties of Tregs, leading to a common pathway of an exaggerated
Th1 and/or Th17 cell response with the characteristic granuloma formation and T
cell alveolitis as result.
Study objective
Our primary objective is to identify which intrinsic defect in Tregs is crucial
for sarcoidosis pathology. To this end we will examine the genetic and
functional properties of Tregs in the peripheral blood and at the site of
disease, i.e. the lung and draining lymph nodes. Our secondary objective is to
identify a possible correlation between genetic and functional properties of
Tregs and disease progression.
Study design
For this study we will compare the numbers, phenotype, function, viability and
gene expression profile of Tregs from sarcoidosis patients with Tregs from
healthy individuals in three different compartments of the immune system, i.e.
blood, lungs and draining lymph nodes. To identify key aspects of the
immunopathology specific for sarcoidosis compared to other granulomatous
disorders, we will also investigate the blood from tuberculosis patients.
During routine diagnostic work-up, patients suspected of sarcoidosis will
undergo a venapuncture and a bronchoscopy with a broncho-alveolar lavage (BAL)
and endobronchial biopsy (EBB) or endoscopic ultrasound fine-needle aspiration
(EUS/EBUS-FNA), depending on hospital protocols and physicians* preference.
During these procedures, additional blood, residual BAL and two additional EBBs
or EUS/EBUS-FNAs are obtained. Similarly, from healthy controls blood, BAL and
EBBs will be obtained. From tuberculosis patients additional blood will be
obtained during routine diagnostic venapuncture.
Study burden and risks
From patients suspected of sarcoidosis, during routine diagnostic procedures,
two additional EBBs or FNAs are obtained, next to collection of residual
material or withdrawal of extra blood during routine venapuncture. A small
questionnaire is taken shortly before the bronchoscopy. After 2 years follow up
the patient will be asked to donate extra blood during routine visits at the
outpatient clinics. We estimate that participation in this study will pose a
minimal additional risk of complications and patient discomfort. For healthy
volunteers, a bronchoscopy together with a BAL and EBB is reported to be a safe
procedure.
We do not expect increased discomfort for tuberculosis patients participating
in this study as no additional intervention will be required to draw extra
blood. Participants will not have direct personal benefit from participating in
this study. The results from this study could be beneficial for the patient
population. Healthy volunteers will receive a financial compensation.
's-Gravendijkwal 230
Rotterdam 3015CE
NL
's-Gravendijkwal 230
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
Sarcoidosis patients should have:
- Newly diagnosed pulmonary sarcoidosis, established using the criteria of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG)
- Written informed consent
- Age > 18;Healthy controls should have:
- Written informed consent;
- Age > 18.;Tuberculosis patients should have:
- Newly diagnosed tuberculosis with pulmonary caseating granulomas.
o Diagnosis is based on European Respiratory Society (ERS) guidelines.
- Written informed consent;
- Age > 18.
Exclusion criteria
Sarcoidosis patients may not have:
- Used oral corticosteroids, antimycotica or antibiotics 1 weeks prior to the collection of materials.
- Used immunosuppressive medication or biologicals 3 months prior to the collection of materials.
- A possible infection of the upper- or lower respiratory tract 4 weeks prior to the collection of materials.
- Other diseases which could influence pulmonary function, granuloma formation and/or the immune system, such as:
o Chronic obstructive pulmonary disorder (COPD) or astma in the medical history;
o Auto-immune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis or Goodpasture*s syndrome;
o Malignancies;
o Human immunodeficiency virus (HIV);
o Pregnancy;
o Allergies such as allergic rhinitis. ;Healthy controls may not have:
- Sarcoidosis;
- An abnormal spirometry with a FVC or FEV1 below the 80% of the predicted value;
- A liaison with the coordinating or principal investigator, which could likely influence the decision to participate in this study voluntarily (in concordance with the WMO -article 5);
- See exclusion criteria sarcoidosis patients. ;Tuberculosis patients may not have:
- Sarcoidosis
- See exclusion criteria sarcoidosis patients.
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 | NL41353.078.12 |