Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03886350 |
Other study ID # |
RIPH3-RNI18 / UNLOCk |
Secondary ID |
2019-A00290-57 |
Status |
Completed |
Phase |
|
First received |
|
Last updated |
|
Start date |
April 3, 2019 |
Est. completion date |
July 20, 2020 |
Study information
Verified date |
June 2022 |
Source |
University Hospital, Tours |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
Cystic fibrosis (CF) is characterized by a decrease in mucociliary clearance, recurrent
infections and airway inflammation. This inflammatory process in airway mucosa is persistent,
uncontrolled, but, somewhat paradoxically, ineffective for pathogen clearance. Neutrophils
are chronically recruited in the airway mucosa by proinflammatory mediators such as
Interleukin (IL)-17. However, mechanisms involved in this dysregulated and persistent immune
response are not well understood.
In this context, a heterogeneous subpopulation of T lymphocytes called "unconventional T
cells" (UTC) should deserve greater attention. UTC play a key role in orchestrating the
ensuing innate and adaptive immune responses and they are endowed with numerous regulatory
and effector properties. UTC mainly establish residency at mucosal sites, including the lung.
To date, however, data related to implication and behavior of UTC during cystic fibrosis are
extremely limited.
The hypothesis is that, given UTC properties, their functions and behavior are altered in CF,
and thus, these cells could be implicated in persistent inflammation and poor response to
infections.
The objective is to study UTC properties and functions in cystic fibrosis using blood and
sputum samples of patients with CF, in correlation with comprehensive clinical and
microbiological data.
The study will enroll adult patients with CF followed-up at University Hospital of Tours,
France. For each patient included, blood and sputum samples will be analyzed during 18 months
1/ from routine tests obtained at steady state and 2/ from tests performed during acute
exacerbations. UTC will be explored in blood and sputum using flowcytometry approach, to
evaluate their relative abundance, activation/inhibition profile and functions (cytokine
production and cytotoxic ability). Correlation will be made with clinical status, with
longitudinal comparison across the study period for each patient, and comparison with the
other patients and healthy volunteers.
This study will add significant knowledge in CF immunopathology by comprehensively assess UTC
presence, functions and activation in CF. Indeed, UTC could be explored for disease
progression marker, and, in a long-term perspective, explored for therapeutic interventions
aiming at modulating their function (by activating or inhibiting UTC), to reshape lung immune
response during CF.
Description:
- Clinical and scientific background
Cystic fibrosis is characterized by functional abnormalities in the cystic fibrosis
transmembrane conductance regulator (CFTR) membrane channel leading to a decrease in
mucociliary clearance, recurrent infections and airway inflammation. This inflammatory
process in airway mucosa is persistent, uncontrolled, but, somewhat paradoxically,
ineffective for pathogen clearance. Neutrophils are chronically recruited in the airway
mucosa by proinflammatory mediators such as IL-17, and probably largely contribute to tissue
damage. However, up-stream mechanisms involved in this dysregulated and persistent immune
response are not well understood.
In this context, seeking for new candidates that may be involved in this chronic inflammation
is critical as there is, to date, no effective treatment to modulate immune response in CF.
To address this, a heterogeneous subpopulation of T lymphocytes called "unconventional T
cells" (UTC) should deserve greater attention. These cells comprise Natural Killer T (NKT)
cells, mucosal associated invariant T cells (MAIT cells) and γδ T cells. The investigators
believe these cells could be instrumental for future immune-intervention in CF
immunopathology. First, UTC play a key role in orchestrating the ensuing innate and adaptive
immune responses. Their pivotal role in mounting host defense during infection have been
demonstrated, by the investigators and others, in different experimental models. Notably,
their pivotal role for IL-17-driven neutrophil recruitment during acute pulmonary infection
is well documented. Second, they are endowed with numerous regulatory and effector
properties. Third, UTC mainly establish residency at mucosal sites, including the lung. Last,
these cells are already investigated for therapeutic interventions (mainly in oncology, with
ongoing phase I and II clinical trials). To date, however, data related to implication and
behavior of UTC during cystic fibrosis are extremely limited and preliminary.
The hypothesis is that, given UTC properties, their functions and behavior are altered in CF,
and thus, these cells could be implicated in persistent inflammation and poor response to
infections.
- Objective of the study: The objective is to study UTC properties and functions in cystic
fibrosis using blood and sputum samples of patients with CF, in correlation with
comprehensive clinical and microbiological data.
- Design:
This is a prospective exploratory single-center study including adult patients with CF whom
follow-up is undertaken at University Hospital of Tours, France.
Number of participants: 80
- Interventions and analysis:
For each patient included, study duration will be 18 months, during which blood and sputum
samples will be analyzed 1/ from routine tests obtained at steady state during annual
check-up and follow-up examination and 2/ from tests performed during acute exacerbations
treated at the hospital or outpatient. To be enrolled in this study does not add any medical
or biological examination compared to the usual follow-up. Each blood or sputum test done
during follow-up examination or treating care will lead to supplementary samples for
research.
Clinical parameters will be collected including clinical status (exacerbation or not),
microbial status, pulmonary function test, drugs used like CFTR modulator therapies
(lumacaftor ivacaftor) or antibiotics.
UTC will be explored in blood and sputum using flowcytometry approach, to evaluate their
relative abundance, activation/inhibition profile and functions (cytokine production and
cytotoxic ability). In some cases, intra-cellular staining will be performed to assess
cytokine production and/or transcription factor expression. Functions of unconventional T
cells will also be performed after ex vivo stimulation on purified population (cell sorting).
Cytokine level sand transcriptomic analyses will also be performed on blood
samples.Correlation will be made with clinical status, with longitudinal comparison across
the study period for each patient, and comparison with the other patients and healthy
volunteers.