Clinical trial NCT05916638: MoMa Signature During Granulomatosis
Official title: Role of Monocytes (Mo) and Macrophages (Ma) in Sarcoidosis and in Tuberculosis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sarcoidosis
Tuberculosis
Keywords: tuberculosis
sarcoidosis
granuloma
monocytes
macrophages
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-06-23
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult patients diagnosed with sarcoidosis or tuberculosis

Brief summary: Sarcoidosis is a systemic inflammatory disease characterized by unspecific granuloma formation. Our hypothesis is that granuloma formation and maintenance mainly relies on the overactivation of monocytes (Mo) and macrophages (Ma). To this end, the study aims (i) to define MoMa systemic signature in sarcoidosis, (ii) to characterize this signature in situ on tissue samples, and (iii) to identify causative factors that participate to the MoMa chronic overactivation. Thus, a cohort of sarcoidosis patients will be compared with tuberculosis patients. The MoMa systemic signature will be defined on whole blood (TruCulture model) and then in situ through different methods (multi-parameter spectral flow cytometry, RNA-seq, Luminex, imaging mass cytometry). The epigenome of monocytes will be studied thanks to CUT\&Tag. The MoMa systemic signature will be defined ex vivo at different time points during the course of the disease with phenotypic, transcriptomic, cytokine and functional approaches. The previously identified signature will be studied in situ and completed by the characterization of granuloma architecture and microenvironmental interactions, which could be modulated by epigenetic modifications. Hence, the epigenome of monocytes will be analyzed in two groups (sarcoidosis and tuberculosis). These results would allow to better understand sarcoidosis physiopathology and, in fine, may raise new therapeutic strategies. Finally, the study could challenge the dogma on innate immunity/auto-inflammation versus adaptive immunity/auto-immunity/memory.

Detailed description: "Sarcoidosis is an inflammatory disease characterized by the presence of coalescing, tightly clustered, non-necrotizing granulomas. The diagnosis is based on three major criteria: a compatible clinical presentation, the presence of non-necrotizing granulomatous inflammation, and the exclusion of alternative granulomatous diseases. A wide range of clinical phenotypes are observed depending on the location of the granulomatous lesions which can affect any organ, with the lungs being the most affected site. Sarcoidosis shares many similarities with tuberculosis, in which granuloma formation is triggered by Mycobacterium tuberculosis (M. tb). These phenotypic similarities between the two diseases present many challenges for diagnosis, clinical management and therapy.

Our understanding of the factors that contribute to sarcoidosis development, granuloma formation and maintenance remains limited. Part of this challenge is that granuloma development may involve both environmental and genetic factors, which contribute to the recruitment of immune cells to form the granuloma. Immune cells involved in the granuloma include (1) CD4 Th1 and Th17 T cells and their associated cytokines (e.g, IFNγ, TNFα, IL-17, IL-2); and (2) monocytes (Mo) and macrophages (Ma) including proinflammatory M1 and pro-fibrosis M2 types. However, the specific factors that contribute to granuloma maintenance and evolution remain to be identified. Among them, we can hypothesized that trained immunity, persistence of the antigen, or the microenvironment are involved in this chronic dysregulated immune response. Such an improved understanding of the pathophysiology of the disease may allow development of new treatments, as currently corticosteroids remain the mainstay of therapy.

Our main hypothesis is that granuloma formation and maintenance mainly relies on the overactivation of monocytes (Mo) and macrophages (Ma). To this end, the study aims (i) to define MoMa systemic signature in sarcoidosis, (ii) to characterize this signature in situ on tissue samples, and (iii) to identify causative factors that participate to the MoMa chronic overactivation. Thus, a cohort of sarcoidosis patients will be compared with tuberculosis patients. The MoMa systemic signature will be defined on whole blood (TruCulture model) and then in situ through different methods (multi-parameter spectral flow cytometry, RNA-seq, Luminex, imaging mass cytometry). The epigenome of monocytes will be studied thanks to CUT\&Tag. The MoMa systemic signature will be defined ex vivo at different time points (M0, M6 and M12) during the course of the disease with phenotypic, transcriptomic, cytokine and functional approaches. The previously identified signature will be studied in situ and completed by the characterization of granuloma architecture and microenvironmental interactions, which could be modulated by epigenetic modifications. Hence, the epigenome of monocytes will be analyzed in two groups (sarcoidosis and tuberculosis). These results would allow to better understand sarcoidosis physiopathology and, in fine, may raise new therapeutic strategies. Finally, the study could challenge the dogma on innate immunity/auto-inflammation versus adaptive immunity/auto-immunity/memory."

Eligibility criteria: Inclusion criteria:

1. Male and female \> 18 years old
2. Diagnosis of sarcoidosis and of tuberculosis
3. Affiliated to medical insurance

Exclusion criteria:

1. HIV infection
2. pregnant or breastfeeding woman
3. Patient under legal protection, guardianship or curators
4. Absence of signed consent"

Primary outcomes:
measure: macrophage activation in sarcoidosis measured by epigenomic
timeFrame: up to 12 months of follow-up.
measure: monocyte activation in sarcoidosis measured by epigenomic
timeFrame: up to 12 months of follow-up.
measure: macrophage activation in sarcoidosis measured by flow cytometry
timeFrame: up to 12 months of follow-up.
measure: monocyte activation in sarcoidosis measured by flow cytometry
timeFrame: up to 12 months of follow-up.
measure: monocyte activation in sarcoidosis measured by transcriptomic
timeFrame: up to 12 months of follow-up.
measure: macrophage activation in sarcoidosis measured by transcriptomic
timeFrame: up to 12 months of follow-up.
measure: macrophage activation in sarcoidosis measured by cytokine measurement
timeFrame: up to 12 months of follow-up.
measure: monocyte activation in sarcoidosis measured by cytokine measurement
timeFrame: up to 12 months of follow-up.
Secondary outcomes:
measure: monocyte activation in tuberculosis measured by epigenomic
timeFrame: up to 12 months of follow-up.
measure: Identification of a pathogen that triggers sarcoidosis development by metagenomic study
timeFrame: Samples collected before treatment/at diagnosis
measure: identification of epigenetic modifications of monocytes by CUT&Tag method
timeFrame: 12 months of follow-up.
measure: Identification of a diagnostic test to discriminate sarcoidosis and tuberculosis
timeFrame: Samples collected before treatment/at diagnosis
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Bichat
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Karim SACRE, MD-PhD, PU-PH
role: PRINCIPAL_INVESTIGATOR
References: