The Role of JAK2 in Alveolar Macrophages (AM's) in Chronic Beryllium Disease (CBD)

Completed

• Conditions: Chronic Beryllium Disease (CBD); Beryllium Sensitization (BeS)
• Interventions: Procedure: Blood draw; Procedure: bronchoscopy

• Registration Number: NCT02596347
• Lead Sponsor: National Jewish Health

Brief Summary

Current studies suggest that alveolar macrophages (AM) act as silencers of most immune responses in the lung. However, in pathological conditions, such as asthma, hypersensitivity pneumonitis, and sarcoidosis, AMs become involved in the maintenance and further expansion of the immune response in the target organ. The Investigator has preliminary data demonstrating that CBD AMs at the site of disease involvement (bronchoalveolar lavage, BAL) display an activated cell surface phenotype compared to AMs from healthy controls. Furthermore, exciting data from our group demonstrates significant differences in gene expression profiles between CBD and Beryllium Sensitivity (BeS) bronchial alveolar lavage (BAL) cells, in pivotal immune response genes and networks. Specifically, the Investigator has found the JAK/STAT pathway and the JAK2 gene was dramatically overexpressed in CBD BAL cells. In addition, constitutively phosphorylated JAK2 (pJAK2) was found in AMs from Chronic Beryllium Disease (CBD) patients by Westernblot and was increased after beryllium (Be) stimulation for 30 min. Moreover, the JAK2 inhibitor TG101348 significantly inhibited Be-induced CBD AMs TNFa and IFNy production. Meanwhile, overexpression of the JAK2 inhibitor SOCS 1 (suppressors of cytokine signaling) protein decreased Be-induced TNFa production from AMs. Based on this information, the Investigator hypothesizes that CBD AMs overexpress JAK2, which augments the immune response to Be and development of CBD but not BeS.

The investigators believe that these studies are highly innovative since they will undoubtedly shed light on exposure-mediated immune dysregulation in Alveolar Macrophages (AMs) that lead to disease development and likely progression and with additional study of this pathway will reveal potential biomarkers for clinical prognosis and diagnosis. The results obtained from this study will improve the investigators understanding of factors involved in the development of Chronic Beryllium disease (CBD), as well as define targets for therapy, and will serve as a model of other exposure-related immune responses and environmentally-induced chronic diseases. Most importantly, these studies will provide the investigator with preliminary data to submit a high quality R01, allowing the Investigator to apply similar approaches to other genes, define a potential target for this and other similar immune-mediated diseases and continue research efforts at National Jewish Health (NJH.)

Detailed Description

Not available

Study Timeline

• Study Start: 2015-04
• Study First Submitted: 2015-10-29
• Study First Submitted QC: 2015-11-02
• Study First Posted: 2015-11-04
• Primary Completion: 2019-12-06
• Study Completion: 2019-12-06
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-14
• Last Update Posted: 2020-10-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

• Chronic Beryllium Disease - These individuals will meet the following inclusion criteria:

Inclusion Criteria:

1. History of beryllium exposure;
2. Positive blood and/or bronchoalveolar lavage (BAL) Beryllium Lymphocyte Proliferation Tests (BeLPT);
3. Biopsy-proven pathologic changes consistent with CBD, specifically non-caseating granulomas and/or mononuclear cell interstitial infiltrates .

Beryllium Sensitization - These individuals will meet the following inclusion criteria:

Inclusion Criteria:

1. History of beryllium exposure;
2. Two or more positive blood beryllium lymphocyte proliferation tests (BeLPT) or positive bronchoalveolar lavage (BAL) BeLPT;
3. Normal lung tissue (no histology suggestive of CBD).

Exclusion Criteria

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Chronic Beryllium Disease(CBD)	Blood draw	blood draw BAL
Beryllium Sensitization (BeS)	Blood draw	Blood draw
Chronic Beryllium Disease(CBD)	bronchoscopy	blood draw BAL

Primary Outcome Measures

Name	Time	Method
The secondary outcomes for the aims are the changes in BeLPT and AMs phenotype from BeS, CBD and Healthy controls (HC).	year 2	The investigator will use repeated measure Welch's ANOVA in SAS 9.4, which correctly accounts for the correlation between measurements and allows for comparisons within and between groups. Normalizing transformations will be performed when necessary to conform to model assumptions and Mauchly's sphericity test will be assessed and adjustments will be added to the analysis as necessary. Estimate and contrast statements will be developed to test hypotheses of interest.
The primary outcome for the aims is the downregulation of Th1 cytokine TNFalpha with the inhibition of the JAK2 using siRNA and the inhibitor INCB018424, CEP-701 and TG101348 in CBD or overexpression of the JAK2 gene.	year 1	As the primary outcome is the downregulation of TNFalpha level with the inhibition of the JAK2 using the inhibitor TG101348 in CBD, we expect a 50% reduction with a standard deviation of 0.2 based on our preliminary data. We will have more than 95% power with n=6 CBD patients for these aims.

Trial Locations

Locations (1)

National Jewish Health; 🇺🇸 Denver, Colorado, United States