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

October 14, 2020 updated by: Li Li, National Jewish Health

The Role of JAK2 in Alveolar Macrophages in Chronic Beryllium Disease

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.)

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

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Study Type

Study Type

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Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Denver, Colorado, United States, 80206
        • National Jewish Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Those diagnosed with Beryllium Sensitization. Those diagnosed with Chronic beryllium disease

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Beryllium Sensitization (BeS)
Blood draw
Procedure: Blood draw
We will draw 4 heparin tubes for peripheral blood mononuclear cells (PBMC)
Chronic Beryllium Disease(CBD)
blood draw BAL
Procedure: Blood draw
We will draw 4 heparin tubes for peripheral blood mononuclear cells (PBMC)
Procedure: bronchoscopy
CBD subjects will undergo a bronchoscopy with lavage. This is the passage of a think flexible tube through the nose into the windpipe then into the bronchial tubes. Sterile saltwater solution is through the flexible tube then immediately removed.
Other Names:
  • BAL

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Time Frame: 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.
year 1
The secondary outcomes for the aims are the changes in BeLPT and AMs phenotype from BeS, CBD and Healthy controls (HC).
Time Frame: 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.
year 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
National Jewish Health

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Li Li, MD, National Jewish Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 6, 2019

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 6, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 29, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 2, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 4, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 19, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 14, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2877

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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