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Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium Disease (CBD) (BeEpiGen)

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ClinicalTrials.gov Identifier: NCT02604693
Recruitment Status : Recruiting
First Posted : November 13, 2015
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Lisa Maier, National Jewish Health

Brief Summary:

This study will provide important results for each aim, while also providing an integrative transcriptional and epigenomic profile of CBD.

In Aim 1 the Investigator will define genome-wide epigenetic alterations of CBD, by determining genes that are DM in pivotal immune cells, in the target organ (CD4+ BAL cells) in CBD compared to BeS and healthy controls. In addition, the Investigator will determine the impact of Be exposure on the methylation profile of CBD and BeS cells compared to each other and normal controls. This information will be used to define DM regions, genes and their networks.

Using the cases and controls from Aim 1, we will evaluate the gene-expression from these same subjects in Aim 2 to define functional epigenetic loci based on DE in CD4+ BAL cells with and without Be exposure. The Investigator will also integrate ENCODE/RE methylation, histone modification, and chromatin accessibility data as well as our genome-wide association study (GWAS) data to prioritize epigenetic marks and networks for confirmation and validation in Aim 3. In Aim 3, the Investigator will test the generalizability of their findings, explore the potential of methylation marks as biomarkers of disease in PBMCs and determine if change in methylation of these targets with AZA or folic acid affects key immune and regulatory pathways in a second set of CBD and BeS subjects. Throughout the Aims, the Investigator will use both fresh CD4+ T cells to directly assess disease relevance and Be-stimulated cultured CD4+ T cells (compared to unstimulated cultured T cells) to assess the impact of environmental exposure .


Condition or disease Intervention/treatment
Chronic Beryllium Disease Other: Nothing

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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium
Actual Study Start Date : December 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Group/Cohort Intervention/treatment
Chronic Beryllium Disease
Those that have been diagnosed with the disease. No interventions will be administered.
Other: Nothing
No interventions will be administered.

Beryllium Sensitization
Those that have been diagnosed with beryllium sensitization and do not have chronic beryllium disease. No interventions will be administered.
Other: Nothing
No interventions will be administered.

normal controls
Those that do not have chronic beryllium disease or beryllium sensitization. No interventions will be administered
Other: Nothing
No interventions will be administered.




Primary Outcome Measures :
  1. Determine the critical immune and environmentally-induced epigenetic alterations in the CD4+ T cells at the site of disease involvement from CBD compared to BeS and control subjects. [ Time Frame: Year 1 through year 2 ]
    The Investigators goal is to define an epigenomic profile for BeS and CBD and for Be exposure in the lung. Most studies using similar methods have demonstrated significant hypo- and hyper-methylation, in disease states, which we also expect to find. In addition, we expect to confirm an association between CBD and Th1 epigenetic regulation, finding DM in regions such as FOXP3, Th1 differentiation pathways and TNFalpha, likely with modulation of these and other regions with Be exposure. There is no information regarding methylation alterations induced by an immune mediated exposure such as Be. The investigator expects to define new and unique genes with DM, some involved in the immune response and others in pathways and networks not known to be associated with granulomatous inflammation, shedding light on the pathogenesis of this and similar diseases.

  2. Define the functional impact of critical immune and environmentally-induced epigenetic alterations in gene expression from BAL CD4+ T cells from CBD compared to BeS and control subjects used in Aim 1 [ Time Frame: year 1 through year 4 ]
    At the end of Aim 2, the Investigator will have 20 genes with validated methylation and expression changes. These methylation changes are likely to be regulatory in CD4+ T cells not only based on relationship with expression but also network analysis of methylation changes (Aim 1), relationship with immune cell phenotypes, cell specific chromatin/histone marks from ENCODE and RE datasets, and our CBD GWAS SNPs (Aim 2). The Investigator has a pipeline of data analysis currently in place as evidenced by our preliminary data; as new approaches such as these become available, we will use them to analyze our data.


Secondary Outcome Measures :
  1. Test the generalizability of our findings and validity of identified methylation and gene expression changes as potential biomarkers and therapeutic targets. [ Time Frame: Year 3 through year 5 ]
    This Aim will result in a set of key data, including potential new biomarkers of disease and exposure in CBD. The Investigator expects to be able to validate the 20 loci identified in Aim 2 in BAL as well as PBMCs. Even with a sample size of n=10 in their gene-expression studies, the Investigator was able to define significant DE in PBMCs in CBD that they are currently exploring as biomarkers in a larger population; the Investigator expects that with changes found evaluating the relationship between DM and DE that they will be able to use the PBMCs as a biomarker of disease and exposure.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
We will enroll subjects using standard case and control definitions. We will enroll up to 150 subjects. Controls will be frequency matched on age, gender, race and smoking status to limit methylation changes related to these factors.
Criteria

Inclusion Criteria:

Chronic Beryllium Disease (CBD):

  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:

  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).

Normal Controls:

  1. No history of beryllium exposure
  2. Former smokers or never smokers -

Exclusion Criteria:

Chronic Beryllium Disease:

  1. Immunosuppressive therapy within the last three months
  2. Current cigarette smoking or smoking within six months prior to the study
  3. Positive lung washing or biopsy cultures for fungi, mycobacteria or other respiratory pathogen consistent with an acute or chronic infection
  4. Weight less than 110 lbs. (for venipuncture)
  5. Pregnancy
  6. Severe room air hypoxemia and or hypercapnia (precluding BAL), e.g., resting PaO2 < 45, PaCO2 > 45 mm Hg; (Denver altitude 5,280 feet)
  7. Presence of another disease that may be expected to significantly affect patient mortality and or the immune response (e.g., HIV, HCV, cancer, uncorrected bleeding diathesis, acute hypercapnia with a resting PaCO2 above 45 mm Hg; serious cardiac arrhythmia, recent myocardial infarction within 6 weeks)
  8. Patient inability to participate in the study, such as inability to undergo venipuncture and BAL procedures that form part of the inclusion/exclusion criteria or part of the outcome measure

Beryllium Sensitization:

  1. Known underlying systemic or lung disease;
  2. Current cigarette smoking or smoking within six months prior to the study
  3. Positive lung pathology consistent with CBD
  4. Pregnancy
  5. Weight less than 110 lbs. (for venipuncture)
  6. Presence of another disease that may be expected to significantly affect patient mortality and or the immune response (e.g., HIV, HCV, cancer, uncorrected bleeding diathesis, serious cardiac arrhythmia; recent myocardial infarction within 6 weeks)
  7. Patient inability to participate in the study, such as inability to undergo venipuncture and BAL procedures that form part of the inclusion/exclusion criteria or part of the outcome measure

Normal Controls:

  1. History of beryllium exposure
  2. Known underlying systemic or lung disease;
  3. Immunosuppressive therapy or other medication for as systemic disease process in the last 3 months;
  4. Current smokers or smoking within 6 months of study
  5. Pregnancy
  6. Weight less than 110 lbs. (for venipuncture)
  7. Inability to undergo BAL or venipuncture procedures -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02604693


Contacts
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Contact: Peggy Mroz, MSPH 303-398-1730 mrozp@njhealth.org
Contact: Christina Riley, BA 303-270-2049 rileyc@njhealth.org

Locations
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United States, Colorado
National Jewish Health Recruiting
Denver, Colorado, United States, 80206
Contact: Peggy M Mroz, MSPH    303-398-1730    mrozp@njhealth.org   
Principal Investigator: Lisa Maier, MD         
Sponsors and Collaborators
National Jewish Health
Investigators
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Principal Investigator: Lisa Maier, MD National Jewish Health

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Responsible Party: Lisa Maier, MD, National Jewish Health
ClinicalTrials.gov Identifier: NCT02604693     History of Changes
Other Study ID Numbers: HS-2866
First Posted: November 13, 2015    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
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Berylliosis
Pneumoconiosis
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Lung Injury
Occupational Diseases