The unifying goals of this POI competing renewal resubmission are to further understand the immune, exposure, and genetic basis of chronic beryllium disease (CBD) and to discover and validate biological markers of disease, prognosis, and therapeutic response. We hypothesize that antigen-induced granulomatous diseases result from an aberrant interplay between genetic susceptibility and exposure, resulting in immunologic and inflammatory consequences. CBD is a model human disorder in which to advance our understanding of antigen sensitization and granulomatous inflammation. Exposure to beryllium continues as a public health concern with approximately one million individuals currently at risk for developing chronic beryllium disease (CBD). In the past five years, this POI has solidified a productive collaborative team at the University of Colorado and National Jewish Health, establishing a large available patient cohort and all of the needed genetic, immunologic, biochemical, and analytic models, technologies and collaborations to 1) identify the beryllium-peptide antigen, 2) establish the genetic basis of disease susceptibility in relation to environmental exposure, 3) establish the immune basis for disease progression and therapeutic response, and 4) develop new clinical biomarkers based on that understanding. This Program proposal is comprised of three Projects with interdisciplinary translational research approaches and three Cores, as previously. Project 1 will determine the structure of the beryllium-peptide antigen, define how HLA-DP plus antigen trigger the beryllium-reactive T cell antigen receptor response, and use the peptides to pilot a new class of disease biomarkers. Utilizing genome-wide association tools and exposure characterization. Project 2 will establish susceptibility factors underlying antigen presentation and immune pathways relevant to sensitization and disease, along with gene-environment interactions, in a collaboration that combines cohorts from three major beryllium research centers. Project 3 will define the immune regulatory mechanisms involved in the progression from beryllium sensitization to disease, evaluate biomarkers that predict risk of progression from sensitization and disease in beryllium-exposed cohorts and observe effects of pharmacologic intervention. The Projects rely on an Administrative Core, a Clinical and Laboratory Core to provide clinical data and specimens, and a Biostatistics/Exposure Core for data management, analysis and exposure assessment. These findings will have important implications for public health and will be applicable to beryllium-exposed individuals and those with other granulomatous diseases. This proposal will define and validate biological markers of disease risk, progression, and prognosis, identify immune pathways in granulomatous disease, and contribute to the understanding of genetic and environmental variation relevant to immune and inflammatory mechanisms in environmental illness. BACKGROUND This is the first revision of a competitive renewal application for a program project to continue studies into immune mechanisms of chronic beryllium disease directed by Dr. Lee Newman. The application consists of three research projects and three support cores. Productivity: Studies from the first round of funding have resulted in 50 peer-reviewed publications that also covers a period with a minimal level of bridge funding from NIEHS to support the cohort. The productivity and continuance demonstrate quality, commitment and ability to work together. PROGRAM AS INTERGRATED EFFORT

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011810-09
Application #
8307971
Study Section
Special Emphasis Panel (ZES1-TN-J (ND))
Program Officer
Nadadur, Srikanth
Project Start
2002-09-12
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$1,582,314
Indirect Cost
$252,304
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Falta, M T; Tinega, A N; Mack, D G et al. (2016) Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice. Mucosal Immunol 9:218-28
Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7
Tooker, Brian C; Ozawa, Katherine; Newman, Lee S (2016) CpG promoter methylation status is not a prognostic indicator of gene expression in beryllium challenge. J Immunotoxicol 13:417-27
Li, Li; Hamzeh, Nabeel; Gillespie, May et al. (2015) Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease. PLoS One 10:e0117276
Tooker, Brian C; Brindley, Stephen M; Chiarappa-Zucca, Marina L et al. (2015) Accelerator mass spectrometry detection of beryllium ions in the antigen processing and presentation pathway. J Immunotoxicol 12:181-7
McKee, A S; Mack, D G; Crawford, F et al. (2015) MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4⁺ T-cell priming. Mucosal Immunol 8:1237-47
Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42
Li, L; Huang, Z; Gillespie, M et al. (2014) p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation. Hum Immunol 75:1155-62
Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8
Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80

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