Sarcoidosis is a chronic multi-system disease of unknown etiology characterized by formation of noncaseating granulomatous infiltrates, most often within the lungs. While the specific causality of sarcoidosis is enigmatic, the granuloma formation and other pathologic findings of this disorder almost certainly reflect a dysregulated immune response to an unidentified antigen among genetically predisposed individuals. The primary hypothesis of this proposal is that systematic collection (Specific Aim 1) and multidisciplinary study of clinical specimens from sarcoidosis patients (Specific Aim 2) will result in new insights into the etiopathogenesis of this disease and identification of prognostic biomarkers. In addition, we also hypothesize that CCRS antagonism in sarcoidosis patients with maraviroc will safely diminish the intrapulmonary immigration and sequestration of monocytes and T-cells, decrease activation and differentiation of these cells, and result in measurable Improvements of abnormal, clinically-relevant inflammatory parameters (Specific Aim 3).
The specific aims of this proposal are 1) To collect residual lymph node specimens (mediastinoscopy and endobronchial ultrasound guided fine needle aspirations [EBUS-FNA]), bronchoalveolar lavage fluid (BALF), skin biopsies, and peripheral blood of sarcoidosis subjects, along with detailed subject clinical data (e.g., demographics, disease phenyotyping) for provision to the collaborative Genomic and Informatics Center (GIC);2) To analyze portions/aliquots of the specimens collected in Aim 1 In immunobiological phenotyping assays. These studies will include measures of protein and.gene expressions related to CD4 T-cell activation and differentiation (using flow cytometry and RT-PCR, respectively) that we have discovered are highly associated with the prognosis of other chronic immunological lung diseases;and 3) To determine effects of CCR5 inhibition on key trafficking, activation, and effector functions of CD4 T-cells and monocytes/macrophages of sarcoidosis patients. The resultant data will shape the design of more definitive clinical trials i sarcoidosis patients to follow, and will provide insight on potential therapeutic uses of CCR5 inhibitors in sarcodosis.

Public Health Relevance

Sarcoidosis is a common inflammatory disease that affects the lungs and other organs. The therapy for active disease involves the use of steroids, which are associated with significant side effects in most patients. This research proposes to contribute sarcoidosis samples to a core facility for molecular biology studies and to study the effect of a novel agent, maraviroc, on disease activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL112711-02
Application #
8474836
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F3))
Program Officer
Punturieri, Antonello
Project Start
2012-06-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$144,111
Indirect Cost
$48,988
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kahloon, Rehan A; Xue, Jianmin; Bhargava, Arpit et al. (2013) Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses. Am J Respir Crit Care Med 187:768-75