Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.

Braun NA, Celada LJ, Herazo-Maya JD, Abraham S, Shaginurova G, Sevin CM, Grutters J, Culver DA, Dworski R, Sheller J, Massion PP, Polosukhin VV, Johnson JE, Kaminski N, Wilkes DS, Oswald-Richter KA, Drake WP
Am J Respir Crit Care Med. 2014 190 (5): 560-71

PMID: 25073001 · PMCID: PMC4214083 · DOI:10.1164/rccm.201401-0188OC

RATIONALE - Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function.

OBJECTIVES - To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity.

METHODS - Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens.

MEASUREMENTS AND MAIN RESULTS - Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression.

CONCLUSIONS - Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.

MeSH Terms (19)

Adult Aged Antibodies B7-H1 Antigen Biomarkers Case-Control Studies CD4-Positive T-Lymphocytes Cell Proliferation Female Flow Cytometry Humans Immunohistochemistry Lung Neoplasms Male Middle Aged Programmed Cell Death 1 Receptor Remission, Spontaneous Sarcoidosis, Pulmonary Up-Regulation

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