Braun, Nicole A.Celada, Lindsay J.Herazo-Maya, Jose D.Abraham, SusammaShaginurova, GuzelSevin, Carla M.Grutters, JanCulver, Daniel A.Dworski, RyszardSheller, JamesMassion, Pierre P.Polosukhin, Vasiliy V.Johnson, Joyce E.Kaminski, NaftaliWilkes, David S.Oswald-Richter, Kyra A.Drake, Wonder P.2016-05-022016-05-022014-09-01Braun, N. A., Celada, L. J., Herazo-Maya, J. D., Abraham, S., Shaginurova, G., Sevin, C. M., … Drake, W. P. (2014). Blockade of the Programmed Death-1 Pathway Restores Sarcoidosis CD4+ T-Cell Proliferative Capacity. American Journal of Respiratory and Critical Care Medicine, 190(5), 560–571. http://doi.org/10.1164/rccm.201401-0188OC1535-4970https://hdl.handle.net/1805/9488RATIONALE: 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.en-USPublisher PolicyAntigens, CD274metabolismCD4-Positive T-LymphocytesphysiologySarcoidosis, PulmonaryimmunologyArticle