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

Nicole A. Braun, Lindsay J. Celada, Jose D. Herazo-Maya, Susamma Abraham, Guzel Shaginurova, Carla M. Sevin, Jan Grutters, Daniel A. Culver, Ryszard Dworski, James Sheller, Pierre P. Massion, Vasiliy V. Polosukhin, Joyce E. Johnson, Naftali Kaminski, David S. Wilkes, Kyra A. Oswald-Richter, Wonder P. Drake

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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<sup>+</sup> 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<sup>+</sup> CD4<sup>+</sup> 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<sup>+</sup> CD4<sup>+</sup> 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<sup>+</sup> T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.

Original languageEnglish (US)
Pages (from-to)560-571
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume190
Issue number5
DOIs
StatePublished - Sep 1 2014

Keywords

  • Gene expression
  • Programmed death-1
  • Programmed death-L1
  • Proliferation
  • Sarcoidosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Braun, N. A., Celada, L. J., Herazo-Maya, J. D., Abraham, S., Shaginurova, G., Sevin, C. M., Grutters, J., Culver, D. A., Dworski, R., Sheller, J., Massion, P. P., Polosukhin, V. V., Johnson, J. E., Kaminski, N., Wilkes, D. S., Oswald-Richter, K. A., & 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. https://doi.org/10.1164/rccm.201401-0188OC