title: Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors: 1 Division of Infectious Diseases.
authors: Nicole A
authors: NA
authors: Braun
authors: Lindsay J
authors: LJ
authors: Celada
authors: Jose D
authors: JD
authors: Herazo-Maya
authors: Susamma
authors: S
authors: Abraham
authors: Guzel
authors: G
authors: Shaginurova
authors: Carla M
authors: CM
authors: Sevin
authors: Jan
authors: J
authors: Grutters
authors: Daniel A
authors: DA
authors: Culver
authors: Ryszard
authors: R
authors: Dworski
authors: James
authors: J
authors: Sheller
authors: Pierre P
authors: PP
authors: Massion
authors: Vasiliy V
authors: VV
authors: Polosukhin
authors: Joyce E
authors: JE
authors: Johnson
authors: Naftali
authors: N
authors: Kaminski
authors: David S
authors: DS
authors: Wilkes
authors: Kyra A
authors: KA
authors: Oswald-Richter
authors: Wonder P
authors: WP
authors: Drake
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism*; D012075:Remission, Spontaneous; D017565:Sarcoidosis, Pulmonary / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: gene expression; programmed death-1; programmed death-L1; proliferation; sarcoidosis