title: CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients.
abstract: BACKGROUND
  Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients.
  
  
  OBJECTIVE
  To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients.
  
  
  METHODS
  Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events.
  
  
  RESULTS
  Findings that CD28 was present on less than 90% of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88%). Perforin and granzyme B were produced by >50% of the CD4(+)CD28(null) cells, but less than 6% of autologous CD4(+)CD28(+) cells (P < 0.006). CD4(+)CD28(null) cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 +/- 1.3%), compared with autologous CD4(+)CD28(+) (9.5 +/- 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4(+)CD28(null) cells by 33 +/- 11% versus 68 +/- 12% inhibition of CD4(+)CD28(+) (P = 0.025). FEV(1) fell 6 months later (0.35 +/- 0.04 L) in recipients with CD4(+)CD28(+)/CD4(total) less than 90% (CD28% Low) compared with 0.08 +/- 0.08 L among CD4(+)CD28(+)/CD4(total) (CD28% High) greater than 90% (CD28% High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28% Low recipients was 32 +/- 10% versus 78 +/- 6% among the CD28% High subjects (P < 0.0001).
  
  
  CONCLUSIONS
  CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4(+)CD28(null) cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.
authors.affiliation: Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Studer
authors.forename: M Patricia
authors.initials: MP
authors.lastname: George
authors.forename: Xuehai
authors.initials: X
authors.lastname: Zhu
authors.forename: Yifang
authors.initials: Y
authors.lastname: Song
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Valentine
authors.forename: Michael W
authors.initials: MW
authors.lastname: Stoner
authors.forename: Jigme
authors.initials: J
authors.lastname: Sethi
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
mesh_terms: D001989:Bronchiolitis Obliterans / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D018106:CD28 Antigens