title: P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection.
abstract: BACKGROUND
  Modulation of P-glycoprotein (P-gp) activity in graft-infiltrating T cells may alter their susceptibility to immunosuppression.
  
  
  METHODS
  P-gp activity was measured by rhodamine efflux in T-cell subsets from bronchoalveolar lavage (BAL) of five healthy volunteers and 27 lung allograft recipients. The effect of T-cell activation on P-gp activity was modeled by stimulation of peripheral blood mononuclear cells with staphylococcal enterotoxin B.
  
  
  RESULTS
  Most BAL T cells expressed memory-effector markers. Patients had a lower proportion of CD4 T cells (P = 0.005), whereas control subjects had CD4-to-CD8 ratios similar to peripheral blood. In controls, basal P-gp activity was greatly increased in both CD4 (35% P-gp active) and CD8 (63%) lung T cells compared with peripheral T cells. Basal P-gp activity was elevated in patient BAL T cells but was lower than control BAL activity (CD4, P = 0.07; CD8, P = 0.03). Lung T cells from transplant patients had modest (CD4) or marked (CD8) increases in substrate-induced P-gp activity compared with normal lung, indicating that P-gp was not irreversibly inhibited. Patients with acute cellular rejection (ACR) had reduced P-gp activity in CD4, but not CD8, BAL T cells compared with patients without ACR (P = 0.004). To determine the relationship between T-cell activation on P-gp modulation, P-gp activity was measured in staphylococcal enterotoxin B-stimulated peripheral blood mononuclear cells. P-gp activity was abrogated in CD71 cycling cells but remained high in a persistent but minor population of resting naive T cells.
  
  
  CONCLUSIONS
  Lung T cells have increased in vivo P-gp activity and therefore may eliminate substrate drugs, resulting in local resistance to immunosuppressive therapy. However, P-gp function is reduced during T-cell activation, providing a window of susceptibility to treatment during ACR.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. donnenbergad@msx.upmc.edu
authors.forename: Vera S
authors.initials: VS
authors.lastname: Donnenberg
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Bartley P
authors.initials: BP
authors.lastname: Griffith
authors.forename: Aldo
authors.initials: A
authors.lastname: Iacono
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
authors.forename: John W
authors.initials: JW
authors.lastname: Wilson
authors.forename: Albert D
authors.initials: AD
authors.lastname: Donnenberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000378:metabolism*; D000208:Acute Disease; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004768:Enterotoxins / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006084:Graft Rejection / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D016040:Lung Transplantation; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004768:Enterotoxins; D005456:Fluorescent Dyes; D020112:Rhodamine 123; C031818:enterotoxin B, staphylococcal