title: Anti-human leukocyte antigen antibodies, vascular C4d deposition and increased soluble c4d in broncho-alveolar lavage of lung allografts.
abstract: BACKGROUND
  The hallmark of humoral rejection is the presence of subendothelial C4d in the allograft. A simultaneous determination of vascular C4d with soluble C4d in broncho-alveolar lavage fluid (BAL) and circulating anti-human leukocyte antigen (HLA) antibodies (HLA-Ab) has not been reported in lung transplantation.
  
  
  METHODS
  Forty-two consecutive lung-transplant patients were included in this cross-sectional study. The presence and specificity of HLA-Ab was determined at the same frequency with transbronchial biopsies. Soluble C4d levels were measured by enzyme-linked immunosorbent assay in all 42 patients. In a subgroup of 32 patients with available timely matched paraffin-embedded tissue sections, the vascular C4d deposition was also assessed.
  
  
  RESULTS
  The presence of HLA-Ab in 16 patients was associated with biopsy-proven acute rejection (10/16 vs. 3/16, P<0.01) and increased immunosuppression (13/16 vs. 4/16, P<0.005). Pulmonary function was also decreased in patients with HLA-Ab (mean forced expiratory volume in 1 second=49%) when compared with the control group (mean forced expiratory volume in 1 second=66%, P<0.05). Nine patients exhibited specific vascular C4d deposition and in eight of nine (89%) cases HLA-Ab were detected, versus 8 of 23 (35%) in C4d-negative patients (P<0.05). Soluble C4d in BAL was highly (>0.5 microg/mL) elevated in patients with HLA-Ab and vascular C4d and was moderately (0.2 microg/mL) increased in patients with antibodies but C4d-negative. In contrast, only a slight elevation of soluble C4d (<0.1 microg/mL) was detected in patients without HLA-specific antibodies.
  
  
  CONCLUSIONS
  The association of HLA-specific antibodies with vascular C4d deposition and soluble C4d in BAL, in addition to the reduced pulmonary function, might constitute a diagnostic triad for antibody-mediated rejection in lung transplant patients.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA. girnitaal@upmc.edu
authors.forename: Alin L
authors.initials: AL
authors.lastname: Girnita
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Lee
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Yousem
authors.forename: Barbara
authors.initials: B
authors.lastname: Detrick
authors.forename: Joseph
authors.initials: J
authors.lastname: Pilewski
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Larry
authors.initials: L
authors.lastname: Jelinek
authors.forename: Jon
authors.initials: J
authors.lastname: Lomago
authors.forename: Diana
authors.initials: D
authors.lastname: Zaldonis
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Spichty
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid; D015935:Complement C4b / Q000737:chemistry*; D005260:Female; D006084:Graft Rejection; D006680:HLA Antigens / Q000737:chemistry*; D006801:Humans; D007518:Isoantibodies / Q000737:chemistry; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry*
chemical_list: D006680:HLA Antigens; D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d