Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: a potential etiological factor for bronchiolitis obliterans syndrome.
BACKGROUND
The main cause of morbidity and mortality after lung transplantation (LT) is bronchiolitis obliterans syndrome (BOS). Anti-HLA antibodies development after LT has been shown to play an important role in BOS pathogenesis. However, the nature of non-HLA antibodies developed after LT and their role in BOS pathogenesis have not been determined.


METHODS
Sera from 16 BOS+ patients and 11 BOS- patients were collected at 12, 24, 36, and 48 months after LT. Anti-HLA class I and class II antibodies were absorbed with pooled human platelets and pooled human lymphoblastoid cell lines, respectively. Then, the presence of non-HLA antibodies against several cell lines from different origin was determined by flow cytometric analysis. Antibody-positive samples were tested for induction of proliferation and growth factor production in two selected airway epithelial cell (AEC) lines.


RESULTS
Five of 16 BOS+ patients (31.2%) and 0 of 11 BOS- patients (0%) developed anti-AEC antibodies after LT (P=0.05). No reactivity against endothelial cells, lymphocytes, monocytes, or granulocytes was detected. Further analysis of two selected sera demonstrated the development of reactivity against a 60-kDa antigen expressed by 60% of AEC lines and only 12% of cell lines from other tissues. Antibody binding to this antigen induced intracellular Ca++ influx, tyrosine phosphorylation, proliferation, and up-regulation of transforming growth factor-beta and heparin-binding epidermal growth factor mRNA transcription in AECs.


CONCLUSIONS
These results indicate that anti-AEC antibodies may play a role in the immunopathogenesis of BOS in the absence of anti-HLA antibodies.
Jaramillo
A
A
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Naziruddin
B
B
Zhang
L
L
Reznik
S I
SI
Smith
M A
MA
Aloush
A A
AA
Trulock
E P
EP
Patterson
G A
GA
Mohanakumar
T
T
D000906:Antibodies / Q000502:physiology*; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology; D006680:HLA Antigens / Q000276:immunology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D016040:Lung Transplantation / Q000276:immunology*; D010766:Phosphorylation; D011184:Postoperative Period; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D000906:Antibodies; C587883:HBEGF protein, human; D006680:HLA Antigens; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D014443:Tyrosine; D004815:Epidermal Growth Factor