Introduction: Antibodies (Abs) to lung self-antigens (SAgs) have been correlated with development of bronchiolitis obliterans syndrome following human lung transplantation. Further, administration of Abs to SAgs following syngeneic murine orthotopic single lung transplantation have shown obliterative airway disease (OAD) lesions only in transplanted but not to native lungs. The goal of this study is to determine the role of primary insult to the lungs in inducing OAD lesions following administration of anti-SAgs and to define the immune responses leading to OAD.

Methods: To induce a primary insult to the native lungs, 0.1M HCl was administered intrabronchially into C57BL6 mice day 0 on all experimental groups (3 per group). Group A animals received intrabronchially 200 ug/ml rabbit anti-Kα1Tubulin (Kα1T), Group B rabbit anti-Collagen V (Col-V), and Group C normal rabbit IgG on days 1, 3, 6 and 15. Sera were collected and analyzed for the Abs for SAgs by ELISA. Serum cytokine was detected by Luminex. Exosomes were isolated and analyzed for lung SAgs by western.

Results: Rabbit anti-Col-V and Kα1T induced the development of Abs against lung SAgs Group A (9.09±1.79 [micro]g/ml Kα1T p=0.002 and 1.56±0.47 [micro]g/ml Col-V p=0.02), and Group B (7.96±1.09 [micro]g/ml Kα1T p<0.001 and 1.69±0.27 [micro]g/ml Col-V p=0.002) when compared with Group C (2.35±0.052[micro]g/ml Kα1T and 0.467±0.179 [micro]g/ml Col-V). Group A and B animals also had increased levels of circulating TNFα (217.6±138.66 Group A p=0.08 and 409±122.01 Group B p=0.006), IL 2 (78.3±28.5 Group A p=0.001 and 94.5±28.2 Group B p=0.032), in comparison to Group C (TNFα 35.7±23.7 and IL2 47.8±26.8). In contrast, IL10 levels were significantly decreased in both Group A and B (3.8±0.75 Group A p=0.07and 3.9±0.88 Group B p=0.08) in comparison to Group C (10.8±5.94). Further, induction of exosomes with increased levels of lung SAgs were demonstrable in the sera from Group A and B, 4 fold increase in Kα1T (Group A and B), 6 fold increase in Group A, and 21 fold in Group B in Col-V.

Conclusion: Administration of Abs to lung SAgs to native lungs following primary insult with 0.1% HCL results in circulating exosomes with lung SAgs leading to pro-inflammatory cytokines, immune responses to lung SAgs resulting in OAD. Primary insult and administration of rabbit IgG did not result in the above described changes.

CITATION INFORMATION: Sharma M., Liu W., Mohanakumar T. Primary Insult to the Native Lungs Are Needed for Antibodies to Lung Self-Antigens, Kα1Tubulin and Collagen V, to Be Pathogenic for the Development of Obliterate Airway Disease Am J Transplant. 2017;17 (suppl 3).

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