IL-17 Receptor on Donor Cells Regulates Acute and Chronic Lung Allograft Rejection Potentiated by Repeated Endotoxin Inhalations

Abstract

<h3>Purpose</h3> Chronic lung allograft dysfunction is a major complication after lung transplantation (LTx). Excessive IL17 receptor A (IL17RA) signaling has been recognized as a key factor; however, its precise mechanism is unclear. In a mouse minor alloantigen mismatched LTx model (C57BL/10 [B10, H-2^b] → C57BL/6 [B6. H-2^b]), we found that repeated airway endotoxin (lipopolysaccharide, LPS) challenge augments airway epithelial damage, acute and chronic rejection with airway obliteration, together with increased IL17A transcription in allografts but not isografts. We hypothesized that both donor and recipient cell responses to IL17A are important in mediating these processes. We therefore investigated the role of IL17RA on donor and recipient cells in the context of chronic rejection. <h3>Methods</h3> B10→B6 LTx and B6→B10 LTx were performed with or without intratracheal LPS administration (5 ug LPS/50 ul PBS, Day 3, 7, 10, 14, 17, 21). B6 IL17RA^−/− mice were used as donors or recipients. Grafts were assessed with micro CT scans on days 3 and 27; histological scoring and quantitative PCR were performed 28 days after LTx. <h3>Results</h3> Without LPS, neither donor nor recipient IL17RA deficiency modified histological scores or lung graft volume or density by CT scan. LPS-treated IL17RA^−/− recipients showed a similar degree of lung radiographic change and histological acute rejection compared to IL17RA^+/+ recipients; however airway obliteration was attenuated (Figure A). In contrast, recipients of IL17RA^−/− donor lungs showed reduced gain of graft density on CT, and diminished acute rejection and peri-airway fibrosis (Figure B-C). IL17RA^−/− donor grafts had fewer CXCL1 (a neutrophil chemoattractant) transcripts (Figure D). <h3>Conclusion</h3> IL17RA signaling on donor cells regulates acute and chronic rejection in LTx recipients experiencing airway inflammation.