Background

The IL-17 axis is implicated in pathogenesis of chronic rejection after human lung transplantation. Using a murine model of obliterative airway disease (OAD), we recently demonstrated that Abs to MHC class I antigens can induce immune responses to self-antigens that contributes to immunopathogenesis of chronic rejection. Using a murine model of OAD, we determined the role of IL-17 family members in induction of autoimmunity leading to OAD after ligation of MHC class I.

Methods

Anti-MHC class I or control antibodies (Abs) were administered intrabronchially to wild-type (WT) and IL-17a knock out (IL-17A-/-) C57BL/6.

Results

By day 30, anti-MHC I administered endobronchially in IL-17A-/-mice demonstrated significant reduction in cellular infiltration, a 36.8% reduction in CD4+ T cells, 62.7% in CD11b+ macrophages, 37.5% in degree of fibrosis, 1.94 fold and 2.17 fold decrease in anti-KAT and anti-Col-V, respectively, when compared with wild-type mice. Analysis of lung infiltrating cells in anti-MHC I WT revealed increase in IL-17A (KAT: 92+ 21, Col-V: 103+ 19spm) and IL-17F (KAT: 5.03%, Col-V: 2.75%) secreting CD4+ T cells. However, administration of anti-MHC I in IL-17A-/-demonstrated increase only in IL-17F for KAT (13.70%) and Col-V (7.08%). Anti-IL-17 (AF) mAb administration after anti-MHC I abrogated OAD in both WT and IL-17A-/-.

Conclusion

Our findings indicate that IL-17A and IL-17F secreted by CD4+ Th17 cells specific to lung self-antigens are critical mediators of autoimmunity leading to the pathogenesis of OAD.