Abstract
Previous studies have shown that intrabronchial administration of antibodies (Abs) to MHC class I resulted in development of obliterative airway disease (OAD), a correlate of chronic human lung allograft rejection. Since development of Abs specific to mismatched donor HLA class II have also been associated with chronic human lung allograft rejection, we analyzed the role of Abs to MHC class II in inducing OAD. Administration of MHC class II Abs (M5/114) to C57BL/6 mice induced the classical features of OAD even though MHC class II expression is absent de novo on murine lung epithelial and endothelial cells. The induction of OAD was accompanied by enhanced cellular and humoral immune responses to self-antigens (Collagen V and K- α1Tubulin). Further, lung-infiltrating macrophages demonstrated a switch in their phenotype predominance from MΦ1 (F4/80+CD11c+) to MΦ2 (F4/80+CD206+) following administration of Abs and prior to development of OAD. Passive administration of macrophages harvested from animals with OAD but not from naïve animals induced OAD lesions. We conclude that MHC class II Abs induces a phenotype switch of lung infiltrating macrophages from MΦ1 (F4/80+CD11c+) to MΦ2 (F4/80+CD206+) resulting in the breakdown of self-tolerance along with an increase in autoimmune Th17 response leading to OAD.
Highlights
Lung transplantation is currently employed as a treatment option for patients with end-stage pulmonary dysfunction
An increase in the CD8 T cell infiltration (Figure 2E–H) around the bronchiole and blood vessels was noted in MHC class II Ab treated animals. These results demonstrates that intrabronchial administration of MHC class II resulted in obliterative airway disease (OAD) lesions in the murine model even though the epithelial and endothelial cells naturally don’t express MHC class II molecules on the cell surface
The long term success of human lung transplantation is limited by the development of chronic rejection predominantly manifested as bronchiolitis obliterans syndrome (BOS) that has an incidence as high as 40–70% by 5 years [5]
Summary
Lung transplantation is currently employed as a treatment option for patients with end-stage pulmonary dysfunction. Several studies have suggested that allorecognition of mismatched donor histocompatibility antigens (HLA) is critical for the pathogenesis of chronic allograft rejection [6,7]. Antibodies (Abs) directed against mismatched donor histocompatibility antigens have been shown to develop during the post-transplant period following kidney, heart, and lung transplantation and has been shown to correlate with both acute and chronic rejection [10,11,12]. The high levels of fibrogenic growth factors in the setting of a proinflammatory microenvironment induces proliferation of fibroblasts and smooth muscle cells leading to tissue remodeling and subsequent luminal obliteration of tubular structures in the graft, a hallmark of chronic rejection [16]
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