Abstract
Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A-/- or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14+ epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived γδ+ and CD4+ T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL-17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post-transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation.
Highlights
Lung transplantation remains the only therapeutic approach for end-stage lung failure
We demonstrated that IL-17A blockade controlled cellular stress, as attested by a reduction of HSP70 mRNA levels in grafts harvested from anti-IL17 treated animals compared to control animals (Figure 3E)
Taking advantage of the Heterotopic trachea transplantation (HTT) model in IL-17A-/mice, we demonstrated a dominant role of IL-17A in early but not late post-transplant airway lesions
Summary
Lung transplantation remains the only therapeutic approach for end-stage lung failure. Primary graft dysfunction (PGD) that occurs during the immediate postoperative period is caused by ischemia-reperfusion injury (IRI), and affects up to 25% of the recipients [2]. Equivalent to an acute respiratory distress syndrome (ARDS), PGD is accompanied with an alteration in the PaO2/FiO2 ratio that may require extracorporeal membrane oxygenation support and remains the major cause of early postoperative morbidity and mortality [2]. No causal relationship linking PGD to OB has been demonstrated, some authors have shown that PGD is associated with a greater risk of OB [5], and histopathologic reports indicate that both inflammation and injury precede an aberrant tissue repair and epithelial regeneration that leads to the fibrous obliteration of the small airways occurring during OB [6]
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