IL-17A mediates early post-transplant lesions after heterotopic trachea allotransplantation in Mice.
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.
Transplantation Medicine, Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium. plemaitr@ulb.ac.be
Philippe H
PH
Lemaître
Benoît
B
Vokaer
Louis-Marie
LM
Charbonnier
Yoichiro
Y
Iwakura
Marc
M
Estenne
Michel
M
Goldman
Oberdan
O
Leo
Myriam
M
Remmelink
Alain
A
Le Moine
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016040:Lung Transplantation / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications; D014132:Trachea / Q000378:metabolism* / Q000473:pathology* / Q000637:transplantation; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta