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. 2013 Jul 30;8(7):e70236.
doi: 10.1371/journal.pone.0070236. Print 2013.

IL-17A mediates early post-transplant lesions after heterotopic trachea allotransplantation in Mice

Philippe H Lemaître  1 , Benoît Vokaer, Louis-Marie Charbonnier, Yoichiro Iwakura, Marc Estenne, Michel Goldman, Oberdan Leo, Myriam Remmelink, Alain Le Moine
Affiliations

IL-17A mediates early post-transplant lesions after heterotopic trachea allotransplantation in Mice

Philippe H Lemaître et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. IL-17A deficiency does not prevent obliterative airway disease.
Fully allogeneic BALB/C tracheas were heterotopically grafted into WT or IL-17A-/- C57BL/6 recipients and harvested after 28 days. A, pathologic scores. B & C, histologic analysis of allografts harvested from one representative WT and IL-17A-/- recipient, respectively. Masson’s trichrome staining of a whole section (magnification x40). D, percentages of lumenal fibrosis. The bars represent the mean ± SEM of 12-15 organs in each group. Data are pooled from three independent experiments.
Figure 2
Figure 2. IL-17A deficiency prevents early allograft lesions.
Fully allogeneic BALB/C tracheas were heterotopically grafted into WT or IL-17A-/-C57BL/6 recipients and harvested after 8 days. A, pathologic scores. B, histologic analysis of allografts harvested from one WT and one IL-17A-/- recipient, respectively. Masson’s trichrome staining of a whole section (magnification x200). The black arrow shows the basal membrane thickening and the black arrowhead identifies epithelial flattening. The empty arrow shows the normal basal membrane and the empty arrowhead identifies the pseudostratified respiratory epithelium. C, CK14+ basal cell count after specific immunostaining. D, a representative picture of a section stained for CK14 in organs harvested from one WT and one IL-17A-/- recipient, respectively. The bars represent the mean ± SEM of 15 organs in each group. Data are pooled from three independent experiments. *, p < 0,05 and **, p < 0,005.
Figure 3
Figure 3. IL-17A blockade prevents early post-transplant airway lesions in syngeneic grafts.
Syngeneic BALB/C tracheas were heterotopically grafted into control or anti-IL17 treated BALB/C recipients and harvested after 5 days. A, pathologic scores. B, histologic analysis of allografts harvested from one control and one anti-IL17 treated recipient, respectively. Masson’s trichrome staining of a whole section (magnification x200). The black arrow shows the basal membrane thickening and the black arrowhead identifies epithelial flattening. The empty arrow shows the normal basal membrane and the empty arrowhead identifies the pseudostratified respiratory epithelium. C, absolute neutrophil count after specific Ly-6G immunostaining. D, IL-6 mRNA. E, HSP 70 mRNA. F, CK14+ basal cell count after specific immunostaining. The bars represent the mean ± SEM of 10 organs in each group. Data are pooled from two independent experiments. ***, p < 0,001.
Figure 4
Figure 4. IL-17A blockade prevents early post-transplant airway lesions in fully allogeneic grafts.
Fully allogeneic C57BL/6 tracheas were heterotopically grafted into control or anti-IL17 treated BALB/C recipients and harvested after 5 days. A, pathologic score. B, histologic analysis of allografts harvested from control and anti-IL17 treated recipients, respectively. Masson’s trichrome staining of a whole section (magnification x200). The black arrow shows the basal membrane thickening and the black arrowhead identifies epithelial flattening. The empty arrow shows the normal basal membrane and the empty arrowhead identifies the pseudostratified respiratory epithelium. C, absolute neutrophil count after specific Ly-6G immunostaining. D, IL-6 mRNA. E, HSP 70 mRNA. F, CK14+ basal cell count after specific immunostaining. The bars represent the mean ± SEM of 10 organs in each group. Data are pooled from two independent experiments. *, p < 0,05; **, p < 0,005 and ***, p < 0,001.
Figure 5
Figure 5. γδ+ and CD4+ T cells are redundant IL-17A producing T cells recruited into the graft.
Flow cytometry and histologic analysis of fully allogeneic BALB/C tracheas grafted into C57BL/6 recipients and harvested after 8 days. A, plot representing the intracellular expression of IL-17A in recipient-derived H-2Kb+ cells. B, plot representing the membranous expression of γδ and αβ TCR in IL-17A+ H-2Kb+ GILs. C, plot representing the distribution of CD4+ and CD8+ T cells among αβ+ IL-17A+ GILs. D, plot representing the membranous CCR6 expression in IL-17A+ γδ+ and IL-17A+ γδ- GILs. E, pathologic scores of control, combined CD4- and γδ-depleted, CD4-depleted and γδ-depleted recipients, respectively. Each FACS plot is representative of 5 organs and percentages are expressed as the mean of 5 organs. The bars represent the mean ± SEM of n = 6-15 organs in each group.
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The Institute for Medical Immunology is funded by research grants of the Walloon Region, the FNRS-Belgium. P.H.L. is a doctoral researcher funded by the FNRS (Fonds National de la Recherche Scientifique, Belgium) and the Fonds Erasme (Université Libre de Bruxelles, Brussels, Belgium). The grants are directly dedicated to the researcher or the lab. (http://www.wallonie.be, http://www1.frs-fnrs.be, http://www.fondserasme.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.