Président du jury Devière, Jacques
Promoteur Goldman, Michel
;Le Moine, Alain Publication Non publié, 2014-06-26
| Résumé : | Lung transplantation is the only therapeutic approach for patients presenting end-stage pulmonary failure. Despite progress made in organ preservation and immunosuppression, primary graft dysfunction and obliterative bronchiolitis still hamper short-term and long-term outcomes, respectively. Interleukin-17 recently emerged as a major actor in several immuno-inflammatory disorders. Clinical and experimental evidence also suggest the implication of interleukin-17 or type 17 CD4+ T cells in lung rejection. We therefore investigated the contribution of this cytokine to graft pathology in a murine model of tracheal transplantation that recapitulates pathological features of lung rejection including the development of obliterative airway disease. We first demonstrated that interleukin-17 contributes to inflammatory lesions in the early phase post-transplantation. Interleukin-17 was found to be produced by + T cells and CD4+ T cells infiltrating the graft and interleukin-17 neutralization significantly reduced the development of epithelial lesions together with inhibition of interleukin-6 and heat-shock-protein 70 gene transcription. We then investigated the contribution of interleukin-17 to obliterative airway disease. Although interleukin-17 did not play a dominant role in absence of immunosuppression, it was found to contribute to airway pathology in animals receiving cyclosporin A. Under this treatment, we first observed dramatic changes in the composition of the lymphocyte populations infiltrating the graft: the numbers of CD8+ T cells producing interferon- and type 1 CD4+ T cells were dramatically decreased while the numbers of type 17, and also type 2 CD4+ T cells were unaffected. The pathological relevance of these findings was first demonstrated by the prolongation of graft survival afforded by the depletion of CD4+ T cells in cyclosporin A-treated animals. Furthermore, graft rejection was also delayed in mice genetically deficient in either interleukin-17 or interleukin-4, providing evidence that type 17 and type 2 CD4+ T cells actively contribute to graft rejection in cyclosporin A-treated recipients. On the other hand, parallel experiments in interferon--deficient mice revealed that interferon- regulates the development of obliterative airway disease in this model. 10 Finally, in vitro studies confirmed the resistance of type 2 CD4+ T cells and memory type 17 CD4+ T cells to cyclosporin-A mediated suppression. Altogether, the results obtained in this model demonstrate that (1) interleukin-17 contributes to airway allograft pathology both in the early and late phases post-transplantation and (2) type 17 and type 2 CD4+ T cell-dependent pathways of rejection are resistant to cyclosporin-A. We conclude that the addition of pharmacological agents targeting interleukin-17, or interleukin-4, to current immunosuppressive regimens might be valuable to improve the outcome of lung transplantation. |
