De pathofysiologische studie van chronische rejectie na longtransplantatie

In the past decade, considerable progress has been made in improving the outcome after lung transplantation. Chronic rejection, clinically referred as CLAD, is known to be the most important risk contributor to late mortality of which two different clinical entities were recently defined being BOS and RAS. Multiple alloimmune and non-alloimmune risk factors for both CLAD and death have been identified. Within this doctoral project we have identified two new risk factors for CLAD and mortality being a genetic variance in caveolin-1 (CAV-1) and airway neutrophilia in patients under azithromycin therapy. Firstly, we demonstrated protective effects of the GG genotype of CAV-1 based on mortality and susceptibility for infectious complications. Secondly, we described patients presenting an azithromycin resistant neutrophilia having an increased rate of mortality and CLAD development. The exact mechanism remains elusive however our data demonstrates that IL-1 might mediate this risk factor of which, at the moment, further research on this IL-1 pathway is performed. Thirdly, we investigated the immunological diversity between BOS and RAS. We demonstrated that the RAS phenotype, representing 30% of the total CLAD population, equals the definition of chronic rejection being a chronic humoral and cell-mediated response leading to irreversible tissue fibrosis, failure of the organ and eventually grafts loss. This immune dysregulation and fibrosis is present in a much lesser degree in BOS, which was up to now considered to reflect chronic rejection. The presence of complement and DSA may indicate that RAS might (at least partly) overlap with AMR. The question remains unsolved if BOS can be really denominated as chronic rejection. The described change regarding the concept of chronic rejection may have major implications regarding therapy in lung transplant patients, certainly for the use of immunosuppression which, at long-term, may cause organ failure. Specifically, for the RAS phenotype, characterized by a worse survival, new anti-fibrotic and/or 156 anti-humoral agents should be tested. These findings could help us to unravel the pathophysiology of CLAD and to achieve a survival comparable to other solid organ transplantations.status: publishe