Onderzoek naar mechanismen van chronische afstoting na longtransplantatie

Chronic lung allograft dysfunction (CLAD) continues to limit long-term survival after lung transplantation (LTx) since three decades. With the recent phenotyping of CLAD into an obstructive and restrictive clinical entity, called bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) respectively, additional questions have emerged concerning underlying mechanisms and specific characteristics between BOS and RAS. Within this PhD project, we aimed to gain more insights into the underlying mechanisms of CLAD, with specific consideration for the RAS phenotype. Firstly, we explored the possibility of a common rejection mechanism in CLAD. Our results demonstrated that the gene expression signature in RAS tissue shows more similarities to rejection post-kidney/liver/heart transplantation than BOS. This finding suggests that the immune activation in RAS, but not BOS, resembles that of rejection in other solid organ transplants. Secondly, we investigated a possible novel mechanism for fibrosis formation in CLAD. We demonstrated a role for TGF-β1 and pleural mesothelial cells via mesothelial-to-mesenchymal transition as an active contributor for fibrosis formation in RAS. Thirdly, we investigated the compartmental differences of donor-specific antibodies (DSA) in BOS and RAS by assessing the presence of graft DSA (gDSA) and associating these to serum DSA (sDSA) found in routine clinical measurements. Our results demonstrated that DSA - whether in serum or graft - were more prominent in RAS and that sDSA negativity did not necessarily mean gDSA negativity, or vice versa, suggesting an added value for complimentary gDSA assessment in CLAD patients. Lastly, the findings over the entire PhD thesis also emphasize the importance of looking directly into tissue itself, given the differences found between results in BAL/blood and tissue. Answering the question whether BOS and RAS should be considered two separate entities remains difficult. However, since interstitial fibrosis is the common feature across chronic organ rejection, which is only visible in RAS and relatively absent in BOS, one may wonder if BOS can be seen as chronic rejection. It might be more correct to view BOS as organ failure due to constant insults leading to obliterative bronchiolitis (OB), without chronic rejection. Our data showing similar immune activation in RAS and chronic rejection after other solid organ transplants, together with the presence of specific fibrotic mechanisms and DSA, suggests that RAS should be seen as the true form of chronic lung allograft rejection, given the typical cellular and humoral immune involvement.

Jaar van publicatie:2020

Toegankelijkheid:Closed