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Project

The roll of regulatory cells in rejection post lung transplant

Chronic lung allograft dysfunction (CLAD) continues to pose a significant challenge to long-term survival after lung transplantation. CLAD is a complex condition caused by a multifactorial process with alloimmune-dependent and -independent factors. Alloimmune-dependent factors are related to the alloimmune response from the recipient directed against the ‘nonself’ donor, referred to as allograft rejection. The objective of this PhD project was to gain more insights into the alloimmune response following lung transplantation leading to chronic graft failure.

Firstly, a retrospective study was performed to investigate the role of eosinophils after human lung transplantation. This study compared CLAD-free and graft survival between patients with high and low blood eosinophils using an 8% threshold. Increased blood eosinophils were correlated with a worse graft and CLAD-free survival. Increased blood (≥8%) and increased eosinophils in bronchoalveolar lavage (BAL) (≥2%) had the worse outcome. However, a specific mechanistic function could not be attributed to the eosinophils in CLAD. Investigating rejection in human lung transplant recipients is challenging, given the variability and confounding factors involved.

Secondly, we discussed the different aspects of animal models of lung transplantation. The utilization of animal models is of great interest to facilitate mechanistical research due to the controlled setting they provide. Orthotopic left lung transplantation in mice and rats is the preferred model to investigate post-lung transplant complications. This experimental model offers advantages such as the available immunological read-outs, genetic models, favorable cost–benefit balance, and the high throughput possibility.

As third, the murine model of orthotopic left lung transplantation was employed to explore the fundamental immunological elements underlying pulmonary rejection. The model was established using a major genetic mismatch between donor and recipient, with daily immunosuppression. The rejection process followed the basic principles of a classic immune response, including innate but mainly adaptive immune cells, peaking at day seven after lung transplantation.

Finally, the structural changes associated with pulmonary rejection following murine lung transplantation were investigated. We demonstrated that pulmonary rejection initiates from the vasculature in the early stage, with subsequent lymphoid follicle formation centered around the blood vessels, progressing to perivascular fibrosis. Notably, CD31+ endothelial cells played a critical role in the rejection process, exhibiting activation and decline at day seven post-transplantation in allografts. However, it is important to acknowledge that the current clinical focus is primarily directed towards the airways, through lung function measurement and pathological obliterated bronchiolitis. Promoting vascular repair and/or protecting the endothelial cells could serve as a vital strategy to improve the outcomes following lung transplantation.

Overall, this PhD thesis provided valuable insights into the fundamental principles of pulmonary rejection, utilizing a relevant pre-clinical animal model. The findings highlight the presence of an all-encompassing immune response following murine lung transplantation, with a significant involvement of the vascular compartment during the initial stage.

Date:1 Oct 2018 →  31 Oct 2023
Keywords:Lung transplantation
Disciplines:Respiratory medicine
Project type:PhD project