Chronic lung allograft dysfunction after lung transplantation: novel insights into immunological mechanisms

Abstract

Lung transplantation (LTx) is the final treatment option for patients suffering from end-stage lung diseases. Survival after LTx is hampered by the development of chronic lung allograft dysfunction which presents itself in an obstructive form as the bronchiolitis obliterans syndrome (BOS). BOS is hallmarked by excessive fibrosis and scar tissue formation leading to small airway obliteration, decrease in lung function, and eventually organ failure. The diagnosis BOS is often late and therefore there is a high clinical need for biomarkers to identify patients at risk for BOS development earlier after LTx. The main purpose of this thesis was to gain insight into the pathological mechanisms preceding BOS development and to identify novel biomarkers for chronic rejection after LTx.

First, we elaborate on our observations on the role of the complement system on transplantation outcome. We show that the capacity of the grafted organ to protect itself from the recipient’s complement system, via the membrane-attached complement regulatory protein CD59, correlates with BOS incidence after LTx. Furthermore, we found that the soluble form of this protein is elevated in the serum of BOS patients at the time of diagnosis compared to clinically matched non-BOS patients. Interestingly, these elevated serum levels were present 6 months post-LTx, prior to any clinical symptoms. We therefore propose that circulation levels of CD59 constitute a novel biomarker for chronic rejection after LTx. We also present data on antibodies directed against apoptotic targets in end-stage lung disease patients and autoantibodies against self-proteins in patients with end-stage cystic fibrosis.

Second, we focus on cellular immunity. We found that the cellular mononuclear cell composition and their subsets differ between BOS+ and BOS- patients. Increased T-cells and monocytes and lowered fractions of B-cells were related to BOS development. During the transplantation procedure, the lung-bloc is subjected to antegrade and retrograde flushing. We found that large numbers of cells are present in the retrograde flush and that the cellular composition largely varies from the circulation. We also observed that patients presented less episodes of acute rejection after implementation of this retrograde flushing method.

Last, we describe the first results from genetic association studies. We show that selected SNPs in the donor promotor region of the chemo-attractant protein TARC/CCL17 and in the immune-regulatory protein PTPN22 in the patient correlate with BOS incidence. Finally, we present our preliminary results on the role of circulating miRNAs as potential biomarker for BOS development.

With this thesis, we stress the importance of cellular and genetic donor factors, which have largely been neglected in literature, on the development of chronic rejection after LTx, but presumably also in other solid-organ transplantation settings. In conclusion, we contribute to a better understanding of the different immunological mechanisms involved in BOS pathogenesis. Also, the biomarker and genetic association studies presented in this thesis could contribute to the generation of a risk-stratification model to earlier identify patients at risk for complications after LTx. Clinical and diagnostic implementations of our findings could lead to novel treatment or prevention modalities and subsequently improve LTx outcome.