Resumen de Cross-platform biomarker signature of long-term survival with normal allograft function after lung transplantation
Lung transplantation (LT) is an established treatment for end-stage respiratory diseases. Short-term survival has progressively improved due to advancements in surgical techniques, donor preservation, immunosuppressive agents and perioperative management. However, the development of chronic lung allograft dysfunction (CLAD) is the main limiting factor of long-term success after LT, with an approximate ten-year survival rate of 34.3%.
The lifelong immunosuppression of solid organ transplant patients leads to severe complications, such as nephrotoxicity, infectious diseases, malignancies, and metabolic disorders, which poorly affect their long-term survival. For this reason, one of the main goals in organ transplantation is achieving an alloantigen-specific unresponsiveness state in the sustained absence of toxic immunosuppressive therapies. In most cases, immunosuppression withdrawal leads to transplant rejection. However, a small group of transplant patients maintains long-term stable graft function despite interrupted treatment (operational tolerance state). This phenomenon is infrequent and varies according to the type of allograft; excluding kidney and liver transplant fields, there are only anecdotal cases in lung, heart and intestine transplantation. Due to the lack of operationally tolerant lung transplant recipients, long-term survivors with normal allograft function (LTS) after LT are the closest group to “operational tolerance” of kidney or liver transplant patients.
Identifying biomarkers of operational tolerance would serve to accurately identify candidate patients for minimization and potential withdrawal of immunosuppression. Furthermore, these potential tolerance biomarkers could provide knowledge of the underlying biological mechanism of tolerance for new tolerogenic therapies. It has been observed that tolerance fingerprints from kidney and liver transplant recipients differ, suggesting that the underlying mechanisms of operational tolerance, not fully elucidated, are organ-specific and consequently, potential renal and liver tolerance biomarkers cannot be extrapolated to lung.
Since no extensive studies examining this LT state have been published, the main objective of this thesis was to screen the greatest number of clinical and immunological parameters to identify potential biomarkers across different platforms in order to provide a better understanding of the biological mechanisms underlying LTS with normal allograft function after LT in comparison with CLAD patients.
The microbiome of the upper respiratory tract and the full transcriptomic expression profile and extensive cell immunophenotyping of peripheral blood samples were studied to assess the particular characteristics of LTS patients. The results derived from bioinformatics analyses of gene and miRNA expression provided a better understanding of the mechanisms involved in long-term survival. Moreover, they proved to be highly accurate in the classification of LT patients by employing gene and multi-biomarker expression profiling using different transcriptional platforms, including microarrays and RT-qPCR arrays.
The findings obtained demonstrated the usefulness of global transcriptome profile and peripheral blood samples to differentiate between LTS and CLAD patients and to identify some of the potential mechanisms responsible for graft acceptance.
Overall, the studies included in this thesis shed light on the biology underlying graft acceptance after LT, suggesting a complex interaction of several immunological mechanisms and opening up new perspectives for future research in LT immunology.
