Abstract
Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD. The expression of a panel of immune molecules (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein) was analyzed by immunohistochemistry in these grafts and in six control lungs. Results showed that RAS compared to BOS grafts were characterized by 1) the inversion of the CD4/CD8 ratio; 2) a higher percentage of T lymphocytes expressing the PD-1, PD-L1, and CTLA4 checkpoint molecules; and 3) a significant reduction of exhausted PD-1-expressing T lymphocytes (PD-1pos/TOXpos) and of exhausted Treg (PD-1pos/FOXP3pos) T lymphocytes. Results herein, although being based on a limited number of cases, suggest a role for checkpoint molecules in the development of graft rejection and offer a possible immunological explanation for the worst prognosis of RAS. Our data, which will need to be validated in ampler cohorts of patients, raise the possibility that the evaluation of immune checkpoints during follow-up offers a prognostic advantage in monitoring the onset of rejection, and suggest that the use of compounds that modulate the function of checkpoint molecules could be evaluated in the management of chronic rejection in LTx patients.
Highlights
Lung transplantation (LTx) is a valuable therapeutic choice for selected patients with end-stage respiratory failure
chronic lung allograft dysfunction (CLAD) includes at least two well described clinical entities: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), the latter being associated with the worst prognosis
These quantifications of the lymphocytic infiltrates were similar in the stromal or alveolar compartments of BOS and RAS lungs (Supplementary Figure 1). These differences were not related to a different number of lymphoid follicles present in the lung parenchyma of BOS and RAS lungs, since neither the number nor the area of the lymphoid follicles was different in the two CLAD types (Supplementary Figure 2)
Summary
Lung transplantation (LTx) is a valuable therapeutic choice for selected patients with end-stage respiratory failure. LTx has a relatively poor long-term prognosis, considering that 6.7 years is the median survival of patients transplanted between 2010 and 2017 [1]. The most common cause of this high mortality is chronic lung allograft dysfunction (CLAD), a clinical condition characterized by progressive and irreversible decline in lung function, which leads to retransplantation or, more often, death. CLAD includes at least two well described clinical entities: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), the latter being associated with the worst prognosis. The mechanisms leading to BOS or RAS are unknown, similar pathways involving innate immunity, antibodymediated rejection, and cellular rejection are likely to be responsible for their pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
