Understanding the Impact of Macrophages on Lung Transplant Outcomes

Lung transplantation (LTx) has become a highly successful therapy for selected patients with end-stage lung disease due to significant advances in transplantation surgery and aftercare. Various complications such as cellular or humoral rejection continue to challenge clinicians and recipients, limiting the average graft survival after LTx to approximately 6.5 years (McQuiston et al., 2021). Chronic lung allograft dysfunction (CLAD) is a major cause of mortality following LTx (Parulekar & Kao, 2019), highlighting the urgent need for effective interventions to prevent it. However, it was possible to identify a group of patients, termed as 'super-survivors', who do not experience any complications for years after LTx at Hannover Medical School. On a histological level, this group is characterized by a high number of macrophages, despite the absence of clinical signs of infection or pulmonary remodeling. To investigate their rolle in graft tolerance, we performed a whole transcriptome analysis of alveolar macrophages in transbronchial biopsies of super survivors (n=16), as well as different CLAD entities including bronchiolitis obliterans syndrome (BOS) (n=12) and restrictive allograft syndrome (RAS) (n=12), as well as healthy controls (n=12) using the novel NanoString GeoMx spatial transcriptomics technology (A). Additionally, we investigated whether these macrophages are of donor or recipient origin using fluorescence in situ hybridization (FISH) of X and Y chromosomes in gender-mismatched transplanted patients (B). We identified a distinct gene expression pattern in alveolar macrophages from super survivors, displaying anti-inflammatory and anti-arteriosclerotic properties, who are mostly descendants of the donor.