Inflammatory Events Precede Development of De Novo DSA after Lung Transplantation

Purpose De novo donor-specific antibodies (dnDSA) are a major risk factor for antibody-mediated rejection in lung transplant patients (LTs). Little is known about specific circumstances that predispose LTs to develop dnDSA. Clinicians use arbitrary intervals to monitor for dnDSA. Since inflammation and injury drive alloimmune responses, we hypothesize that events like infection or acute cellular rejection (ACR) may predispose LTs for dnDSA production. To test this, we assessed i) inflammatory events preceding dnDSA development, and ii) whether these inflammatory events trigger allograft injury using a sensitive biomarker (donor-derived cell-free DNA-%ddcfDNA). Methods 311 LTs from three prospective cohort studies with a median follow-up of 3.4 years were analyzed. LTs underwent DSA testing before transplantation, after transplantation at fixed intervals and at time of allograft dysfunction. Positive DSA (mean fluorescent intensity ≥ 1000 units) were adjudicated based on the post-transplant day of first detection, as preformed ( Results 42.3% of LTs showed positive DSA with 16.9% preformed (n=54) and 24.8% dnDSA (n=79). Median time from transplantation to first dnDSA detection was 210 days. Class II dnDSA (83.5%) were more common than class I (7.6%) or mixed class I and II (8.9%). We identified an inflammatory event preceding 72.2% of dnDSA: infectious causes (39.2%, n=31), ACR (22.8%, n=18), other histopathology findings (10.2%). Respiratory bacteria (45.0%) and viruses (41.9%) accounted for the most infectious organisms identified. Median time-lag from inflammatory event to first DSA detection was 28.5 days (range = 0- 88 days). These inflammatory events were accompanied by a rise in %ddcfDNA from 0.32% (baseline) to 1.14% (median). Conclusion Primarily, respiratory viruses, bacteria, or ACR preceded dnDSA development, suggesting significant interrelation among allograft inflammation, injury, and DSA development. Incorporating these findings in monitoring protocol may enable timelier detection of dnDSA.