Role of PD-L1 in heart transplant rejection

Abstract

Abstract Background Acute cellular rejection remains a major cause of morbidity after heart transplantation with up to 30% of patients experiencing at least one rejection episode during the first year. Unfortunately, the mechanism underling rejection remains poorly understood and the gold standard for diagnosing rejection remains frequent cardiac biopsy for rejection surveillance – a process that is both invasive and costly. Purpose PD-L1 is a co-inhibitory transmembrane protein that interacts with PD-1 on T cells to inhibit T cell activation. Endothelial PD-L1 expression in the heart has been shown in mouse models to play a key role in attenuating immune-mediated cardiac disease like myocarditis. Recent data that anti-PD-1 and anti-PD-L1 therapy can lead to myocarditis further supports a role for PD-1/PD-L1 signaling in cardiovascular homeostasis. We hypothesize that PD-L1 expression correlates with rejection severity. Methods Endomyocardial biopsy from a cohort of 19 heart transplant patients were analyzed for PD-L1 expression using immunohistochemistry and image analysis with HALO software. Each patient had biopsies corresponding to 0R, 1R, and 2R grades of rejection (n=57) and thus each patient served as their own internal control. Detailed clinical data was also collected on these patients from the electronic medical record. Results Average PD-L1 levels associated with 0R (n=19), 1R (n=21), and 2R (n=17) rejection were 1.54, 9.15, and 18.90 respectively (P<0.001). In patients who were treated for 2R rejection with increased immunosuppression (n=9), PD-L1 levels decreased from an average of 21.72 before treatment to an average of 5.64 after treatment (P<0.05). A multiple regression was run to see if PD-L1 level was associated with right heart pressures, EKG intervals, echo data, or common lab values. Accounting for age, race, and sex, it was found that PD-L1 was significantly associated with PA pressure (P<0.01, beta = 0.45), PCW pressure (P<0.01, beta = 0.42), and BNP (P<0.01, beta = 0.55). Conclusions Upregulation of PD-L1 in the heart is strongly associated with severity of cellular rejection after heart transplantation. Successful treatment of rejection with immunosuppression decreases PD-L1 levels. These data suggest that PD-L1 is a potential biomarker for heart transplant rejection. Further correlation of PD-L1 levels with signs of right heart strain (increased PA and PCW pressure) and systolic dysfunction (BNP) supports a clinical picture of PD-L1 as a useful biomarker for detecting both cellular rejection and reversal of rejection after treatment. Cohort identification and results Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466