#5611 ASSOCIATION BETWEEN LOSS OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 AND ACTIVE ANCA-ASSOCIATED RENAL VASCULITIS

Abstract

Abstract Background and Aims Immune checkpoint inhibitors (ICIs) have made an important contribution on the survival of patients with certain cancers. ICIs interrupt co-inhibitory signalling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. Immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Therefore, we here aimed to analyze abundance of immune checkpoint molecules PD-1/PD-L1 and its implications in ANCA-associated renal vasculitis. Method We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total number of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointer-stitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1). Results We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent to the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between im-paired PD-1/PD-L1 signalling, complement factor B, and active ANCA-associated renal vasculitis. Conclusion These findings could be of relevance because experimental data have already been described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.