Deoxy Mab 1 Mediated Inhibition of Neutrophil Extracellular Traps: Mitigating Kidney Inflammation via DNA Repair Mechanism Interference in Experimental Anti-Neutrophil Cytoplasmic Antibody Vasculitis

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B627
Abstract ID: 5900

Presenting Author:
Kim Maree O'Sullivan , Research Fellow at Monash Univ. Fac. of Med., Nursing and Hlth. Sci.

Abstract:

Objectives: Anti-Neutrophil cytoplasmic antibody vasculitis (AAV) is an autoimmune disease which is characterised by kidney inflammation due to Neutrophil Extracellular Traps (NET), mediated damage. We aimed to test DX-1, an antibody which inhibits DNA repair mechanisms, for its potential to prevent NET formation in human neutrophils. Additionally, we sought to demonstrate DX-1's therapeutic promise in targeting NETs and reducing inflammation in an established AAV experimental model.

Methods: In vitro NET assays were performed from isolated neutrophils from whole blood from healthy donors (n=20). We used a well-established 20 day model of anti-myeloperoxidase (MPO) glomerulonephritis (GN). Mice were randomised to receive either vehicle control (n=8) or intravenous DX-1 (n=8) after establishment of autoimmunity to MPO on day 16.

Results: DX-1 inhibited NET formation in human neutrophils without affecting phagocytosis, or triggering apoptosis, necrosis or the release of pro-inflammatory enzymes (all P<0.05 compared to non-treated). In mice, DX-1 treatment led to reduced MPO-specific IFNγ and IL17a splenocytes (both P<0.05) and mitigated kidney injury, evidenced by reduced segmental necrosis (P<0.001 compared to controls), decreased protein and leukocytes in urine, as well as decreased glomerular NETs and inflammation.

Conclusions: Targeting NETs with DX-1 in an experimental model reduced inflammation and kidney injury, suggesting its potential as a treatment for AAV.