J JAW1,2, M ALIKHAN1, K KISHIMOTO1, J OOI1, S HOLDSWORTH1,2, A R KITCHING1,2,3
1Centre for Inflammatory Diseases, Department of Medicine, Monash University , Clayton, Australia, 2Department of Nephrology, Monash Health, Clayton, Australia, 3Department of Paediatric Nephrology, Monash Health, Clayton, Australia
Aim: To investigate IL-7Rα signalling in experimental anti-myeloperoxidase (MPO) glomerulonephritis (GN) by inhibiting IL-7Rα using a neutralising, non-depleting monoclonal antibody.
Background: Microarray profiling of T cells from patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has demonstrated that signalling through the memory T cell receptor IL-7Rα predicts relapse and overall severity, but whether IL-7Rα has any direct functional role is unknown.
Methods: Anti-MPO GN was induced by immunising mice with MPO, then GN triggered with low dose anti-mouse basement membrane globulin 4 days before the end of experiments. Autoimmunity was either acute (immunizations days 0, 7; ending day 21) or chronic (immunizations days 0, 7, 42; ending day 56). Anti-IL-7Rα (or control) antibodies were administered (ip) after the onset of autoimmunity, one day before GN was triggered. In a further experiment in the chronic model, anti-IL7Rα treatment commenced on day 35. Treatment was administered every second day.
Results: Control ovalbumin-immunized mice given anti-basement membrane globulin developed minimal injury. Compared with mice with anti-MPO GN given control antibodies, anti-IL-7Rα antibodies administered after the induction of anti-MPO autoimmunity (day 17) attenuated GN at day 21 with reduced albuminuria, glomerular segmental necrosis, tubulointerstitial injury, glomerular and interstitial leukocytes and intrarenal chemokines, with no corresponding increase in intrarenal PD-1 expression. Anti-IL-7Rα therapy in the 56-day model dampened systemic pro-inflammatory immune responses and renal leukocyte infiltration, without affecting albuminuria or glomerular histology. Prophylactic therapy prior to the induction of disease in the chronic model resulted in a similar outcome.
Conclusion: These findings mechanistically validate a role for the IL-7Rα in AAV and suggest that neutralizing anti-IL-7Rα therapies could be pursued as potential therapeutic strategies in this disease.
Dr Juli Jaw is a Consultant Nephrologist at Monash Health and Teaching Associate at Monash University. She obtained her medical degree from The University of Melbourne in 2006 and completed her Nephrology training in 2016. She is currently undertaking a PhD at the Centre for Inflammatory Diseases in the Department of Medicine at Monash University under the supervision of Professor Richard Kitching, Dr Maliha Alikhan and Dr Joshua Ooi. Her PhD focuses on understanding the functional role of CD8+ T cells and latent cytomegalovirus infection in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.