SP114
DYNAMICS OF RENAL T-CELL INFLAMMATION IN ANCA-ASSOCIATED RENAL VASCULITIS: DOMINANCE OF ANTIGENSPECIFIC TH17 CELLS

INTRODUCTION AND AIMS: Anti-neutrophil-cytoplasmic-antibody (ANCA)-associated vasculitis (AAV) is an autoimmune small-vessel-vasculitis. T-cells play a pivotal role in pathogenesis as drivers of autoantibody formation and mediate vasculitic damage. However, the involvement of T-cells in renal inflammation due to ANCA-vasculitis is understood poorly. It is the aim to this study to investigate the dynamics of renal T-cell inflammation in a rat model of AAV and pauci-immune glomerulonephritis.

METHODS: Pauci-immune glomerulonephritis and experimental ANCA-vasculitis was induced by immunizing Wistar-Kyoto-rats with human myeloperoxidase (MPO) emulsified in Freunds Adjuvant. Control rats were immunized with Freunds Adjuvant only. Albuminuria was determined weekly and rats were culled after two, four and six weeks. At the time of harvest, renal T-cells were isolated and characterized by flow cytometry. Antigen-specificity was determined by ELiSPOT. Gene expression was determined by real-time PCR and is expressed as fold change relative to controls.

RESULTS: All rats immunized with MPO developed detectable titres of anti-MPO by week two. By week six, all MPO animals (n=20) but one developed significant albuminuria. Accordingly, MPO animals showed significant crescent formation as compared to the controls (% of affected glomeruli: 11.4 ±10.5% vs. 0.4 ±0.7%, p<0.005). From week two on, Th17 cells inflamed the kidney as determined by PCR. The Th17 infiltrate was heaviest at week 6. The intra-renal T-cell response was skewed towards Th17 as compared to the frequency of splenic Th17 cells in rats immunized with MPO (9.1 ±4.3% vs. 1.9 ±0.6%, p<0.005). The majority of intra-renal Th17 cell was MPO-specific.

CONCLUSIONS: Th17 cells are drivers of renal inflammation in ANCA-associated pauci-immune glomerulonephritis. IL-17 blockade may have a therapeutic role in ANCA-vasculitis and pauci-immune glomerulonephritis.