Abstract: SA-PO589
Fostamatinib Treatment of a New Model of Myeloperoxidase-ANCA Vasculitis
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Prendecki, Maria, Imperial College London, London, United Kingdom
- McAdoo, Stephen Paul, Imperial College London, London, United Kingdom
- Turner-Stokes, Tabitha, Imperial College London, London, United Kingdom
- Cook, H. Terence, Imperial College London, London, United Kingdom
- Tam, Frederick W.K., Imperial College London, London, United Kingdom
- Pusey, Charles D., Imperial College London, London, United Kingdom
Background
EAV is a model of MPO-AAV induced by immunising rats with human myeloperoxidase (hMPO). Animals develop lung haemorrhage and proliferative GN, but disease is milder than human AAV. To augment disease severity, we immunised animals with an additional subnephritogenic dose of rabbit nephrotoxic serum (NTS). Fostamatinib, a small molecule Syk inhibitor, was used to evaluate therapeutic manipulation in this new model.
Methods
WKY rats were immunised IV with diluted NTS to establish a subnephritogenic dose. For EAV+NTS experiments, animals were immunised IM with hMPO (or human serum albumin (HSA)) on day 0 and 1:100 NTS IV (or normal rabbit serum (NRS)) at day 14. When fostamatinib was used, this (or vehicle) was administered by oral gavage from day 24-27, and animals culled on day 28. Infiltrating glomerular leucocytes were isolated and analysed by flow cytometry.
Results
A sub-nephritogenic dose of NTS was identified as a 1:100 dilution. Animals immunised with hMPO and 1:100 NTS had significantly more proteinuria and glomerular abnormalities at day 28 than the hMPO+NRS group or HSA controls (Fig1A). There was no detectable immune deposits by immunofluorescence or electron microscopy in any of the groups. In animals immunised with hMPO and 1:100 NTS, there were significantly more infiltrating glomerular leukocytes with greater increase in classical compared to non-classical monocytes (Fig1A). Fostamatinib treatment significantly reduced lung haemorrhage, glomerular, urinary abnormalities and infiltrating gloemrular leucocytes (Fig1B).
Conclusion
A subnephritogenic dose of NTS 14 days after hMPO significantly augments disease severity without evidence of deposited antibody or immune complexes. Characterisation of glomerular infiltrating cells shows significant infiltration of classical monocytes and we suggest it may be these cells which are stimulating crescent formation. Administration of fostamatinib for 4 days was sufficient to significantly decrease disease severity.