Treatment With a Spleen Tyrosine Kinase Inhibitor Reduced Inflammation and Protected Kidney Function in Experimental Renal Allograft Rejection.

Abstract

Introduction: Spleen tyrosine kinase (SYK) mediates signalling of immune receptors. We have shown that fostamatinib, a SYK inhibitor, was effective in treatment of antibody mediated experimental glomerulonephritis (JASN. 21:231, 2010). We have now studied SYK inhibition for prevention of renal allograft rejection. Method: We studied the effect of fostamatinib (from Rigel Pharmaceuticals and AstraZeneca) in a rat (Brown Norway (BN) to Lewis (LEW)) model of renal allograft rejection. In experiment 1, the left kidney of a LEW rat was replaced by a left kidney from a BN rat. This is a severe model of rejection characterised by cortical infarction by day 7. Severity of rejection was analysed after 7 days. The percentage of the cortex of the allograft with infarction was assessed by a pathologist blinded to treatment group on to the following scale: 0=0, 0-10%=1, 11-25%=2, 26-50% =3, 51-75%=4, >75%=5. In experiment 2, bilateral nephrectomy was performed in the recipient LEW rat at the time of transplantation so that transplant kidney function could be assessed by creatinine clearance (CrCl); rats were culled on day 6 for assessment of cell infiltrates before graft infarction. Treatment was given by gavage twice daily. The results are median values analysed by non-parametric tests. Results: In experiment 1, control rats (vehicle or no treatment, n=10), showed severe allograft infarction, grade 5. In the fostamatinib treated rats, there was complete prevention of allograft infarction grade 0 and 0 in rats treated with 30 mg/kg (n=7) or 20 mg/kg (n=7) respectively twice daily (p<0.001). In experiment 2, treatment was started on day 2 when the rats recovered from surgery. Treatment with 30 mg/kg of fostamatinib twice daily from day 2-6 reduced severity of tubulointerstitial injury, grade 3, in the fostamatinib treated group (n=8) v grade 5, (p<0.005) in the vehicle treated group (n=7), reduced cortical infiltration by macrophages (1.7 v 10.5 au by image analysis, p<0.005) and CD8+ cells (1.7 v 7.4 au, p<0.05) and protected renal function compared with the vehicle treatment (CrCl 4.2 v 0.1 ml/min, p<0.005). Conclusion: Treatment with a SYK inhibitor reduces the severity of experimental renal allograft rejection and protects renal function. DISCLOSURE:Masuda, E.: Employee, Rigel Pharmaceuticals, Other, Rigel Pharmaceuticals, Stock option. Tam, F.: Grant/Research Support, AstraZeneca, Other, Rigel Pharmaceuticals, Consultancy.