SYK inhibition reduces acute antibody mediated rejection of renal allografts in sensitized rats.

Aim: The aim of the study is to determine the therapeutic potential of spleen tyrosine kinase (Syk) inhibition in a rat model of antibody-mediated renal allograft rejection in sensitized recipients in which cellular rejection is minimized. Background(s): Syk mediates leukocyte signalling via Fc-receptors, the B cell receptor, some integrins and GPVI making this a potential therapeutic target in acute antibody-mediated rejection (AMR). Method(s): Recipient Lewis rats were immunized with donor (Dark Agouti) spleen on day 5. Recipients underwent bilateral nephrectomy and orthotopic renal transplantation (day 0). Groups received Syk inhibitor (SYK-A, 30mg/kg/bid) (n=11) or vehicle (n = 12) from 1 hr until being euthanized on day 3. Cellular rejection was minimized by administration of the IL- 2 inhibitor, Tacrolimus, given from day 1. Result(s): Vehicle treated recipients exhibited delayed graft function on day 1 which worsened by day 3 (363 +/- 192umol/ L serum creatinine vs 45 +/- 5umol/L normal). Allografts showed severe damage (thrombosis, acute tubular injury and capillaritis), with infiltrates of macrophages, neutrophils, NK cells and B cells. High-serum-levels of donor-specific antibodies (DSA) were evident with rat IgG and C3 deposited in allografts. SYK-A did not prevent delayed graft function on day 1 but significantly improved graft function on day 3 (199+/- 131umol/L; P<0.05 vs vehicle) with reductions in capillaritis, tubular injury and thrombosis. Infiltration by macrophages, neutrophils and NK cells were significantly reduced by SYK-A while a marked reduction in NOS2 and IFN-g mRNA levels indicated inhibition of macrophage activation. Serum DSA levels and the minor T cell infiltrate were not affected by SYK-A. Conclusion(s): Syk inhibition significantly attenuated allograft injury in a model of severe antibody-mediated damage in highly sensitized recipients. These findings suggest Syk inhibition as a potential adjunctive treatment in clinical AMR.