The role of spleen tyrosine kinase in acute renal allograft rejection in the rat.

Spleen tyrosine kinase (Syk) is involved in the antibody response (via B-cell receptor signalling) and antibody-dependent activation of macrophages, neutrophils and NK cells (via FcgR signalling), whereas Syk is not expressed by T-cells. However, the role of Syk in antibody-mediated rejection has not been examined. Therefore, this study investigated the function of Syk signalling in a model of acute renal allograft rejection. Groups of 6 Sprague-Dawley rats underwent bilateral nephrectomy and an orthotopic transplant with a MHC mis-matched Wistar rat kidney. Recipient rats were treated with a Syk inhibitor (CC0482417, 30mg/kg/bid) or vehicle from 1hr before surgery until being killed on day 5. Vehicle treated recipients developed severe allograft failure (serum creatinine 304+/-130 vs 46+/-7umol/L in isograft; P<0.001). Histologic damage included glomerular and peritubular capillaritis, tubular injury (tubulitis, necrosis, dilation) affecting 90+/-9% of tubules, and T-cell, macrophage and neutrophil infiltration. Allografts showed IgG and C3 deposition and circulating donor-specific antibodies (DSA) were identified by flow cytometry. CC0482417 improved allograft function (serum creatinine 149+/-18umol/L; P<0.05 vs vehicle), with reduced tubular damage (47+/-19%; P<0.001) and a reduction in capillaritis. CC0482417 treatment did not affect T-cell infiltration or activation (IL-2, granzyme B, IL-2Ra). However, CC0482417 treatment reduced macrophage and neutrophil infiltration by 40 and 45%, respectively (P<0.05 vs vehicle). Of note, CC0482417 reduced serum IgM and IgG DSA levels by 60% (P<0.01). In conclusion, this study has identified a functional role for Syk signalling in antibody-mediated, but not T-cell mediated, acute renal allograft rejection. Further studies should examine Syk inhibition in a specific model of antibody-mediated rejection.