Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

Summary Kidney allografts induce strong T ‐cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase ( S yk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the F cγ‐receptor, B ‐cell receptor and some integrins. A role for S yk signalling has been established in antibody‐dependent native kidney disease, but little is known of S yk in acute renal allograft rejection. Sprague– D awley rats underwent bilateral nephrectomy and received an orthotopic W istar renal allograft. Recipient rats were treated with a S yk inhibitor ( CC 0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle‐treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration ( T cells, macrophages, neutrophils and NK cells) and deposition of I g M , I g G and C 3. Immunostaining identified S yk expression by many infiltrating leucocytes. CC 0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC 0482417 failed to prevent T ‐cell infiltration and activation within the allograft. However, CC 0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for S yk in acute renal allograft rejection. S yk inhibition may be a useful addition to T ‐cell‐based immunotherapy in renal transplantation.