The role of spleen tyrosine kinase in antibody mediated rejection of renal allografts

Abstract

The non-receptor tyrosine kinase, spleen tyrosine kinase (SYK), is expressed by a variety of immune cells, plays a key role downstream of multiple immunoreceptor signalling, and is important in the pathogenesis of many immunological conditions.

Antibody mediated rejection (AMR) is a significant barrier to allograft survival post transplantation and is the leading cause of allograft loss. NK cells are key mediators of allograft injury in AMR due to their potential to mediate both antibody dependent and missing-self induced effector functions, with both distinct activatory pathways utilising SYK as a key signalling molecule.

The aims of my project were to determine a role for SYK in the pathogenesis of AMR, to investigate its importance in NK cell activatory signalling and to assess the efficacy and safety of SYK inhibition in the treatment of chronic active AMR in patients.

I have studied the expression of SYK protein and mRNA in biological samples from patients with AMR and found it to be upregulated in both histological lesions and peripheral immune cells. Furthermore, I have shown infiltration of NK cells expressing SYK into areas of glomerulitis and peritubular capillaritis. I have studied FcR signalling in human NK cells, showing that SYK is phosphorylated downstream of FcR ligation and is closely associated with NK cell effector function. Using pharmacological SYK inhibition, I have found that broad NK cell effector function can be abrogated. Finally, I report here the results of the FOSTAMR study, where fostamatinib, an oral SYK inhibitor, was used for the first time in patients with chronic active AMR of their renal allograft.

These data suggest that SYK is important in the pathogenesis of AMR. The key mediators of allograft injury in AMR, NK cells, use SYK for activatory signalling and SYK inhibition may be an effective treatment strategy for this condition.