Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization

Abstract

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis

“…The clinical application of Sunitinib, Imatinib, Pexidartinib and Lapatinib needs to be extremely cautious. Fostamatinib has been found to improve heart transplant rejection by inhibiting the production of graft-specific antibodies 67 , warranting further investigation. In summary, tyrosine kinase inhibitors may be a promising direction for the development of novel drugs for heart transplant rejection.…”

Antibody-mediated rejection: prevention, monitoring and treatment dilemmas

“…imilfidase) [ 91 ], newer generation anti-CD20 antibodies (e.g. obinutuzumab) [ 92 ], anti-CD38 antibodies [ 93 ], proteasome inhibitors [ 94 ], complement inhibitors [ 95 ], anti-IL-6/IL-6-receptor antibodies [ 96 , 97 ▪▪ ] and tyrosine kinase inhibitors [ 98 ] (Fig. 2 ).…”