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- W3161594552 abstract "Background: Antibodymediated rejection (AMR) remains a major cause of graft failure post-renaltransplantation, as current therapies are suboptimal. A potential newtherapeutic strategy is the blockade of the intracytoplasmic tyrosine kinase,Syk (Spleen Tyrosine Kinase) which is involved in the signalling of Fcγreceptors, B cell receptors, integrins and GPVI collagen receptors on leukocytesand platelets. Aims: I explored the effect of Syk blockade in experimentalrenal allograft rejection. First a mixed model of rejection in non-sensitizedrats was used. A selective Syk inhibitor was the only treatment administeredfrom time of transplantation until the day of kill. We then created a puremodel of AMR in sensitized rats in which endogenous production of anti- MHC(major histocompatibility complex) antibodies was induced pre transplantationby immunization. Cellular rejection was minimized by tacrolimus therapy pre-and post- surgery. A Syk inhibitor was administered from time oftransplantation until animals were killed. Lastly, I looked at leukocyticinfiltration in acute and chronic human AMR and the effect of commonly useddrugs on the infiltrates. Results: In both the non-sensitized model of mixed rejectionand the sensitized model of acute AMR, Syk inhibition improved renal allograftfunction. In the mixed model, macrophage and neutrophil numbers were reduced,as was extent of thrombosis but no effect was seen on T cell infiltration andactivation due to the lack of Syk in mature T cells. In the sensitized model,there was a large decrease in macrophage numbers and activation as well as areduction in neutrophil and NK cell activation and extent of thrombosis. DSAlevels were unchanged by Syk inhibition in the sensitized model, as high levelsof DSAs were present pre-transplantation. DSA deposition within the allograftwas not significantly changed by Syk inhibition. In the human studies,macrophage and T cell rich glomerulitis was shown to be a bad prognostic sign.High dose intravenous immunoglobulins (IVIG) and plasma exchange (PEX) causedan increase in macrophage numbers in chronic and acute AMR respectively. Conclusion: The intracytoplasmic tyrosine kinase, Syk, playsa role in the pathogenesis of AMR and thus Syk may represent a new therapeutictarget in AMR. High numbers on T cells and macrophages in glomeruli are badprognostic signs in AMR and IVIG and current therapies in AMR cause an increasein macrophage numbers." @default.
- W3161594552 created "2021-05-24" @default.
- W3161594552 creator A5063617647 @default.
- W3161594552 date "2017-03-20" @default.
- W3161594552 modified "2023-09-23" @default.
- W3161594552 title "Signalling Pathways in Antibody-Mediated Renal Allograft Rejection" @default.
- W3161594552 doi "https://doi.org/10.4225/03/58d0589d163c7" @default.
- W3161594552 hasPublicationYear "2017" @default.
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