Signalling Pathways in Antibody-Mediated Renal Allograft Rejection
thesis
posted on 2017-03-20, 22:32 authored by Sharmila Ramessur ChandranBackground: Antibody
mediated rejection (AMR) remains a major cause of graft failure post-renal
transplantation, as current therapies are suboptimal. A potential new
therapeutic strategy is the blockade of the intracytoplasmic tyrosine kinase,
Syk (Spleen Tyrosine Kinase) which is involved in the signalling of Fcγ
receptors, B cell receptors, integrins and GPVI collagen receptors on leukocytes
and platelets.
Aims: I explored the effect of Syk blockade in experimental renal allograft rejection. First a mixed model of rejection in non-sensitized rats was used. A selective Syk inhibitor was the only treatment administered from time of transplantation until the day of kill. We then created a pure model of AMR in sensitized rats in which endogenous production of anti- MHC (major histocompatibility complex) antibodies was induced pre transplantation by immunization. Cellular rejection was minimized by tacrolimus therapy pre- and post- surgery. A Syk inhibitor was administered from time of transplantation until animals were killed. Lastly, I looked at leukocytic infiltration in acute and chronic human AMR and the effect of commonly used drugs on the infiltrates.
Results: In both the non-sensitized model of mixed rejection and the sensitized model of acute AMR, Syk inhibition improved renal allograft function. In the mixed model, macrophage and neutrophil numbers were reduced, as was extent of thrombosis but no effect was seen on T cell infiltration and activation 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 a reduction in neutrophil and NK cell activation and extent of thrombosis. DSA levels were unchanged by Syk inhibition in the sensitized model, as high levels of DSAs were present pre-transplantation. DSA deposition within the allograft was 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) caused an increase in macrophage numbers in chronic and acute AMR respectively.
Conclusion: The intracytoplasmic tyrosine kinase, Syk, plays a role in the pathogenesis of AMR and thus Syk may represent a new therapeutic target in AMR. High numbers on T cells and macrophages in glomeruli are bad prognostic signs in AMR and IVIG and current therapies in AMR cause an increase in macrophage numbers.
Aims: I explored the effect of Syk blockade in experimental renal allograft rejection. First a mixed model of rejection in non-sensitized rats was used. A selective Syk inhibitor was the only treatment administered from time of transplantation until the day of kill. We then created a pure model of AMR in sensitized rats in which endogenous production of anti- MHC (major histocompatibility complex) antibodies was induced pre transplantation by immunization. Cellular rejection was minimized by tacrolimus therapy pre- and post- surgery. A Syk inhibitor was administered from time of transplantation until animals were killed. Lastly, I looked at leukocytic infiltration in acute and chronic human AMR and the effect of commonly used drugs on the infiltrates.
Results: In both the non-sensitized model of mixed rejection and the sensitized model of acute AMR, Syk inhibition improved renal allograft function. In the mixed model, macrophage and neutrophil numbers were reduced, as was extent of thrombosis but no effect was seen on T cell infiltration and activation 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 a reduction in neutrophil and NK cell activation and extent of thrombosis. DSA levels were unchanged by Syk inhibition in the sensitized model, as high levels of DSAs were present pre-transplantation. DSA deposition within the allograft was 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) caused an increase in macrophage numbers in chronic and acute AMR respectively.
Conclusion: The intracytoplasmic tyrosine kinase, Syk, plays a role in the pathogenesis of AMR and thus Syk may represent a new therapeutic target in AMR. High numbers on T cells and macrophages in glomeruli are bad prognostic signs in AMR and IVIG and current therapies in AMR cause an increase in macrophage numbers.
