A mechanistic analysis of strategies targeting innate immunity to prevent kidney allograft rejection
Access status:
Open Access
Type
ThesisThesis type
Doctor of PhilosophyAuthor/s
Kwan, Tony King-TakAbstract
Renal transplantation remains the optimal method of renal replacement therapy for patients with end-stage renal disease, but long-term outcomes are poor. Both immune and non-immune mechanisms contribute to the development of allograft injury and failure. Therefore, therapeutic ...
See moreRenal transplantation remains the optimal method of renal replacement therapy for patients with end-stage renal disease, but long-term outcomes are poor. Both immune and non-immune mechanisms contribute to the development of allograft injury and failure. Therefore, therapeutic strategies to improve long-term transplant recipient outcomes are needed. Previous work from our group found that the absence of MyD88, a key signalling adaptor molecule of the Toll-like receptor pathway involved in innate immunity, induces donor-specific tolerance in our model of renal allograft transplantation, and is associated with an increased ratio of Treg:Th17 cells in the allograft and the spleen. This thesis attempts to clarify the mechanisms by which MyD88 deficiency achieves this, by examining both upstream signalling via TLR4 and the downstream roles of Th17 and Treg cells play in this process. A fully MHC-mismatched, heterotopic renal allograft transplantation mouse model was utilised for this work. Despite the protective effects of TLR4 deficiency in renal ischaemia-reperfusion injury, TLR4 knockout mice only had improvement in short-term, but not long-term renal allograft function. Attenuating Th17 effector cell function via IL-17 deficiency resulted in improvements in allograft function and survival, with an impaired Th1 immune response. Depletion of CD4+CD25+ Tregs reversed the benefits conferred by IL-17 deficiency. Finally, dietary administration of the microbial metabolite sodium acetate also resulted in improvements in allograft function and survival, a process also mediated by CD4+CD25+ Tregs. In contrast to the IL-17 data, this appears to be mediated via enhanced induction of Tregs rather than impairment of the Th1 immune response. In summary, the data in this thesis suggest that innate immunity play an important, but not essential, role in the alloimmune rejection response.
See less
See moreRenal transplantation remains the optimal method of renal replacement therapy for patients with end-stage renal disease, but long-term outcomes are poor. Both immune and non-immune mechanisms contribute to the development of allograft injury and failure. Therefore, therapeutic strategies to improve long-term transplant recipient outcomes are needed. Previous work from our group found that the absence of MyD88, a key signalling adaptor molecule of the Toll-like receptor pathway involved in innate immunity, induces donor-specific tolerance in our model of renal allograft transplantation, and is associated with an increased ratio of Treg:Th17 cells in the allograft and the spleen. This thesis attempts to clarify the mechanisms by which MyD88 deficiency achieves this, by examining both upstream signalling via TLR4 and the downstream roles of Th17 and Treg cells play in this process. A fully MHC-mismatched, heterotopic renal allograft transplantation mouse model was utilised for this work. Despite the protective effects of TLR4 deficiency in renal ischaemia-reperfusion injury, TLR4 knockout mice only had improvement in short-term, but not long-term renal allograft function. Attenuating Th17 effector cell function via IL-17 deficiency resulted in improvements in allograft function and survival, with an impaired Th1 immune response. Depletion of CD4+CD25+ Tregs reversed the benefits conferred by IL-17 deficiency. Finally, dietary administration of the microbial metabolite sodium acetate also resulted in improvements in allograft function and survival, a process also mediated by CD4+CD25+ Tregs. In contrast to the IL-17 data, this appears to be mediated via enhanced induction of Tregs rather than impairment of the Th1 immune response. In summary, the data in this thesis suggest that innate immunity play an important, but not essential, role in the alloimmune rejection response.
See less
Date
2019-05-09Licence
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and Health, Central Clinical SchoolAwarding institution
The University of SydneyShare