Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Jevnikar, Anthony M.

2nd Supervisor

Zhang, Zhu-Xu

Co-Supervisor

Abstract

Transplantation is invariably associated with ischemia reperfusion injury (IRI) which causes organ dysfunction. IRI is also directly linked to several forms of programmed cell death including apoptosis and necroptosis, which increase kidney dysfunction, promote inflammation and may contribute to premature graft failure. The contribution of necroptosis and apoptosis following kidney IRI to cell-free DNA (cfDNA) generation and the potential of cfDNA to activate effectors such as NK cells involved in kidney IRI have not been defined. Our data indicate that necroptotic microvascular endothelial cells (MVECs) release considerably more cfDNA than apoptotic MVECs or untreated controls (p

Summary for Lay Audience

Transplantation is invariable associated with injury to the donor organ. During this injury various forms of cell death occur, and contribute to organ injury. During this cell death, molecules are released from dying cells in a controlled fashion. One such molecule that has generated interest is termed cell-free DNA (cfDNA), as it is released from dying cells, and is also capable of stimulating the immune system. We have shown that cfDNA is released by dying cells by a variety of different cell death programs. We have also shown that cfDNA is released into the blood in a mouse model of transplant-associated organ injury, and that this release of cfDNA can be limited when certain forms of cell death are genetically impaired. We have also shown that cfDNA is a more sensitive marker of organ injury than currently used clinical standards, such as the measurement of serum creatinine levels. Lastly, we have shown that immune cells, NK cells in particular, are activated by cfDNA, which may therefore be promoting inflammation in the transplant recipient. As such, we have shown that cfDNA is a sensitive biomarker of cellular injury that is also capable of activating the immune system, thereby promoting inflammation. Strategies to reduce the release of cfDNA and the inflammatory response would be expected to improve kidney function following transplantation.

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