Biomarkers of islet cell loss after transplantation

Abstract

Islet transplantation is the only approved cell-based therapy for individuals with type 1 diabetes (T1D) who have severe hypoglycaemic unawareness, providing physiological insulin secretion and improved glycaemic control. However, the long-term success of this therapy remains limited by progressive islet cell loss following transplantation. The early posttransplant period is characterised by inflammatory and immune-mediated stressors, including instant blood-mediated inflammatory reaction (IBMIR), hypoxia, oxidative damage, and both innate and adaptive immune responses. These processes collectively contribute to early graft loss and long-term functional decline. Current clinical monitoring relies primarily on glucose and C-peptide measurements, which are insufficiently sensitive to detect early islet injury. This limitation highlights the urgent need for reliable, minimally invasive biomarkers that can signal islet stress or death before clinical dysfunction becomes apparent. This thesis investigates the utility of circulating biomarkers—including microRNAs and proteins (including cytokines)—as indicators of islet cell loss after transplantation. Longitudinal plasma samples from recipients at pre-transplant, 1-hour, and 24-hour timepoints were analysed using OpenArray for microRNA profiling and Olink proximity extension assays for protein profiling. Statistical analyses, including Wilcoxon matched-pairs signed rank testing with Benjamini–Hochberg false discovery rate (FDR) correction, and penalised logistic regression (PLR) modelling, were applied to identify differential expression patterns and predictive biomarker signatures. Integration across platforms provided complementary insights into the dynamic regulation of immune and apoptotic pathways. Findings from this study demonstrate that several immune and inflammatory mediators—including interleukins, chemokines, and stress-associated microRNAs—are significantly altered within the first 24 hours post-transplantation. The integration of microRNA and proteomic data revealed coordinated molecular responses that may serve as early indicators of islet injury and loss. These results contribute to a growing framework for multi-omic biomarker discovery in transplantation medicine and offer the potential to improve monitoring and therapeutic decision-making in islet transplantation.

Date of Thesis submission	2025
Original language	English
Awarding Institution	Western Sydney University
Sponsors	Australian Government Research Training Program Scholarship
Supervisor	Mugdha Joglekar (Supervisor), Anand Hardikar (Supervisor), Wilson Wong (Supervisor) & Ho Trong Nhan Pham (Supervisor)