A5045746547- Pancreatic function and diabetes
- Xenotransplantation and immune response
- Organ Transplantation Techniques and Outcomes
- Renal Transplantation Outcomes and Treatments
- Diabetes and associated disorders
- Organ Donation and Transplantation
- Diabetes Management and Research
- Tissue Engineering and Regenerative Medicine
- T-cell and B-cell Immunology
- Animal Genetics and Reproduction
- Cannabis and Cannabinoid Research
- Immunotherapy and Immune Responses
- Virus-based gene therapy research
- Hernia repair and management
- Immune Cell Function and Interaction
- Anesthesia and Neurotoxicity Research
- Liver Disease and Transplantation
- Pancreatic and Hepatic Oncology Research
- Transplantation: Methods and Outcomes
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Minimally Invasive Surgical Techniques
- Genetics and Neurodevelopmental Disorders
- Metabolism, Diabetes, and Cancer
- Congenital Diaphragmatic Hernia Studies
The University of Sydney
2016-2025
Westmead Hospital
2016-2025
Westmead Institute for Medical Research
2016-2025
Westmead Institute
2012-2024
Metabolism and Renal Physiology
2014-2024
University of Fribourg
2023
UCLouvain
2023
Hudson Institute
2023
Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital
2023
Western Sydney University
2012-2021
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest it can be active under normoxic conditions. We hypothesized required for normal beta cell function and reserve dysregulation may contribute to pathogenesis type 2 diabetes (T2D). Here we show present at low in mouse human cells islets. Decreased impaired glucose-stimulated ATP generation function....
Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim this single-arm, multicenter study was to evaluate an immunosuppressive protocol antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching sirolimus MMF. Islets were cultured for 24 h prior transplantation. primary end-point HbA1c <7% cessation severe hypoglycemia. Seventeen recipients ≥ 12...
The instant blood-mediated inflammatory reaction (IBMIR) is a major obstacle to the engraftment of intraportal pig islet xenografts in primates. Higher expression galactose-α1,3-galactose (αGal) xenoantigen on neonatal cell clusters (NICC) than adult islets may provoke stronger reaction, but this has not been tested baboon model. Here, we report that WT NICC triggered profound IBMIR baboons, with intravascular clotting and graft destruction occurring within hours, which was prevented by...
In this state-of-the-art review we detail the journey of xenotransplantation from its infancy, detailing one first published cases and subsequent field took in inception development. With a focus on science, technological advances, precautions required along with potential limitations application, ethics, guidance’s, legislative advances that are to reach safe efficacious clinical application xenotransplantation. Along view over past several decades overall significant advancements...
In the context of islet transplantation, experimental models show that induction intrinsic NF-κB-dependent proinflammatory genes can contribute to graft rejection. Isolation human islets triggers activation NF-κB and mitogen-activated kinase (MAPK) stress response pathways. However, downstream target induced in during isolation process are poorly described. Therefore, this study, using microarray, bioinformatic, RTqPCR approaches, we determined pattern expressed by a set 14 preparations. We...
REPORT (d) transgenic pig facilities; (e) biomaterials and encapsulation; (f) immunosuppression tolerance induction.The guidance document from the Second Global Consultation (Geneva, 2011) was also included in these discussions.
Foxp3+ regulatory T cells (Tregs) have an essential role in immune and allograft tolerance. However, both kidney liver transplantation humans, FOXP3+ Tregs been associated with clinical rejection. Therefore, the function of graft infiltrating great interest. In studies outlined, we demonstrated that were expanded tolerant allografts draining lymph nodes DBA/2 (H-2d) to C57BL/6 (H-2b) mouse spontaneous tolerance model. Kidney was abrogated after deletion DEpletion REGulatory (DEREG) mice....
Abstract In 2009, the International Xenotransplantation Association ( IXA ) published a consensus document that provided guidelines and “recommendations” not regulations) for those contemplating clinical trials of porcine islet transplantation. These included 's opinion on what constituted “rigorous pre‐clinical studies using most relevant animal models” were based “non‐human primate testing.” We now report our discussion following careful review 2009 as they relate to testing. summary, we...
Abstract Aims/hypothesis We hypothesised that human beta cells are structurally and functional polarised with respect to the islet capillaries. set out test this using confocal microscopy map 3D spatial arrangement of key proteins live-cell imaging determine distribution insulin granule fusion around cells. Methods Human pancreas samples were rapidly fixed processed pancreatic slice technique, which maintains structure architecture. Slices stained immunofluorescence for polarity markers...
Abstract Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution CD4+ cells from BALB/c mice. Twelve days after reconstitution, purified macrophages (depleted of cells) isolated cell-reconstituted FPP recipient and adoptively transferred to nonreconstituted counterparts. After adoptive macrophage transfer, demonstrated...
T cell-mediated rejection remains a barrier to the clinical application of islet xenotransplantation. Regulatory cells (Treg) regulate immune responses by suppressing effector cells. This study aimed determine ability human Treg prevent xenograft and mechanism(s) involved. Neonatal porcine transplanted NOD-SCID IL2rγ−/− mice received peripheral blood mononuclear (PBMC) with in vitro expanded autologous absence or presence anti-human interleukin-10 (IL-10) monoclonal antibody. In addition,...
A high proportion of β-cells die within days islet transplantation. Reports suggest that induction hypoxia-inducible factor-1α (HIF-1α) predicts adverse transplant outcomes. We hypothesized this was a compensatory response and HIF-1α protects during Transplants were performed using human islets or murine β-cell-specific HIF-1α-null (β-HIF-1α-null) with without treatment deferoxamine (DFO) to increase HIF-1α. β-HIF-1α-null transplants had poor outcomes, demonstrating lack impaired efficiency....
Beta cell replacement is a potential cure for type 1 diabetes. In humans, islet transplants are currently infused into the liver via portal vein, although this site has disadvantages. Here, we investigated alternative transplantation sites human and murine islets in recipient mice, comparing vein with quadriceps muscle kidney, spleen capsules. Murine were isolated from C57BL6/J mice transplanted syngeneic recipients. Human either severe combined immunodeficiency (SCID) or...
The aim was to compare efficacy of multiple daily injections (MDI), continuous subcutaneous insulin infusion (CSII) and islet transplantation reduce hypoglycemia glycemic variability in type 1 diabetes subjects with severe hypoglycemia.This a within-subject, paired comparison MDI CSII 12 months postislet 10 referred hypoglycemia, suitable for transplantation. Individuals were assessed HbA1c, Edmonton Hypoglycemia Score (HYPOscore), glucose monitoring (CGM) 8 measurements using standard...
Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels relatively short periods in the preclinical diabetic rhesus model but met with limited success stringent baboon model. Here we report that NICC from genetically modified (GM) pigs deleted αGal and expressing human complement regulators...