53 research outputs found
Gene therapy studies of Adenoviral IL-10 transduced Dendritic cells in allotransplantation / by Toby Coates.
No full textBibliography: leaves 151-186.187 leaves, [26] leaves of plates : ill. (chiefly col.) 29 cm.Studies the capacity of dendritic cells transduced with the immunosuppressive gene construct adenoviral interleukin-10 to inhibit alloimmune responses in both small and large animal transplantation models. There is promising in vitro evidence for gene therapy to modify dendritic cell function, which in small animal models can modify skin graft rejection. In large animals, genetically modified dendritic cells alone were not capable of prolongation of allograft survival, suggesting that these cells may require adjuvant immunosuppressive therapy to be used in future protocols.Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 200
118.9: Growing pancreatic organoids for hereditary pancreatitis
No full textAbstract - 118.9James Zuiani, Denghao Wu, Griffith Perkins, Shane Grey, Christopher Drogemuller, Patrick Toby Coate
337.2: The Epidemiology of Hereditary Pancreatitis in Australia and its effect on patient of Total Pancreatectomy with Islet Auto-Transplantation (TPIAT).
No full textAbstract - 337.2Denghao Wu, James Zuiani, Christopher Drogemuller, Sunita De Sousa, David Adelson, David J Torpy, Patrick Toby H Coate
Transplant glomerulopathy and rapid allograft loss in the presence of HLA-Cw7 antibodies
No full textLetter to the EditorNatasha M. Rogers, Greg D. Bennett, and Patrick Toby Coate
Hyperparathyroidism and Vitamin D Deficiency Predispose to Bone Loss in Renal Transplant Recipients
No full textBackground. Bone disease is common postrenal transplantation resulting in increased fracture rates and morbidity. The cause is multifactorial including hyperparathyroidism, corticosteroids, and possibly calcium and vitamin D deficiencies. The aim of this study was to identify modifiable factors contributing to bone disease in long-term renal transplant (RT) recipients. Methods. Ninety-seven RT recipients were prospectively recruited over a 6-month period from a single center. Bone-related parameters were collected including bone mineral density at lumbar spine and total hip sites, serum and urinary markers of bone-turnover and calcium metabolism, and intact parathyroid hormone levels. Results. The mean time posttransplant of RT recipients was 9.5 years and mean estimated glomerular filtration rate was 70.3 mL/min. Up to 50% of recipients had biochemical evidence of calcium and vitamin D deficiencies. In the multiple regression models, elevated intact parathyroid hormone levels and calcium deficiency, which are affected by estimated glomerular filtration rate and vitamin D levels, are significantly associated with reduction in bone mineral density measurements. Conclusions. Hyperparathyroidism and vitamin D deficiency are common and are likely to contribute to bone loss postrenal transplantation. Measures aim to correct these problems pre- and posttransplant may improve bone health in RT recipients.Lim Wai H., Coates Penelope S., Russ Graeme R. and Coates Patrick Toby H
Modulation of antigen presenting cell function to affect innate and adaptive immune responses: implications for organ transplantation.
No full textTransplantation is the best form of treatment for end-stage kidney disease, by improving quality of life, reducing mortality and lowering healthcare costs. However, the immunosuppressive medications required have non-selective mechanisms of action, affecting both patient and graft longevity. Tolerance, the acceptance of an allograft in the absence of immunosuppression, remains a major goal in clinical transplantation research. Dendritic cells (DC) are potent antigen-presenting cells (APC) capable of promoting anti-donor immunity and antigen-specific tolerance, and are a promising target for immunomodulation. Current tolerogenic techniques involve ex vivo DC manipulation which limits immediate clinical applicability. The scope of this thesis involves identification of a novel biologic agent, curcumin, to induce tolerogenic DC and the use of this immunomodulatory agent within a liposomal construct to target and modify DC function in vivo.
Chapter 1 discusses the context of this thesis and contains a comprehensive literature review.
Chapter 2 outlines methodology and materials utilised in this thesis.
Chapter 3 demonstrates the use of curcumin for in vitro generation of tolerogenic DC that promote expansion of functional FoxP3+ regulatory T-cells (Tregs). In vivo infusion of curcumin-treated DC was also able to induce subsequent immune hyporesponsiveness mediated by FoxP3+ Tregs, and represents a potential avenue for transplant recipient conditioning using donor (or recipient) -derived DC.
Chapter 4 demonstrates the use of liposomes to target APC in vivo. Liposomal incorporation of immunomodulatory agents facilitates targeted cellular delivery to tissue-resident APC and
forms a basis for in vivo modulation of APC function. This work demonstrates that the in vitro results demonstrated in Chapter 3 can be replicated in vivo, potentially eliminating the need for ex vivo DC manipulation in a transplant setting.
Chapter 5 demonstrates the utility of liposomal curcumin in ameliorating aspects of ischaemiareperfusion injury (IRI), a consequence of transplant surgery that promotes graft
immunogenicity and limits graft longevity. For the first time renal tubular epithelial and antigen-presenting cell endocytosis of liposomes is demonstrated, as is salvage of renal function
which is mediated by reduced pro-inflammatory cytokine and chemokine production, and diminished oxidative stress. The results also identify thioredoxin-interacting protein (TXNIP) as
a potential novel marker of tissue injury in IRI, and curcumin effectively reduces this aspect of cellular redox stress These data represent a novel and effective delivery method for this
immunmodulatory agent, preventing significant renal damage in a manner that has immediate clinical applicability.
Chapter 6 describes a refinement in liposomal targeting of DC, using a DC-specific liposome capable of binding to human monocyte-derived DC with high affinity via the receptor DCSIGN.
The gene for marmoset DC-SIGN was cloned and the cross-reactivity of a human-DC-targeted liposome to its marmoset counterpart was investigated in vitro. Additional attempts were made to synthesize a marmoset DC-targeted liposome through basic, non-specific, chemical modification of a monoclonal antibody to DC-SIGN known to be cross-reactive with both humans and marmosets, with the aim of creating a cell-free DC-targeted negative vaccine that could be tested in non-human primates.
Thus, the work presented in this thesis creates a platform for future studies from which DC-based cellular and cell-free immune tolerance therapies can be developed in a transplant model.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201
Calcific uraemic arteriolopathy: an update
No full textCopyright © 2008 Lippincott Williams & Wilkins, Inc.Purpose of reviewCalcific uraemic arteriolopathy (CUA) or calciphylaxis is a rare but important cause of morbidity and mortality in patients with chronic kidney disease. The prevalence of CUA is increasing in patients with renal failure, and the condition is also being recognized in nonuraemic patients.Recent findingsThere has been increasing understanding of the molecular basis of vascular calcification, in particular on the important role of the uraemic microenvironment in the factors implicated in the differentiation of vascular smooth muscle cells into osteoblasts. New options for treatment of hyperphosphataemia and secondary hyperparathyroidism in patients with chronic kidney disease have become available in the last few years and these have begun to be used in patients with CUA. These include bisphosphonates, newer noncalcium/nonaluminium-containing phosphate binders and case reports of use of cinacalcet. Other treatments for CUA that are not targeted directly at calcium/phosphate homeostasis include hyperbaric oxygen and the antioxidant cation chelator sodium thiosulphate.SummaryClinicians managing patients with CUA should consider a combination approach of treating deranged calcium/phosphate with newer therapeutic agents and promoting wound healing with other older modalities such as hyperbaric oxygen and sodium thiosulphate infusions. Randomized controlled trials for treatments in CUA are still lacking.Rogers, Natasha M; Coates, Patrick Toby
Investigations into the role of zinc and zinc transporters in the pathogenesis of type 2 diabetes in db/db mice
No full textZn is critical for the synthesis, storage and release of insulin and abnormalities in Zn and Zn transporters occur in type 1 and 2 diabetes. However, the mechanism by which Zn is regulated in islet cells is still poorly understood. The major goal of this thesis was to investigate the role of Zn and Zn transporters in the pathogenesis of normal and type two diabetic pancreatic islets, using the type 2 db/db mouse model. There is limited information available on the physiological role of Zn and Zn transporters in these mice. The following hypotheses were tested. 1) There is an early loss of Zn in the development of type 2 diabetes which contributes to the transition to established diabetes; 2) The loss of Zn causes a block in insulin maturation resulting in impaired glucose responsiveness, hyperglycemia and decline in beta cell function; 3) This loss of Zn is due to alterations in Zn transporter proteins and metallothionein at the gene and protein level. Specifically changes in the organelle Zn transporters ZnT7 and ZnT8 result in the block in insulin maturation, while dysregulation of the inflammation related plasma membrane Zn transporter protein ZIP14 contributes to inflammation that results in further beta cell dysfunction. The major aims of the project were to determine whether in early and late diabetes there are changes in 1) total and labile Zn and metallothionein, 2) Zn transporter gene expression; and 3) Zn transporter proteins. Whole pancreata from the db/db mice and age matched controls at various ages were used to investigate Zn, metallothionein protein, gene expression and subcellular distribution of Zn transporters and Zn related proteins. Immunofluorescence, immunoperoxidase and western blotting were used to investigate the Zn transporter protein expression and distribution. The major findings in this study were in early diabetes 1) loss of Zn occurred in the labile islet beta cells Zn pools without decrease in systemic Zn ; 2) There were no changes at the gene level of Zn transporters ZnT1-10 and ZIP1-14 or metallothionein; 3)There was a significant increase in islet ZnT7 protein with a golgi like appearance; 4) ZnT8 protein was downregulated in islet beta cells but not alpha cells; 5) ZIP4 was expressed almost exclusively in the somatostatin producing delta cells; 6) ZIP14 staining was signficantly increased and coincided with islet macrophages. Changes in ZnT7, ZnT8 and ZIP14 expression may be factors leading to the loss of islet beta granule Zn. ZIP4 may be the major influx transporter for Zn in delta cells, ZnT8 is the transporter regulating Zn in insulin secretory granules and ZIP14 may be a novel marker of macrophage infiltration in diabetic islets. There are two potential clinical implications. The first is in understanding better the early events in development of type 2 diabetes, how these are influenced by Zn status and whether Zn supplements have a role to play in slowing down the transition from pre-diabetes to established diabetes. The second is a better understanding of islet Zn homeostasis with potential benefits for outcomes of islet transplantation.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2015
Immune profiling and cancer post transplantation
No full textHalf of all long-term (> 10 year) australian kidney transplant recipients (KTR) will develop squamous cell carcinoma (SCC) or solid organ cancer (SOC), making cancer the leading cause of death with a functioning graft. At least 30% of KTR with a history of SCC or SOC will develop a subsequent SCC or SOC lesion. Pharmacological immunosuppression is a major contributor of the increased risk of cancer for KTR, with the cancer lesions themselves further adding to systemic immunosuppression and could explain, in part, these phenomena. Immune profiling includes; measuring immunosuppressive drug levels and pharmacokinetics, enumerating leucocytes and leucocyte subsets as well as testing leucocyte function in either an antigen specific or non-specific manner. Outputs can vary from assay to assay according to methods used. In this review we define the rationale behind post-transplant immune monitoring assays and focus on assays that associate and/or have the ability to predict cancer and rejection in the KTR. We find that immune monitoring can identify those KTR of developing multiple SCC lesions and provide evidence they may benefit from pharmacological immunosuppressive drug dose reductions. In these KTR risk of rejection needs to be assessed to determine if reduction of immunosuppression will not harm the graft.Christopher Martin Hope, Patrick Toby H Coates and Robert Peter Carrol
Favourable cardiac remodeling and functional cardiac benefits assessed with cardiac magnetic resonance imaging following ligation of arteriovenous fistula in stable kidney transplant recipients: a randomized, controlled, open label study
No full textCardiovascular morbidity and mortality remains high in recipients of kidney transplantation. Persistence of arteriovenous fistula (AVF) may contribute to maladaptive cardiovascular remodelling in this cohort. We aimed to establish whether ligation of an arteriovenous fistula would improve cardiovascular structure and function in stable kidney transplant recipients, assessed utilizing cardiac magnetic resonance imaging (MRI). In this non-blinded, parallel group, randomized controlled trial, we recruited participants who were aged 18 years or older who had stable kidney function twelve months post kidney transplantation, and had a functioning AVF from a tertiary network of kidney transplantation service in Australia. Participants were randomly assigned (1:1) to have their AVF ligated or not have any intervention, with all participants undergoing a baseline cardiac MRI scan followed by a repeat scan six months following AVF ligation. We followed up participants for over 12 months. The primary outcome was change in left ventricular mass at 6 months, analyzed with mixed effect models according to intention-to-treat principles. Results: Between January 2013 and June 2016 we enrolled 93 participants. 63 eligible participants underwent randomization. 54 out of 63 participants completed assessments after second cardiac MRI. All eligible participants were included in the analyses. At follow-up, the mean left ventricular mass decreased by 14.7% (151.2 + 36.5 gm vs. 129.1 + 32.4 gm p <0.001 in the intervention group vs 153.4 + 47.8 gm vs 154.6 + 43.0 gm, p=0.69 in the non-intervention group). Significant improvements were also noted in LVEDV, LVESV, right ventricular structure and function. There was a reduction noted in left atrial volumes as well. No significant complications were noted after AVF ligation. The NT pro BNP fell significantly in the intervention group over a period of 6 months [424.78 (558.59) to 161.91 (133.60), p=0.02] whereas no change was seen in the control group [462.0 (524.90) to 500.14 (604.28), p=0.10]. Interpretation: In our randomized controlled trial for adults with stable kidney transplantation and functioning AVF, elective ligation of AVF is association with marked improvements in cardiac structure and function.Thesis (MPhil) -- University of Adelaide, Adelaide Medical School, 201
- …
