Graduation date: 1996

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 238-276). Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 238-276). Also available in print.

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

The aim of this project was to develop an in vitro functional assay for the prediction of allograft rejection following renal transplantation. This assay was also used to study acute GVHD following identical sibling bone marrow transplantation. Lymphocyte cytokine profiles were measured by ELISA (protein secretion) and flow cytometry (cytokine expression) following mitogen stimulation and MLR. In normal individuals, considerable inter-individual variations were found in both protein secretion (IL-2, IL- 4, IL-10 and IFN-γ) and cytokine expression (IL-2 and IFN-γ). Strong relationships were found between IL-2 protein and expression, IL-2 and IL-10 protein, and IL-10 and IFN-γ protein secretion. Analysis of cytokine gene polymorphisms showed no correlation between IFN-y protein secretion, frequency or gene polymorphism. Pre-transplant MLRs were set up between renal transplant patient/donors pairs and cytokine protein secretion (IL-2, IL-4, IL-6, IL-10 and IFN-γ) measured by ELISA. Analysis was performed to ascertain predictive factors of allograft rejection. Inter-individual variations were found for all cytokine profiles. Significant correlations were found between individual cytokine protein profiles including IL-10 and IFN-γ. In addition, a correlation was found between HLA-DR mismatching and both IL-10 and IFN-γ protein secreted in the MLR. Primary univariate analysis revealed that HLA and HLA-DR mismatching, female donor sex, MLR-stimulated IL-10, MLR-stimulated IFN-γ and spontaneous IL-4 secretion were associated with an increased risk of rejection. Multivariate analysis showed the strongest correlations for predicting risk of rejection to be female donor sex, HLA mismatching and MLR-stimulated IL-l 0 secretion. A combination of high HLA mismatching and high IL-l 0 secretion in MLR gave the highest risk of rejection (RR=25.5). Finally, cytokine secretion decreased when measured post-transplant. Prediction of graft survival could not be analysed due to the low number (n=6) of patients that suffered graft failure in the group. Cytokine protein secretion (IL-2, IL-4, IL-10 and IFN-γ) in MLR was also studied for prediction of GVHD after bone marrow transplantation. There was a very low MLR response by all BMT pairs, therefore analysis could not be performed.

Diss. Linköping : Linköpings universitet, 2006.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease affecting people of various ages across the globe. Treatment for the disease is in the form of immunosuppressive drugs. Due to either the treatment of the disease or the disease itself, SLE patients have been shown to have abnormal immune function. This dysfunction accounts for an increased rate of infections in this population. Reactivation of the varicella zoster virus (VZV), herpes zoster (HZ), has been shown to occur in the SLE population at higher rates than the general, healthy population. Recently a vaccine for HZ was approved by the Food and Drug Administration for individuals 50 years of age and older. STUDY: In this study we examined the safety and immunogenicity of the HZ vaccine, Zostavax, in a small sample of SLE patients. This study was a case-control with a ratio of 1:1, SLE patients to healthy controls. The total sample size was 20 with an average age of 57.9. All study participants were seen in a clinical setting at the Oklahoma Medical Research Foundation and signed informed consents. Subjects were seen for an initial baseline visit, and were administered the vaccine. Follow-up visits were scheduled at 2, 6 and 12 weeks. RESULTS: The notable finding of this study is a lack of significant differences between SLE patients and healthy individuals with one exception. At the 6-week point a significant difference was found (P=0.03) between SLE patients and healthy controls, with regards to the number of VZV-specific cells stimulated to produce interferon gamma. No vaccine-induced illness was evident and there was no sign of an increase in SLE disease activity in patients.

Glioblastoma is the most common and aggressive type of adult brain tumour. It is currently incurable and requires more effective treatments. Tissue transglutaminase 2 (TGM2) has previously been suggested to have a role in glioblastoma. Previous studies focused on TGM2 expression and inhibition in glioblastoma cells. Here we were interested in TGM2 expression in glioblastoma-associated microglia/macrophages and in identifying the role it plays in the tumor microenvironment. Based on data from bioinformatics, cell culture experiments, immunohistochemistry and immunofluorescence on mouse samples and human samples, we have shown that glioblastoma-associated microglia/macrophages are the major source of TGM2 in the tumor microenvironment. We also identified a novel role for TGM2 in efferocytosis in glioblastoma; this suggests a role for TGM2 in the maintenance of an immunosuppressive environment in this cancer. With this, we hope that further studies will be designed to evaluate the use of TGM2 antagonists as therapeutic agents for glioblastoma.

Bibliography: leaves 234-257. Three separate clinical studies in organ transplant recipients are presented. The aims are to examine fundamental questions regarding the clinically and economically important pharmokinetic interaction between diltiazem and cyclosporin, an interaction widely utilised in organ transplantation. The data contained should assist the development of soundly based policies that will ensure a benefit exists before a sparing agent is coprescribed, and that the lowest effective dose of sparing agent is used.

Bibliography: leaves 234-257. / xi, 277 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Three separate clinical studies in organ transplant recipients are presented. The aims are to examine fundamental questions regarding the clinically and economically important pharmokinetic interaction between diltiazem and cyclosporin, an interaction widely utilised in organ transplantation. The data contained should assist the development of soundly based policies that will ensure a benefit exists before a sparing agent is coprescribed, and that the lowest effective dose of sparing agent is used. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 2001