ORCID Profile
0000-0002-6824-4189
Current Organisations
American Society for Histocompatibility and Immunogenetics
,
Royal Australasian College of Physicians
,
Royal College of Pathologists of Australasia
,
Pathwest Laboratory Medicine
,
University of Western Australia
,
Fiona Stanley Hospital
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Publications
Preferential HLA-B27 Allorecognition Displayed by Multiple Cross-Reactive Antiviral CD8+ T Cell Receptors
Publisher: Frontiers Media SA
Date: 19-02-2020
High transplant rates of highly sensitized recipients with virtual crossmatching in kidney paired donation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-10-2012
Virus-specific T cell clonotypes may contribute to drug hypersensitivity reactions via heterologous immunity
Publisher: Elsevier BV
Date: 08-2019
Modeling the Benefits and Costs of Integrating an Acceptable HLA Mismatch Allocation Model for Highly Sensitized Patients
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2014
Allograft and Patient Outcomes between Indigenous and Nonindigenous Kidney Transplant Recipients
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2020
Providing better-matched donors for HLA mismatched compatible pairs through kidney paired donation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
Peri-operative third party red blood cell transfusion in renal transplantation and the risk of antibody-mediated rejection and graft loss
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.TRIM.2013.09.008
Abstract: Historic red blood cell transfusion (RBCT) may induce anti-HLA antibody which, if donor specific (DSA), is associated with increased antibody-mediated rejection (AMR). Whether post-operative RBCT influences this risk is unknown. We examined the RBCT history in 258 renal transplant recipients stratified according to prevalent recipient HLA antibody (DSA, Non-DSA or No Antibody). AMR occurred more frequently in patients who received RBCT both pre and post transplant compared with all other groups (Pre+Post-RBCT 21%, Pre-RBCT 4%, Post-RBCT 6%, No-RBCT 6%, HR 4.1 p=0.004). In the 63 patients who received Pre+Post-RBCT, 65% (13/20) with DSA developed AMR compared with 0/6 in the Non-DSA group and 2/37 (5%) in the No-Antibody group (HR 13.9 p<0.001). In patients who received No-RBCT, Pre-RBCT or Post-RBCT there was no difference in AMR between patients with DSA, Non-DSA or No-Antibody. Graft loss was independently associated with Pre+Post-RBCT (HR 6.5, p=0.001) AMR (HR 23.9 p<0.001) and Non-AMR (6.0 p=0.003) after adjusting for DSA and delayed graft function. Re-exposure to RBCT at the time of transplant is associated with increased AMR only in patients with preformed DSA, suggesting that RBCT provides additional allostimulation. Patients receiving Pre+Post-RBCT also had an increased risk of graft loss independently of AMR or DSA. Both pre and post procedural RBCT in renal transplantation is associated with modification of immunological risk and warrants additional study.
Correlating HLA associations with follicular lymphoma in an Australian data set: A pilot study
Publisher: Wiley
Date: 11-06-2020
DOI: 10.1111/TAN.13918
Comparison of time on the deceased donor kidney waitlist versus time on the kidney paired donation registry in the Australian program
Publisher: Frontiers Media SA
Date: 14-08-2012
DOI: 10.1111/J.1432-2277.2012.01541.X
Abstract: In the Australian kidney paired donation (KPD) program matching is based on acceptable mismatches, whereas deceased donor waitlist (DDWL) patients are allocated kidneys based on HLA antigen matching rules. Herein, we compared waiting time for a KPD match to the waiting time on the DDWL and the occurrence of matching in the DDWL for patients who were registered in both programs. Data on first dialysis, matches on the DDWL, KPD program entry, matches and transplant dates were assessed in 26 KPD recipients of the Australian program. There were 22 recipients who were listed in the DDWL and received kidney transplants by KPD. Time on dialysis until KPD transplantation was 808 ± 646 days. Eleven patients had never been matched with a deceased donor (waiting time 345 ± 237 days) and 11 had been matched on average 3 ± 5 times (waiting time 1227 ± 615 days, P < 0.0001 vs. never matched), but did not progress to transplantation because of positive crossmatch or class II donor-specific antibody. Mean time from registration in the KPD program until kidney transplantation was 153 ± 92 days (P < 0.0001 vs. DDWL). KPD allocation using the acceptable mismatch approach is effective in identifying suitable live donors for some recipients within a relatively short time-frame.
The association between broad antigen HLA mismatches, eplet HLA mismatches and acute rejection after kidney transplantation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
Influence of implant abutment angulations on the fracture resistance of overlaying CAM‐milled zirconia single crowns
Publisher: Wiley
Date: 30-05-2011
DOI: 10.1111/J.1834-7819.2011.01314.X
Abstract: An in vitro study was performed to assess the effect of three implant abutment angulations and three core thicknesses on the fracture resistance of overlaying computer-aided manufacturing (CAM) milled zirconia (Cercon(®) system) single crowns. Three groups, coded A to C, with different implant abutment angulations (group A/0°, group B/15° and group C/30° angulation) were used to construct 15 crowns for each angulation. Forty-five overlay restorations were milled using the Cercon(®) system with zirconium core thicknesses of 0.4, 0.6 and 0.8 mm using five crowns for each angulation. The final restorations were prepared and stored in distilled water at mouth temperature (37°C) for 24 hours prior to testing. The restorations were cemented using Temp Bond(®) . The load required to break each crown and the mode of failure were recorded. All the results obtained were statistically analysed by the ANOVA test (level of significance p < 0.05). Tested crowns were examined using a stereomicroscope at 40X and selected crowns (five randomly selected from each group were further examined by scanning electron microscopy) to reveal the zirconia-ceramic interface and to determine the fracture origin. Implant abutment angulations significantly (p 0.05) affect the fracture resistance of the CAM-milled zirconia single crowns. SEM showed that the origin of the fracture appeared to be located at the occlusal surfaces of the crowns and the crack propagation tended to radiate from the occlusal surface towards the gingival margin. The implant angulation of 30° significantly (p 0.05) the fracture resistance of overlaying CAM-milled zirconia single crowns.
ABO-incompatible matching significantly enhances transplant rates in kidney paired donation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2013
TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2012
Screening of viral specific T-cell lines for HLA alloreactivity prior to adoptive immunotherapy may prevent GvHD
Publisher: Elsevier BV
Date: 04-2011
Audit of emergency department assessment and management of patients presenting with community-acquired needle stick injuries
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/AH09846
Abstract: Objectives. To describe characteristics and management of people with community acquired needle stick injuries (CANSI) attending urban emergency departments and suggest a guideline to improve assessment, management, and documentation. Methods. A retrospective analysis of cases with CANSI attending emergency departments in two tertiary hospitals between 2001 and 2005 using medical record review with follow up phone and written survey. Results. Thirty-nine cases met the criteria for CANSI. Persons younger than 30 years sustained 48.72% of all injuries. Source serology was available for only five cases (12.82%). Thirty-one of thirty-nine patients (79.49%) were classed as not immune to hepatitis B but only four of these (12.90%) received both hepatitis B vaccination and hepatitis B immunoglobulin. Six patients (15.38%) received HIV prophylaxis of which two (33.33%) did not receive baseline HIV testing. Of ten patients referred to immunology clinic for follow up only two (20.00%) attended at 6 months. Conclusion. We have identified groups that are at high risk of CANSI, including young males, security workers and cleaners. In the majority of cases protection against hepatitis B was inadequately provided, and a substantial proportion had inadequate baseline assessment and documentation. A guideline is suggested that may be used to improve these deficits. What is known about this topic? Occupationally acquired needle stick injury guidelines are well established, but no guidelines currently exist for community acquired needle stick injuries (CANSI) which may require different risk stratification, assessment and management. Management of CANSI in Emergency Departments has not been well described. What does this paper add? An audit of Emergency Department management of community acquired needle stick injuries demonstrates deficits in risk assessment, documentation and use of post-exposure immunisation and prophylaxis. A guideline is suggested that may be used to improve these deficits. What are the implications for practitioners? Practitioners need to perform and document a risk assessment of the injury, perform baseline serology, and provide tetanus and hepatitis B immunisation. Use of HIV post-exposure prophylaxis is determined by local prevalence of disease, injury risk assessment, source serology if known, and time since injury.
A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JMOLDX.2022.02.007
Abstract: With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted licon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies-Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted licon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted licon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.
Rapid high‐resolution HLA genotyping by MinION Oxford nanopore sequencing for deceased donor organ allocation
Publisher: Wiley
Date: 26-04-2020
DOI: 10.1111/TAN.13901
Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-08-2007
Detection of allo-HLA cross-reactivity by virus-specific memory T-cell clones using single HLA-transfected K562 cells.
Publisher: Humana Press
Date: 2012
DOI: 10.1007/978-1-61779-842-9_19
Abstract: The ability to directly measure virus-specific lymphocytes using fluorochrome-labeled tetrameric complexes has proven a great advancement for the transplantation field. Viral peptide/HLA tetrameric complexes allow the rapid generation of virus-specific clones using single cell sorting apparatus, permitting the determination of alloreactivity from a single TCR with known specificity. When combined with new target "detector" cells called single HLA antigen-transfected K562 cells (SALs), the human alloresponse can for the first time be examined specifically and reliably. Here we describe a method for detection of "heterologous immunity" from virus-specific memory T-cells using single HLA expressing cell lines as allogeneic targets.
Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
Protective HLA-B57: T cell and natural killer cell recognition in HIV infection
Publisher: Portland Press Ltd.
Date: 16-09-2022
DOI: 10.1042/BST20220244
Abstract: Understanding the basis of the immune determinants controlling disease outcome is critical to provide better care to patients and could be exploited for therapeutics and vaccine design. The discovery of the human immunodeficiency virus (HIV) virus as the causing agent of acquired immunodeficiency syndrome (AIDS) decades ago, led to a tremendous amount of research. Among the findings, it was discovered that some rare HIV+ in iduals, called HIV controllers (HICs), had the ability to control the virus and keep a low viral load without the need of treatment. This ability allows HICs to delay or avoid progression to AIDS. HIV control is strongly associated with the expression of human leukocyte antigen (HLA) alleles in HICs. From the HIV protective HLAs described, HLA-B57 is the most frequent in HIC patients. HLA-B57 can present a large range of highly conserved Gag-derived HIV peptides to CD8+ T cells and natural killer (NK) cells, both the focus of this review. So far there are limited differences in the immune response strength, magnitude, or receptor repertoire towards HIV epitopes that could explain viral control in HICs. Interestingly, some studies revealed that during early infection the large breadth of the immune response towards HIV mutants in HLA-B57+ HIC patients, might in turn influence the disease outcome.
High-resolution human KIR genotyping.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2022
DOI: 10.1007/S00251-021-01247-0
Abstract: Killer immunoglobulin-like receptors (KIR) regulate the function of natural killer cells through interactions with various ligands on the surface of cells, thereby determining whether natural killer (NK) cells are to be activated or inhibited from killing the cell being interrogated. The genes encoding these proteins display extensive variation through variable gene content, copy number and allele polymorphism. The combination of KIR genes and their ligands is implicated in various clinical settings including haematopoietic stem cell and solid organ transplant and infectious disease progression. The determination of KIR genes has been used as a factor in the selection of optimal stem cell donors with haplotype variations in recipient and donor giving differential clinical outcomes. Methods to determine KIR genes have primarily involved ascertaining the presence or absence of genes in an in idual. With the more recent introduction of massively parallel clonal next-generation sequencing and single molecule very long read length third-generation sequencing, high-resolution determination of KIR alleles has become feasible. Determining the extent and functional impact of allele variation has the potential to lead to further optimisation of clinical outcomes as well as a deeper understanding of the functional properties of the receptors and their interactions with ligands. This review summarizes recently published high-resolution KIR genotyping methods and considers the various advantages and disadvantages of the approaches taken. In addition the application of allele level genotyping in the setting of transplantation and infectious disease control is discussed.
C3d‐binding assay for the detection of complement activating HLA antibodies: A useful tool for allocation to highly sensitised recipients in the post‐CDC era?
Publisher: Wiley
Date: 08-03-2023
DOI: 10.1111/TAN.15010
Abstract: The CDC crossmatch test is being phased out in solid organ donor allocation, and standard luminex single antigen bead assays do not differentiate complement activating function of HLA antibodies. The current study investigated the LIFECODES C3d‐binding assay to determine if it could accurately predict actual T and B cell CDC results in a cohort of highly sensitised patients. Nineteen serum s les from different highly sensitised solid organ patients were crossmatched against cells from 62 unique donors, with 174 total T and B cell crossmatches performed. The sera also underwent SAB assay using OLI and LC platforms, and C3d‐binding assay. Complement activating ability of each unique HLA antibody specificity detected using SAB was assigned based on the actual CDC results, which was then used to determine the accuracy of the C3d‐binding assay. The C3d‐binding assay was found to be highly accurate, with sensitivity of 95%, specificity 89% and negative predictive value 97% for class I DSA and the T cell CDC crossmatch results. Furthermore, we found 100% accuracy for prediction of the complement activating function of HLA‐C antibodies. Negative predictive value of above 90% was also found for HLA class II DSA. C3d‐binding proved more accurate than virtual crossmatch alone to predict CDC results. This study confirms that the C3d‐binding assay predicts actual CDC crossmatch results accurately. In particular, the high negative predictive value of the C3d‐binding assay may be extremely useful to define HLA antibodies that do not activate complement in highly sensitised recipients.
New tools to monitor the impact of viral infection on the alloreactive T‐cell repertoire
Publisher: Wiley
Date: 17-09-2009
DOI: 10.1111/J.1399-0039.2009.01311.X
Abstract: Accumulating evidence suggests that alloreactive memory T-cells may be generated as a result of viral infection. So far, a suitable tool to define the in idual human leukocyte antigen (HLA) cross-reactivity of virus-specific memory T-cells is not available. We therefore aimed to develop a novel system for the detection of cross-reactive alloresponses using single HLA antigen expressing cell lines (SALs) as stimulator. Herein, we generated Epstein-Barr Virus (EBV) EBNA3A specific CD8 memory T-cell clones (HLA-B*0801/FLRGRAYGL peptide restricted) and assayed for alloreactivity against a panel of SALs using interferon-gamma Elispot as readout. Generation of the T-cell clones was performed by single cell sorting based on staining with viral peptide/major histocompatibility complex-specific tetramer. Monoclonality of the T-cell clones was confirmed by T-cell receptor (TCR) polymerase chain reaction analysis. First, we confirmed the previously described alloreactivity of the EBV EBNA3A-specific T-cell clones against SAL-expressing HLA-B*4402. Further screening against the entire panel of SALs also showed additional cross-reactivity against SAL-expressing HLA-B*5501. Functionality of the cross-reactive T-cell clones was confirmed by chromium release assay using phytohemagglutinin blasts as targets. SALs are an effective tool to detect cross-reactivity of viral-specific CD8 memory T-cell clones against in idual class I HLA molecules. This technique may have important implications for donor selection and monitoring of transplant recipients.
Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients
Publisher: SAGE Publications
Date: 02-2021
Abstract: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L ( nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L ( th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.
Different eplet software programs give discordant and incorrect results: An analysis of HLAMatchmaker vs Fusion Matchmaker Eplet calling software
Publisher: Wiley
Date: 26-04-2020
DOI: 10.1111/TAN.13897
Report from the extended HLA‐DPA1 ~ promoter ~ HLA‐DPB1 haplotype of the 18th international HLA and immunogenetics workshop
Publisher: Wiley
Date: 14-07-2023
DOI: 10.1111/TAN.15155
Abstract: The primary goal of the HLA‐DPA1 ~ promoter ~ HLA‐DPB1 haplotype component of the 18th IHIWS was to characterise the extended haplotypes within the HLA‐DP region and survey the extent of genetic ersity in this region across human populations. In this report, we analysed single‐nucleotide polymorphisms (SNPs) in 255 subjects from 6 different cohorts. The results from the HLA‐DP haplotype component have validated findings from the initial pilot study. SNPs in this region were inherited in strong linkage, particularly HLA‐DPA1, SNP‐linked promoter haplotypes and motifs in exon 2 of HLA‐DPB1. We reported 17 SNP‐linked haplotypes in the promoter region. Together with HLA‐DPA1 and HLA‐DPB1 alleles, they formed 74 distinct extended HLA‐DP haplotypes in 438 sequences. We also observed the presence of region‐specific alleles and promoter haplotypes. Our approach involved phasing extended SNPs including promoter SNPs, HLA‐DPA1 and HLA‐DPB1 alleles, in a 22 kb region, GRCh38/hg38 (chr6:33,064,111‐33,086,679), followed by clustering of these SNPs as one extended haplotype. This hierarchical clustering revealed four major clades, suggesting that haplotypes within each clade may have erged from a common ancestral haplotype and undergone similar evolutionary processes. The correlation between HLA‐DPA1 and the promoter region raises questions about the role of HLA‐DPA1 antigen in the heterodimer. This finding requires validation on a larger s le size specifically designed for anthropological analysis. Nevertheless, the results from this study highlight the clinical potential of selecting better‐matched donors for patients awaiting haematopoietic stem cell transplants from genetically overlapping groups that share common ancestral haplotypes.
Alloreactivity from human viral specific memory T-cells
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.TRIM.2010.06.008
Abstract: The mechanisms by which alloreactive memory T-cells are generated in non-sensitized in iduals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an essential feature of the T-cell receptor. Indeed it has recently been shown that alloreactivity from viral specific memory T-cells is far more common than predicted, 45% of viral specific T-cell clones were found to be allo-HLA crossreactive. In this overview the evidence for crossreactive alloresponses from human viral specific memory T-cells is discussed with special emphasis on the unexpected high frequency of these crossreactive responses, the peptide and tissue specificity of the responses, and the mechanistic insights gleaned from the elucidation of the crystal structure of an allo-HLA crossreactive viral specific TCR. The possible implications for clinical solid organ and bone marrow transplantation and tolerance induction will be discussed.
Drug-induced alloreactivity: A new paradigm for allorecognition
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1111/AJT.15470
Abstract: Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ in iduals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ in iduals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-γ production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed.
Imbalanced effector and regulatory cytokine responses may underlie mycobacterial immune restoration disease
Publisher: Springer Science and Business Media LLC
Date: 29-04-2008
Abstract: Immune restoration disease (IRD) is an adverse consequence of antiretroviral therapy, where the restored pathogen-specific response causes immunopathology. Mycobacteria are the pathogens that most frequently provoke IRD and mycobacterial IRD is a common cause of morbidity in HIV-infected patients co-infected with mycobacteria. We hypothesised that the excessive effector immune response in mycobacterial IRD reflects impaired regulation by IL-10. We studied two patients who experienced mycobacterial IRD during ART. One patient developed a second episode of IRD with distinct clinical characteristics. Findings were compared with patients 'at risk' of developing IRD who had uneventful immune recovery. Peripheral blood mononuclear cells (PBMC) from all subjects were stimulated with mycobacterial antigens in the form of purified protein derivative (PPD). Supernatants were assayed for IFNγ and IL-10. In response to PPD, PBMC from IRD patients generated IFNγ during the first IRD episode, whilst cells from non-IRD controls produced more IL-10. We present preliminary data from two HIV-infected patients showing an imbalance between IFNγ and IL-10 responses to mycobacterial antigens during mycobacterial IRD. Our findings suggest that imbalanced effector and regulatory cytokine responses should be investigated as a cause of IRD.
Stimulation of HIV-specific T cell clonotypes using allogeneic HLA
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.CELLIMM.2017.03.004
Abstract: We hypothesized that HIV-specific CD8 T cell clonotypes can be stimulated by allogeneic HLA molecules. Multiple HIV-specific CD8 T cell clones were derived from 12 in iduals with chronic HIV infection, specific for 13 different HIV Gag antigens and restricted to 7 different HLA molecules. The generated T cell clones were assayed for alloreactivity against a panel of single HLA class I expressing cell lines (SALs). HIV-specific T cells recognising at least one allogeneic HLA molecule could be identified from 7 of 12 patients tested. Allorecognition was associated with IFNγ cytokine production, CD137 upregulation and cytotoxicity, suggesting high avidity allo-stimulation. Allo-HLA recognition by HIV-specific T cells was specific to the HIV target peptide/HLA restriction and TCR TRBV usage of the T cells. HIV-specific T cells do crossreact against allogeneic HLA molecules in an epitope and TRBV specific manner. Therefore allo-HLA stimulation could be exploited to induce or augment HIV-specific T cell responses.
Polymorphism clustering of the 21.5 kb DPA‐promoter‐DPB region reveals novel extended full‐length haplotypes
Publisher: Wiley
Date: 16-07-2020
DOI: 10.1111/TAN.13975
Vaccine-Induced Allo-HLA–Reactive Memory T Cells in a Kidney Transplantation Candidate
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-03-2011
Molecular insights into the HLA‐B35 molecules' classification associated with HIV control
Publisher: Wiley
Date: 09-10-2023
DOI: 10.1111/IMCB.12698
CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses
Publisher: Elsevier BV
Date: 05-2021
Tissue Specificity of Cross-Reactive Allogeneic Responses by EBV EBNA3A-Specific Memory T Cells
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2011
Assessment of European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines in an Australian paediatric population
Publisher: Elsevier BV
Date: 08-2020
Abacavir-reactive memory T cells are present in drug naïve individuals
Publisher: Public Library of Science (PLoS)
Date: 12-02-2015
Role of HLA-DQ typing and anti-tissue transglutaminase antibody titers in diagnosing celiac disease without duodenal biopsy in type 1 diabetes: A study of the population-based pediatric type 1 diabetes cohort of Western Australia
Publisher: Hindawi Limited
Date: 02-05-2019
DOI: 10.1111/PEDI.12857
Abstract: The primary aim of the present study was to determine if it is cost effective to use human leukocyte antigen (HLA) typing as a first-line screening test for celiac disease (CD) in children with type 1 diabetes (T1D), as recommended by the European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). The second aim was to investigate whether anti-tissue transglutaminase IgA (anti-tTGA) antibodies can be used to diagnose CD without the need for a confirmatory duodenal biopsy in T1D. Data for all T1D patients aged <18 years, who attended the diabetes clinics in Western Australia up to June 2017, were extracted from the Western Australian Children's Diabetes Database (WACDD) and analyzed for their demographic data and CD permissive HLA alleles (DQ2, DQ8, and DQ7). For T1D patients already diagnosed with CD, the mode of diagnosis of CD, anti-tTGA titers, and CD permissive HLA alleles were analyzed. Of the 936 eligible T1D patients identified, HLA-DQ typing was available for 551 (59%). Of these 551 patients, 504 (91.2%) were positive for celiac permissive HLA alleles. Eight percent (n = 75) of the T1D patients had a co-diagnosis of CD. High anti-tTGA titers were observed in those who were diagnosed with a positive duodenal biopsy. HLA-DQ typing is not cost effective as a first-line screening test for CD in T1D patients because of over-representation of CD permissive HLA alleles in this group. Anti-tTGA titers may be useful in diagnosing CD in T1D without duodenal biopsy, as high levels were found to be strongly predictive of CD.
A novel allocation strategy for the difficult‐to‐allocate donor: audit of deceased donor kidneys utilised for preemptive recipients within Western Australia
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/IMJ.15950
Abstract: Kidney donor allocation can occasionally be difficult in Australia given a small population spread over vast distances. Therefore, between 2017 and 2019 our service allowed transplantation from deceased donors into local (same‐state) preemptive recipients , only if no well‐matched dialysis‐dependent transplant waitlist recipient was available. Transplantation using this novel allocation pathway was associated with good clinical and immunological outcomes.
Endogenous-peptide-dependent alloreactivity: new scientific insights and clinical implications
Publisher: Wiley
Date: 06-05-2013
DOI: 10.1111/TAN.12115
Abstract: T-cell alloreactivity is generated via immune responsiveness directed against allogeneic (allo) human leucocyte antigen (HLA) molecules. Whilst the alloresponse is of extraordinary potency and frequency, it has often been assumed to be less peptide-specific than conventional T-cell reactivity. Recently, several human studies have shown that both alloreactive CD8(+) and CD4(+) T cells exhibit exquisite allo-HLA and endogenous peptide specificity that has also underpinned tissue-specific allorecognition. In this review, we summarize former and recent scientific evidence in support of endogenous peptide (self-peptide)-dependence of T-cell alloreactivity. The clinical implications of these findings will be discussed in the context of both solid organ transplantation and haematopoietic stem cell transplantation (HSCT). Insights into the understanding of the molecular basis of T-cell allorecognition will probably translate into improved allograft survival outcomes, lower frequencies of graft vs host disease and could potentially be exploited for selective graft vs leukaemia effect to improve clinical outcomes following HSCT.
Transfer of donor anti-HLA antibody expression to multiple transplant recipients: A potential variant of the passenger lymphocyte syndrome?
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1111/AJT.15262
Abstract: Antibody-mediated rejection, whereby transplant recipient B cells and/or plasma cells produce alloreactive anti-human leukocyte antigen (HLA) antibodies, negatively influences transplant outcomes and is a major contributor to graft loss. An early humoral immune response is suggested by the production of anti-HLA donor-specific antibodies (DSA) that can be measured using solid phase assays. We report the early posttransplant coexistence of a shared anti-HLA antibody profile in 5 solid organ transplant recipients who received organs from the same donor. Retrospective analysis of the donor's serum confirmed the presence of the same anti-HLA profile, suggesting the transfer of donor-derived anti-HLA antibodies, or the cells that produce them, to multiple solid organ transplant recipients. The time frame and extent of transfer suggest a novel variant of the passenger lymphocyte syndrome. These findings have important implications for the consideration of all posttransplant antibody measurements, particularly the interpretation of non-DSAs in the sera of transplant recipients.
Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2011
Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study
Publisher: Elsevier BV
Date: 2020
A novel multiplexed 11 locus HLA full gene amplification assay using next generation sequencing
Publisher: Wiley
Date: 24-10-2019
DOI: 10.1111/TAN.13729
Abstract: The rapid progress of HLA typing techniques has contributed to improving the outcome of haematopoietic stem cell transplantation (HSCT). However, unambiguous HLA typing remains challenging. Next generation sequencing (NGS) has been shown to resolve the HLA typing ambiguity and simplify HLA typing workflows. The aim of this study is to develop a multiplexed full-gene PCR assay for 11 HLA loci that can be used on any NGS platform to provide additional information to the traditionally sequenced regions. The entire gene of HLA-A, HLA-B, HLA-C, DRB1, DRB3/4/5, DQB1, DQA1, DPB1, and DPA1 were lified in four multiplexed reactions. A DNA reference panel of 47 s les representing the most common allele groups was selected to evaluate this novel assay using the Ion Torrent sequencing platform. The specificity and sensitivity of this assay was confirmed on additional 158 s les from a local Caucasian control cohort. Full gene sequences from start to stop codons including some UTR regions were obtained for all 11 HLA loci with complete gene coverage and sufficient read-depth for 3619 alleles. The whole licon was analysed for HLA class I genes, while only exons were analysed for class II genes. All alleles were lified as expected with 100% concordance at full gene resolution for HLA class I and exon resolution for HLA class II loci when compared with previously used NGS or Sanger sequencing methods. In summary, the novel multiplexed PCR approach for full-gene HLA typing enabled for a large amount of genetic information to be generated in a simple and fast workflow.
Comparison of the Incidence, Risk Factors and Types of Acute Rejection between Indigenous and Non-Indigenous Australians with Kidney Transplants
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2018
Tracheobronchitis in ulcerative colitis: a case report of therapeutic response with infliximab and review of the literature
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1186/S12876-019-1091-0
Abstract: The extra-intestinal manifestation of tracheobronchitis is a rare complication of ulcerative colitis (UC). Here, we present a case of UC-related tracheobronchitis wherein the positive clinical effects of infliximab are demonstrated. We report the case of a 39-year old woman who presented with a chronic productive cough on a distant background of surgically managed ulcerative colitis (UC). Our patient failed to achieve a satisfactory clinical improvement despite treatment with high dose inhaled corticosteroids, oral corticosteroids and azathioprine. Infliximab therapy was commenced and was demonstrated to achieve macroscopic and symptomatic remission of disease. We present the first case report documenting the benefits of infliximab in UC-related tracheobronchitis.
Graft nephrectomy for people with a failed kidney transplant
Publisher: Wiley
Date: 20-10-2016
Refractory anti-phospholipid antibody syndrome treated with cyclophosphamide, resulting in a successful pregnancy
Publisher: Oxford University Press (OUP)
Date: 10-06-2019
Allo-HLA reactivity of virus-specific memory T cells is common
Publisher: American Society of Hematology
Date: 15-04-2010
DOI: 10.1182/BLOOD-2009-07-234906
Abstract: Graft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells. Because a range of acute viral infections have been linked to initiating these complications, we hypothesized that the cross-reactive potential of virus-specific memory T cells to allogeneic (allo) HLA molecules may be able to mediate these complications. To analyze the allo-HLA reactivity, T cells specific for Epstein-Barr virus, cytomegalovirus, varicella zoster virus, and influenza virus were tested against a panel of HLA-typed target cells, and target cells transduced with single HLA molecules. Eighty percent of T-cell lines and 45% of virus-specific T-cell clones were shown to cross-react against allo-HLA molecules. The cross-reactivity of the CD8 and CD4 T-cell clones was directed primarily against HLA class I and II, respectively. However, a restricted number of CD8 T cells exhibited cross-reactivity to HLA class II. T-cell receptor (TCR) gene transfer confirmed that allo-HLA reactivity and virus specificity were mediated via the same TCR. These results demonstrate that a substantial proportion of virus-specific T cells exert allo-HLA reactivity, which may have important clinical implications in transplantation settings as well as adoptive transfer of third-party virus-specific T cells.
ORIGINAL ARTICLE: The reliability of long and short cases undertaken as practice for a summative examination
Publisher: Wiley
Date: 08-2010
DOI: 10.1111/J.1445-5994.2009.01970.X
Abstract: This study explores whether long and short cases performed in the workplace during training could be integrated into an overall summative assessment. Less examiner training and a less formalized structure might compromise reliability, but increased testing time might improve it. Results of practice long and short cases, undertaken in preparation for the Royal Australasian College of Physicians clinical examination, were compared with actual examination results. The effects on reliability of the examination were compared by modelling varying combinations of practice and examination long and short cases. Fifty-nine candidates in two centres undertook 256 practice long cases and 154 practice short cases. Two practice long cases correlated with two examination long cases (r= 0.46). The reliability of a single long case was 0.22 under practice conditions and 0.36 under examination conditions. The reliability of a single short case was similar under either condition (0.18 vs 0.21). Reliability of over 0.80 could be achieved by assimilating two examination long cases and four examination short cases with varying combinations of seven practice cases. Long cases undertaken in the workplace are not as reliable those undertaken under examination conditions, but short cases have similar reliability under either condition.
Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules
Publisher: The American Association of Immunologists
Date: 15-11-2012
Abstract: Viral infection is a major cause of morbidity and mortality, and there are few therapeutic options available to augment a virus-specific T cell response. Although allo-HLA cross-reactivity from virus-specific memory T cells is common, it is unclear whether priming with specific allogeneic cells could conversely elicit a viral peptide/self-HLA restricted cytotoxic T cell response in humans. First, we used the previously described allo-HLA-B*44:02 cross-reactivity of EBV peptide/HLA-B8 restricted T cells, to determine whether allogeneic HLA stimulation can elicit a cytolytic immune response against EBV. HLA-B8+ HLA-B44− EBV-seropositive PBMCs were stimulated with either HLA-B*44:02+ or HLA-B*44:03+ mismatched irradiated PBMCs in a 7–10 d MLR. The allo-HLA stimulated responder cells were then evaluated for cytotoxicity using EBV peptide loaded autologous target cells and unloaded HLA-B8+ EBV LCL target cells. PBMCs from EBV-seropositive donors gained EBV-specific cytolytic effector function following specific allo-HLA stimulation. Finally, we also elicited cytolytic CMV-specific responses using specific allogeneic cell stimulation, to confirm that this technique can be used to elicit viral peptide/self-HLA restricted responses even from nonpublic TCR responses. Allogeneic cell stimulation used as a cell therapy may be a potential tool to augment an antiviral T cell response in patients with EBV or CMV infection.
Optimizing adherence to advice from antimicrobial stewardship audit and feedback rounds
Publisher: Informa UK Limited
Date: 05-06-2017
Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods
Publisher: Impact Journals, LLC
Date: 02-2018
Nanopore sequencing data analysis using Microsoft Azure cloud computing service
Publisher: Public Library of Science (PLoS)
Date: 02-12-2022
DOI: 10.1371/JOURNAL.PONE.0278609
Abstract: Genetic information provides insights into the exome, genome, epigenetics and structural organisation of the organism. Given the enormous amount of genetic information, scientists are able to perform mammoth tasks to improve the standard of health care such as determining genetic influences on outcome of allogeneic transplantation. Cloud based computing has increasingly become a key choice for many scientists, engineers and institutions as it offers on-demand network access and users can conveniently rent rather than buy all required computing resources. With the positive advancements of cloud computing and nanopore sequencing data output, we were motivated to develop an automated and scalable analysis pipeline utilizing cloud infrastructure in Microsoft Azure to accelerate HLA genotyping service and improve the efficiency of the workflow at lower cost. In this study, we describe (i) the selection process for suitable virtual machine sizes for computing resources to balance between the best performance versus cost effectiveness (ii) the building of Docker containers to include all tools in the cloud computational environment (iii) the comparison of HLA genotype concordance between the in-house manual method and the automated cloud-based pipeline to assess data accuracy. In conclusion, the Microsoft Azure cloud based data analysis pipeline was shown to meet all the key imperatives for performance, cost, usability, simplicity and accuracy. Importantly, the pipeline allows for the on-going maintenance and testing of version changes before implementation. This pipeline is suitable for the data analysis from MinION sequencing platform and could be adopted for other data analysis application processes.
Autosomal recessive transmission of TRAPS in a family with a novelTNFRSF1Amutation
Publisher: Informa UK Limited
Date: 06-03-2015
Allogeneic hematopoietic stem cell transplantation recipients have defects of both switched and IgM memory B cells
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BBMT.2008.11.024
Abstract: Allogeneic hematopoietic stem cell transplant (HSCT) recipients were assessed to elucidate memory B cell defects underlying their increased susceptibility to infections, particularly by encapsulated bacteria. Circulating IgM memory B cells (CD19+, CD27+, IgM+) and switched memory B cells (CD19+, CD27+, IgM(-)) were enumerated in allogeneic HSCT recipients (n = 37) and healthy controls (n = 35). T lymphocyte subpopulations and serum levels of immunoglobulins, including IgG subclasses, and antibodies to pneumococcal polysaccharides were also assayed. Allogeneic HSCT recipients were deficient in both switched memory and IgM memory B cells compared to healthy controls (both P < .0001), irrespective of time post-HSCT. Switched memory B cell deficiency correlated with CD4+ T cell deficiency, and both correlated with serum levels of IgG1 (P < .0001), possibly reflecting impaired B cell isotype switching in germinal centres. "Steady-state" serum levels of antibodies to pneumococcal polysaccharides did not correlate with circulating memory B cells. Graft-versus-host disease (GVHD) was associated with lower IgM memory B cell counts and lower serum levels of IgG2, IgG4, IgA, and pneumococcal antibodies. The increased susceptibility of allogeneic HSCT patients to infection may reflect a combination of memory B cell defects, which are most common in patients with a history of GVHD.
Related Organisations
American Society For Histocompatibility And Immunogenetics
Location: United States of America
Related Funding Activities
No related grants have been discovered for Lloyd J. D'Orsogna.