ORCID Profile
0000-0001-8206-1939
Current Organisations
University of Adelaide
,
Women's and Children's Hospital
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Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1038/KI.2013.538
Abstract: High regulatory T-cell (Treg) numbers predict recurrent cutaneous squamous cell carcinoma in kidney transplant recipients, and the Treg immune phenotype may identify kidney transplant recipients at risk of developing squamous cell carcinoma and/or solid-organ cancer. To investigate this, a total of 116 kidney transplant recipients, of whom 65 had current or past cancer, were immune-phenotyped and followed up prospectively for a median of 15 months. Higher Treg (CD3+CD4+FOXP3+CD25(Hi)CD127(Lo)) proportion and numbers significantly increased the odds of developing cancer (odds ratios (95% CI) 1.61 (1.17-2.20) and 1.03 (1.00-1.06), respectively) after adjusting for age, gender, and duration of immunosuppression. Class-switched memory B cells (CD19+CD27+IgD-) had a significant association to cancer, 1.04 (1.00-1.07). Receiver operator characteristic (ROC) curves for squamous cell carcinoma development within 100 days of immune phenotyping were significant for Tregs, memory B cells, and γδ T cells (AUC of 0.78, 0.68, and 0.65, respectively). After cancer resection, Treg, NK cell, and γδ T-cell numbers fell significantly. Immune-phenotype profiles associated with both squamous cell carcinoma and solid-organ cancer in kidney transplant recipients and depended on the presence of cancer tissue. Thus, immune profiling could be used to stratify kidney transplant recipients at risk of developing cancers to identify those who could qualify for prevention therapy.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.HUMIMM.2016.08.009
Abstract: Angiotensin II type 1 antibodies (AT1Rab) can mediate antibody mediated rejection (AMR). Pre transplant AT1Rab levels, and risk of rejection were assessed in Kidney Transplant Recipients (KTR) transplanted in our centre from 2013 to 2014 (n=145). 14/145 (9.7%) KTR experienced antibody mediated rejection (AMR). The Hazard Ratio for AMR=3.7 [95% CI 2-26] (p=0.009) for KTR with AT1Rab levels >17.5U/ml. 6/11 of KTR with levels >25U/ml experienced AMR. In 2015 (n=80) KTR were transplanted and 6/80 KTR experienced rejection (2 AMR and 4 TCMR with vascular lesions). 7/80 of KTR had AT1Rab 17.5-25U/ml and none experienced rejection and were induced with ATG and candesartan. 7/80 had AT1Rab 25-40U/ml and received pre and post-operative plasma exchange, ATG and candesartan and 1/7 experienced TCMR with a vascular lesion. This perioperative regimen may alter the risk of rejection in patients with high levels of AT1Ab and further studies are needed.
Publisher: Oxford University Press (OUP)
Date: 23-06-2015
DOI: 10.1002/STEM.2075
Abstract: Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25− T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application. Stem Cells 2015 :2850–2863 Video Highlight: youtu.be/gP6GONfRP80
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2021
DOI: 10.1101/2021.07.30.21261234
Abstract: Increasing evidence suggests immune dysregulation in in iduals recovering from SARS- CoV-2 infection. We have undertaken an integrated analysis of immune responses at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 in iduals recovering from mild, moderate, severe, or critical COVID-19. Anti-Spike and anti-RBD IgG responses were largely stable up to 24wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3 + monocytes) and adaptive immune populations (T helper, T follicular helper and regulatory T cells) in COVID-19 convalescents compared to healthy controls, which were most strongly evident at 12 and 16wpi. RNA sequencing suggested ongoing immune and metabolic dysregulation in convalescents months after infection. Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some in iduals.
Publisher: Baishideng Publishing Group Inc.
Date: 2015
DOI: 10.5527/WJN.V4.I1.41
Publisher: The American Association of Immunologists
Date: 08-2019
Abstract: Regulatory T cells (Tregs) are essential for maternal tolerance in allogeneic pregnancy. In preecl sia, Tregs are fewer and display aberrant phenotypes, particularly in the thymic Treg (tTreg) compartment, potentially because of insufficient priming to male partner alloantigens before conception. To investigate how tTregs as well as peripheral Tregs (pTregs) respond to male partner seminal fluid, Foxp3+CD4+ Tregs were examined in the uterus and uterus-draining lymph nodes in virgin estrus mice and 3.5 d postcoitum. Mating elicited 5-fold increases in uterine Tregs accompanied by extensive Treg proliferation in the uterus-draining lymph nodes, comprising 70% neuropilin 1+ tTregs and 30% neuropilin 1− pTregs. Proliferation marker Ki67 and suppressive competence markers Foxp3 and CTLA4 were induced after mating in both subsets, and Ki67, CTLA4, CD25, and GITR were higher in tTregs than in pTregs. Analysis by t-stochastic neighbor embedding confirmed phenotypically distinct tTreg and pTreg clusters, with the proportion of tTregs but not pTregs among CD4+ T cells expanding in response to seminal fluid. Bisulphite sequencing revealed increased demethylation of the Treg-specific demethylation region in the Foxp3 locus in tTregs but not pTregs after mating. These data show that tTregs and pTregs with distinct phenotypes both respond to seminal fluid priming, but the Foxp3 epigenetic signature is uniquely increased in tTregs. We conclude that reproductive tract tTregs as well as pTregs are sensitive to local regulation by seminal fluid, providing a candidate mechanism warranting evaluation for the potential to influence preecl sia susceptibility in women.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1038/KI.2015.237
Publisher: Frontiers Media SA
Date: 29-07-2015
DOI: 10.1111/TRI.12638
Abstract: Few data exist on how immunosuppression is altered in kidney transplant recipients (KTR) following a diagnosis of cancer. This study investigated how immunosuppression was altered in KTR after cancer diagnosis and its effect on patient and graft survival. All KTR diagnosed with cancer at our centre from 1990 to 2012 were assessed. Drug regime and serum creatinine levels were recorded 1 year before, at time of, and 1 year after cancer diagnosis. Of 87 KTR who developed cancer (7.3% of transplanted population, n = 1189), 30 developed haematological malignancies and 57 developed solid organ cancers (SOC). In total, 38% of KTR presented with nodal or metastatic disease and 23 of 87 (26%) KTR died within 6 months of cancer diagnosis. Fifty-five KTR had records of pre- and postcancer diagnosis drug regimes. Thirty-six KTR had a (>50%) dose reduction or cessation of 1 or more immunosuppressive agents, and 19 no reduction in immunosuppression. In total, 2 of 36 (6%) of KTR who underwent a dose reduction suffered acute rejection that was reversed with methylprednisolone. Dose reduction/cessation of immunosuppression did not impair graft function, but also did not affect cancer free survival. Further larger prospective studies are needed to determine whether dose reduction alters relapse free cancer survival in KTR.
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2021
DOI: 10.1101/2021.11.08.21266035
Abstract: The duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination. Serum and PBMC were collected from mild-COVID-19 convalescents at ∼6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens. At 12 months after mild-COVID-19, % of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in % of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4 + and 0.11-0.35% in CD8 + T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike ‘high-responder’ convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected. SARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses. This work was funded by project grants from The Hospital Research Foundation and Women’s and Children’s Hospital Foundation, Adelaide, Australia. MGM is THRF Early Career Fellow. BGB is THRF Mid-Career Fellow. This project has been supported partly with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.S. and Contract No. 75N9301900065 to A.S, D.W. We regularly searched on PubMed and Google Scholar in June-October 2021 using in idual or combinations of the terms “long-term immunity”, “SARS-CoV-2”, “antigenic breadth”, “variant of concern” and “COVID-19”. We found studies that had assessed immune correlates at multipe time points after COVID-19 disease onset in convalescents, but not the antigenic breadth of T cells and antibodies and not in relation to VoC. Other immune studies in virus naive vaccinees, or vaccinated convalescents evaluated VoC-specific immunity, but not in convalescents that have not been vaccinated. In summary, we could not find long-term studies providing and in-depth evaluation of functionality of humoral and cell-mediated immunity, combined with addressing the adaptability of these immune players to VoC. The window of opportunity to conduct studies in COVID-19 convalescents (i.e. natural immunity to SARS-CoV-2) is closing due to mass vaccination programs. Here, in a cohort of unvaccinated mild-COVID-19 convalescents, we conducted a comprehensive, longitudinal, long-term immune study, which included functional assays to assess immune fitness against antigenically different VoC. Importantly, the cohort resided in a SARS-CoV-2-free community for the duration of the study with no subsequent re-exposure or infection. Our findings reveal a deeply weakened humoral response and functional vulnerability of T cell responses to VoC Spike antigens. This study provides a valuable snapshot of the quality of SARS-CoV-2 natural immunity and its durability in the context of a pandemic in which new variants continuously emerge and challenge pre-existing immune responses in convalescents and vacinees. Our results serve as a warning that delays in vaccination programs could lead to an increase in re-infection rates of COVID-19 convalescents, caused by virus variants that escape humoral and cell-mediated immune responses. Furthermore, they reinforce the potential benefit of booster vaccination that is tuned to the active variants.
Location: Australia
No related grants have been discovered for Christopher M. Hope.