ORCID Profile
0000-0002-5193-3404
Current Organisation
Murdoch University
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Systems Physiology | Medical Physiology | Systems Biology | Crop and Pasture Biochemistry and Physiology
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Publisher: Springer Science and Business Media LLC
Date: 02-09-2013
DOI: 10.1038/PR.2013.145
Abstract: Deficiencies in phagocytosis may contribute to the increased susceptibility of infants to early life infections. Data on phagocytosis of the major neonatal pathogens Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Escherichia coli (EC) by preterm infant leukocytes are inconsistent. Cord and <24-h peripheral blood were collected from very preterm (<30.1 wks gestational age (GA)) and term (37-42 wks GA) infants. Monocyte and neutrophil phagocytosis of pHrodo-labeled SE, SA, and EC were analyzed using a small-volume flow cytometry assay, with simultaneous characterization of surface activation marker expression. Preterm infants had lower proportions of monocytes and neutrophils capable of phagocytosis than term infants, but preterm infant phagocytes had higher phagocytic capacity. Phagocytosis was strongly correlated between cord and <24-h peripheral blood. Supplementation with exogenous complement significantly increased phagocytosis of EC but not of SE or SA. Monocyte human leukocyte antigen (HLA)-DR expression was lower in preterm infants but did not correlate with phagocytosis. There is no defect in phagocytosis by monocytes and neutrophils from preterm compared with term infants, although preterm infants possess fewer phagocytes, possibly contributing to susceptibility to bacterial infection. Further investigation into the development of postnatal phagocytic competence is warranted.
Publisher: CSIRO Publishing
Date: 2016
DOI: 10.1071/AN15085
Abstract: Functional deficiencies of the immune system are known to predispose human and animal neonates to death. Thus, immune competency may be a significant factor influencing the mortality of lambs. Vitamin D has been recognised to improve immune function and is transferred across the placenta. This study tested the hypotheses that (1) supplementation of Merino ewes with cholecalciferol during late pregnancy will increase the concentrations of vitamin D in the ewe and lamb at birth and (2) supplementation of Merino ewes with cholecalciferol during late pregnancy is correlated with an increase in innate phagocytic and adaptive antibody immune responses in the lamb. Merino ewes (n = 53) were injected intramuscularly with 1 × 106 IU cholecalciferol at Days 113 and 141 of pregnancy. A control group (n = 58) consisted of ewes receiving no additional nutritional treatments. The vitamin D status of ewes and lambs was assessed up until 1 month post-lambing. Lamb immune function was assessed by analysing the functional capacity of phagocytes, and the plasma IgG and anti-tetanus-toxoid antibody concentrations between birth and weaning. Maternal supplementation with cholecalciferol increased the plasma 25(OH)D concentrations of both ewes (137 vs 79 nmol/L P 0.001) and lambs (49 vs 24 nmol/L P 0.001) at birth compared with the controls. Supplementation with cholecalciferol had no significant effect on the phagocytic capacity of monocytes or polymorphonuclear leukocytes, the concentration of IgG in the colostrum or plasma of lambs, or the vaccine-specific antibody response against tetanus toxoid. Overall, the results support our first hypothesis, but suggest that maternal supplementation with 1 × 106 IU cholecalciferol does not improve innate, passive or adaptive immune function in lambs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2007
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/539519
Abstract: Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are critical for the generation of effective cytotoxic T lymphocyte (CTL) responses however, their function and phenotype are often defective or altered in tumor-bearing hosts, which may limit their capacity to mount an effective tumor-specific CTL response. In particular, the manner in which exogenous tumor antigens are acquired, processed, and cross-presented to CD8 T cells by DCs in tumor-bearing hosts is not well understood, but may have a profound effect on antitumor immunity. In this paper, we have examined the role of DCs in the cross-presentation of tumor antigen in terms of their subset, function, migration, and location with the intention of examining the early processes that contribute to the development of an ineffective anti-tumor immune response.
Publisher: Canadian Science Publishing
Date: 12-2018
Abstract: This study examined the effect of 2 forms of exercise on glucose tolerance and the concurrent changes in markers associated with the interleukin (IL)-6 pathways. Fifteen sedentary, overweight males (29.0 ± 3.1 kg/m 2 ) completed 2 separate, 3-day trials in randomised and counterbalanced order. An oral glucose tolerance test (OGTT 75 g) was performed at the same time on each day of the trial. Day 2 of each trial consisted of a single 30-min workload-matched bout of either high-intensity intermittent exercise (HIIE alternating 100% and 50% of peak oxygen uptake) or continuous moderate-intensity exercise (CME 60 % of peak oxygen uptake) completed 1 h prior to the OGTT. Venous blood s les were collected before, immediately after, 1 h after, and 25 h after exercise for measurement of insulin, C-peptide, IL-6, and the soluble IL-6 receptors (sIL-6R soluble glycoprotein 130 (sgp130)). Glucose area under the curve (AUC) was calculated from capillary blood s les collected throughout the OGTT. Exercise resulted in a modest (4.4% p = 0.003) decrease in the glucose AUC when compared with the pre-exercise AUC however, no differences were observed between exercise conditions (p = 0.65). IL-6 was elevated immediately after and 1 h after exercise, whilst sgp130 and sIL-6R concentrations were reduced immediately after exercise. In summary, exercise was effective in reducing glucose AUC, which was attributed to improvements that took place between 60 and 120 min into the OGTT, and was in parallel with an increased ratio of IL-6 to sIL-6R, which accords with an increased activation via the “classical” IL-6 signalling pathway. Our findings suggest that acute HIIE did not improve glycaemic response when compared with CME.
Publisher: American Medical Association (AMA)
Date: 08-2005
Publisher: Springer Science and Business Media LLC
Date: 13-11-2017
DOI: 10.1007/S00109-017-1609-2
Abstract: Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to "immature" innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37-40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-κB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN-genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis.
Publisher: Informa UK Limited
Date: 25-02-2015
Publisher: The American Association of Immunologists
Date: 05-2009
Abstract: Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers. However, for therapy to be effective against a broad range of solid tumor types, it must promote a strong systemic antitumor response that targets metastases in addition to primary tumor. We therefore investigated the potential of locally delivered imiquimod to stimulate an effective systemic antitumor response in a murine model of malignant mesothelioma (AB1-HA) with primary and distal tumors (dual tumor). Persistent delivery of imiquimod into primary tumor significantly retarded tumor growth in all treated mice compared with vehicle control. This local antitumor immune response required both CD8 T cells and NK cells, but not CD4 T cells, and was reliant on type I IFN induction. In vivo CTL studies and Ly6A/E staining of lymphocytes suggested that local imiquimod treatment had indeed induced a systemic, Ag-specific CD8 response. However, notably this response was not sufficient to retard the growth of an untreated distal tumor. Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor. These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
Publisher: Elsevier BV
Date: 2023
Abstract: Tick-borne diseases (TBDs) are a growing global health concern. Despite extensive studies, ill-defined tick-associated pathologies remain with unknown aetiologies. Human immunological responses after tick bite, and inter-in idual variations of immune-response phenotypes, are not well characterised. Current reductive experimental methodologies limit our understanding of more complex tick-associated illness, which results from the interactions between the host, tick, and microbes. An unbiased, systems-level integration of clinical metadata and biological host data - obtained via transcriptomics, proteomics, and metabolomics - offers to drive the data-informed generation of testable hypotheses in TBDs. Advanced computational tools have rendered meaningful analysis of such large data sets feasible. This review highlights the advantages of integrative system biology approaches as essential for understanding the complex pathobiology of TBDs.
Publisher: Wiley
Date: 16-06-1970
DOI: 10.1111/IMCB.12037
Abstract: Preterm infants are uniquely susceptible to late-onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40-70% of preterm pregnancies. Chorioamnionitis alters the risk of late-onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA-seq was performed on purified cord blood monocytes from very preterm infants (<32 weeks gestation, with and without chorioamnionitis-exposure) and term infants (37-40 weeks), pre- and postchallenge with live S. epidermidis. Preterm monocytes from infants without chorioamnionitis-exposure did not exhibit an intrinsically deficient transcriptional response to S. epidermidis compared to term infants. In contrast, chorioamnionitis-exposure was associated with hypo-responsive transcriptional phenotype regarding a subset of genes involved in antigen presentation and adaptive immunity. Overall, our findings suggest that prenatal exposure to inflammation may alter the risk of sepsis in preterm infants partly by modulation of monocyte responses to pathogens.
Publisher: Elsevier BV
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2006
Publisher: SAGE Publications
Date: 31-08-2010
Abstract: Background: In vitro investigations of human innate immune responses to extracellular bacteria commonly utilise killed preparations in preference to live organisms. The effects of the bacterial preparation method on the activation of innate signalling pathways by the common opportunistic pathogen Staphylococcus epidermidis (SE) are unknown. Materials and methods: Mononuclear cell cytokine expression patterns induced by live (LSE), heat-killed (HKSE) and ethanol-killed SE (EKSE) were characterized at the transcriptional and translational level. Toll-like receptor (TLR)-activating capacity of the preparations was analysed using TLR-transfected human embryonic kidney cells. Results: Live SE activated NF-κB, STAT1, type I interferon, and inflammasome pathways. Killed preparations engaged the NF-κB pathway, but had significantly lower capacity to activate other innate immune pathways. Conclusions: Killing of extracellular bacteria has significant qualitative and quantitative effects on key aspects of innate responses in vitro. Interpretation of in vitro data and extrapolation of findings should take into account the potential effects of bacterial preparation and should not assume that responses to killed bacteria are predictive of responses to live organisms.
Publisher: Wiley
Date: 15-12-2015
Abstract: Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.
Publisher: Public Library of Science (PLoS)
Date: 09-04-2010
Publisher: Elsevier BV
Date: 05-2021
Publisher: Public Library of Science (PLoS)
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 16-11-2007
Abstract: Chemotherapy and immunotherapy can be either synergistic or antagonistic modalities in the treatment of cancer. Cytotoxic chemotherapy not only affects the tumor but also targets iding lymphocytes, the very cells that are required to develop an immune response. For this reason, chemo- and immunotherapy have been seen as antagonistic. However, cell death can be immunogenic and the way in which chemotherapeutic drug kills a tumor cell is likely to be an important determinant of how that dying cell interacts with the immune system and whether the interaction will lead to an immune response. When a cell dies as the result of infection, the immune system responds rapidly and the system of Toll-like receptors (TLR) plays a key role in this process. In this review, we will briefly summarize the intracellular signaling pathways that link TLR ligation with immune activation and we will address the questions where and how TLRs recognize their targets.
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2006
DOI: 10.1158/0008-5472.CAN-05-2967
Abstract: This review shows how tumor antigen cross-presentation is affected by the major therapeutic modalities including chemotherapy, radiotherapy, and surgery. We argue that this process could affect the way that a tumor works as its own cellular vaccine, and that it is differentially modulated by the choice of treatment. (Cancer Res 2006 66(2): 601-4)
Publisher: S. Karger AG
Date: 2020
DOI: 10.1159/000509404
Abstract: b i Background: /i /b Preterm infants are at a high risk of developing late-onset sepsis (LOS). Lactoferrin is one of the most abundant endogenous antimicrobial proteins expressed in breast milk, stools, and blood, and a candidate for preventive intervention. Large clinical trials have recently investigated whether enteral supplementation with bovine lactoferrin reduces LOS. b i Aim: /i /b To characterize lactoferrin levels in preterm infants with and without LOS during the first month of life. b i Methods: /i /b Very preterm and term infants were recruited and serial bios les collected during the first month of life. Lactoferrin levels were determined by immunoassay in cord blood and peripheral blood on days 1, 7, 14, 21, and 28 in the stools on days 1 and 28 and in the mother’s breast milk on days 7 and 21. Furthermore, we assessed the capacity of the peripheral blood to release lactoferrin in response to an in vitro challenge with live i Staphylococcus epidermidis /i , lipopolysaccharide, and fibroblast-stimulating lipopeptide 1. b i Results: /i /b Plasma lactoferrin levels were higher in cord blood and day 1 peripheral blood and declined during the first month of life. Plasma lactoferrin levels were similar in term infants and in preterm infants with ( i n /i = 32) and without LOS ( i n /i = 53). i S. epidermidis /i -induced lactoferrin levels were lower following the sepsis episode. b i Conclusions: /i /b Endogenous lactoferrin expression in preterm infants does not appear to affect their risk of developing LOS. These findings are in line with the lack of benefit recently observed in large trials of enteral supplementation with bovine lactoferrin to prevent LOS.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2009
DOI: 10.1007/S00262-008-0628-9
Abstract: Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Public Library of Science (PLoS)
Date: 02-02-2015
Publisher: Informa UK Limited
Date: 10-2012
DOI: 10.4161/ONCI.20924
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000501280
Publisher: Wiley
Date: 29-12-2020
DOI: 10.1002/JMV.26730
Publisher: Wiley
Date: 26-06-2021
DOI: 10.1111/APA.15969
Abstract: Preterm infants are particularly susceptible to bacterial late‐onset sepsis (LOS). Diagnosis by blood culture and inflammatory markers have sub‐optimal sensitivity and specificity and prolonged reporting times. There is an urgent need for more rapid, accurate adjunctive diagnostics in LOS to improve management and minimise antibiotic exposure. We measured the diagnostic performance of secretory phospholipase A2 type IIA (sPLA2‐IIA) in very preterm infants ( weeks gestational age) with suspected LOS. Plasma sPLA2‐IIA levels were elevated in infants with LOS ( n = 28) compared to those without LOS ( n = 21 median 30,970 vs. 2534 pg/ml, p 0.0001). The mean area under the curve was 0.884 (95% CI: 0.771, 0.977) with a sensitivity of 0.907 (95% CI: 0.667, 1.00) and specificity of 0.804 (95% CI: 0.600, 1.00). The positive and negative predictive values were 0.833 (95% CI: 0.664, 0.927) and 0.842 (95% CI: 0.624, 0.945), respectively. This pilot study suggests that sPLA2‐IIA may have clinical utility for the early diagnosis of LOS in very preterm infants, potentially informing clinical management and antibiotic stewardship.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2017
Publisher: Wiley
Date: 18-04-2017
DOI: 10.1111/APA.13826
Abstract: To characterise the secreted and inducible antimicrobial protein and peptide (APP) levels in a prospective cohort of preterm infants (<30 weeks gestational age) with or without Bifidobacterium breve M16V supplementation during the first month of life. We analysed serial bios les of infants who did (n = 13) or did not receive (n = 62) B. breve (3 × 10 Stool, plasma and stimulated blood APP levels changed significantly during the first month of life. Supplementation with B. breve did not affect basal or stimulated APP levels except for a transient increase in inducible BPI. Supplementation with B. breve does not appear to act via modulation of systemic or enteric APP expression in preterm infants although small effects cannot be excluded. Further work with other probiotic preparations is warranted.
Publisher: BMJ
Date: 06-2020
DOI: 10.1136/BMJOPEN-2019-035930
Abstract: The effect of early and sustained administration of daily probiotic therapy on patients admitted to the intensive care unit (ICU) remains uncertain. The Restoration Of gut microflora in Critical Illness Trial (ROCIT) study is a multicentre, randomised, placebo-controlled, parallel-group, two-sided superiority trial that will enrol 220 patients in five ICUs. Adult patients who are within 48 hours of admission to an ICU and are expected to require intensive care beyond the next calendar day will be randomised in a 1:1 ratio to receive early and sustained Lactobacillus plantarum 299v probiotic therapy in addition to usual care or placebo in addition to usual care. The primary endpoint is days alive and out of hospital to day 60. ROCIT has been approved by the South Metropolitan Health Service Human Research Ethics Committee (ref: RGS00000004) and the St John of God Health Care Human Research Ethics Committee (ref: 1183). The trial results will be submitted for publication in a peer-reviewed journal. Australian and New Zealand Clinical Trials Registry (ANZCTR12617000783325) Pre-results.
Publisher: Frontiers Media SA
Date: 29-11-2018
Publisher: Public Library of Science (PLoS)
Date: 26-12-2019
Publisher: Informa UK Limited
Date: 23-06-2011
DOI: 10.3109/14767058.2010.482605
Abstract: Neonates, particularly those born prematurely, are exquisitely vulnerable to life-threatening infections. This increased susceptibility to infection is maintained into childhood. Despite the considerable human and economic cost of infection-related neonatal morbidity and mortality, the mechanisms underlying this heightened susceptibility are only partly understood. It is increasingly recognised that innate immune responses are key to the protection against infection early in life, and emerging data suggest that such responses are deficient in the newborn and especially in preterm infants. Here we review the current understanding of the maturation of the innate immune response in human neonates highlighting the clinical relevance and possible avenues for therapeutic intervention.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Springer Science and Business Media LLC
Date: 10-02-2021
Publisher: Informa UK Limited
Date: 27-07-2016
Publisher: Georg Thieme Verlag KG
Date: 2003
Abstract: Lung disease is the leading cause of morbidity and mortality in in iduals with cystic fibrosis (CF), with P. aeruginosa the main pulmonary infectious agent. Although CF patients can become infected with other microorganisms (such as Burkholderia cepacia complex, Staphylococcus aureus, Haemophilus influenzae, and atypical mycobacteria), P. aeruginosa predominates, eventually infecting approximately 80% of patients. Once established, P. aeruginosa infection usually persists until death. The interaction between the CF host and this opportunistic pathogen is unique and most likely directly contributes to the classical end-stage pathology of CF lung disease. However, the extent to which this constitutes success by the pathogen or failure by the host, or both, is yet to be determined. Many important questions remain regarding host susceptibility, the role of both innate and adaptive immune defenses, bacterial infectivity and transmission, and pathogen virulence factors. Here, we discuss some recent advances toward understanding this complex interaction between host and pathogen and how the interplay influences the CF lung lesion.
Publisher: Public Library of Science (PLoS)
Date: 10-09-2009
Publisher: Elsevier BV
Date: 05-2005
Publisher: Public Library of Science (PLoS)
Date: 02-03-2022
DOI: 10.1371/JOURNAL.PONE.0264768
Abstract: Composition of leukocyte populations in the first month of life remains incompletely characterised, particularly in preterm infants who go on to develop late-onset sepsis (LOS). To characterise and compare leukocyte populations in preterm infants with and without LOS during the first month of life. Single-centre prospective observational cohort study. Infants born weeks gestational age (GA). Peripheral blood s les were collected at 1, 7, 14, 21 and 28 days of life. Leukocyte populations were characterised using 5-fluorophore-6-marker flow cytometry. Absolute leukocyte counts and frequency of total CD45 + leukocytes of each population were adjusted for GA, birth weight z-scores, sex and total leukocyte count. Of 119 preterm infants enrolled, 43 (36%) had confirmed or clinical LOS, with a median onset at 13 days (range 6–26). Compared to infants without LOS, the adjusted counts and frequency of neutrophils, basophils and non-cytotoxic T lymphocytes were generally lower and immature granulocytes were higher over the first month of life in infants who developed LOS. Specific time point comparisons identified lower adjusted neutrophil counts on the first day of life in those infants who developed LOS more than a week later, compared to those without LOS, albeit levels were within the normal age-adjusted range. Non-cytotoxic T lymphocyte counts and/or frequencies were lower in infants following LOS on days 21 and 28 when compared to those who did not develop LOS. Changes in non-cytotoxic T lymphocytes occurred following LOS suggesting sepsis-induced immune suppression.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.CLIM.2006.10.012
Abstract: Human primary immunodeficiencies affecting Toll-like receptor (TLR) signalling reveal a non-redundant role for TLR function in defense against pneumococcal infection. To determine the clinical relevance of TLR abnormalities, we studied a population predicted to be enriched for TLR defects-healthy children who had developed invasive pneumococcal infection in the absence of classic risk factors for infection. We describe the development and optimization of a peripheral blood TLR assay. By testing 38 healthy control neonates, children and adults we demonstrated that TLR function was stable over the first six decades of life. We tested 50 children with a history of invasive pneumococcal infection and although TLR defects were predicted to be over-represented in this population, we did not identify any TLR abnormalities. Although TLR signalling defects are associated with greatly enhanced susceptibility to invasive pneumococcal infection, our results suggest that routine clinical screening for TLR defects in healthy children who develop invasive pneumococcal infection is not justified.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0091-6749(03)01626-9
Abstract: Allergens are frequently found within or attached to particulate material. For ex le, house dust mite fecal pellets (HDMFP) contain the major mite allergens, exposure to which have been implicated in the development of asthma. Although several studies have examined the ability of purified allergens to generate inflammatory responses, few studies have investigated whether HDMFP per se, are biologically active. Our objective was to examine the ability of whole HDMFP to stimulate nitric oxide (NO) release from alveolar macrophages. The rat alveolar macrophage cell line, NR8383, was exposed to HDMFP, Der p 1, or Der p 2, and nitrite levels in the culture supernatants were measured with the Griess reagent. NO synthase mRNA expression was determined by RT-PCR. HDMFP stimulated the production of NO in a dose-dependent and time-dependent manner, with maximum NO levels measured after 48 hours of exposure. Inclusion of polymyxin B did not influence NO production, suggesting that LPS was not responsible for NO production. HDMFP-mediated NO release was down-modulated after treatment with N(G)-nitro-l-arginine methyl ester (L-NAME), dexamethasone, EDTA, and cysteine, but not heat treatment. Inducible nitric oxide synthase mRNA was observed 3 hours after HDMFP exposure, with maximum levels after 48 hours. Both purified Der p 1 and Der p 2 induced NO production, and inhibition of the cysteine protease activity of Der p 1 had little effect on NO production. HDMFP, Der p 1 and Der p 2 are potent inducers of NO. Neither LPS nor the enzymatic activity of Der p 1 was responsible for NO production observed.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.CIMID.2016.04.005
Abstract: Understanding immune function is critical to conserving wildlife in view of infectious disease threats, particularly in threatened species vulnerable to stress, immunocompromise and infection. However, few studies examine stress, immune function and infection in wildlife. We used a flow cytometry protocol developed for human infants to assess phagocytosis, a key component of innate immunity, in a critically endangered marsupial, the woylie (Bettongia penicillata). The effects of stress physiology and Trypanosoma infection on phagocytosis were investigated. Blood and faecal s les were collected from woylies in a captive facility over three months. Trypanosoma status was determined using PCR. Faecal cortisol metabolites (FCM) were quantified by enzyme-immunoassay. Mean phagocytosis measured was >90%. An interaction between sex and FCM influenced the percentage of phagocytosing leukocytes, possibly reflecting the influence of sex hormones and glucocorticoids. An interaction between Trypanosoma status and FCM influenced phagocytosis index, suggesting that stress physiology and infection status influence innate immunity.
Publisher: Oxford University Press (OUP)
Date: 03-1999
DOI: 10.1046/J.1365-2249.1999.00829.X
Abstract: The amount of (1→3)-β- d-glucan in pollen from different plants was evaluated using the Limulus assay with a specific lysate. The amount ranged from 79 to 1800 ng/106 pollen. A calculation of the inhaled dose suggests that the amount of (1→3)-β-d-glucan present during periods with a high pollen content in the air exceeds levels that cause airways inflammation.
Publisher: Public Library of Science (PLoS)
Date: 14-05-2020
Publisher: Public Library of Science (PLoS)
Date: 05-04-2018
Publisher: Elsevier BV
Date: 10-2012
Publisher: Frontiers Media SA
Date: 2013
Publisher: BMJ
Date: 19-09-2008
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.VACCINE.2011.05.054
Abstract: Increased numbers of children presenting with febrile adverse events following trivalent influenza vaccine (TIV) were noted in Australia in 2010. We describe the epidemiology and clinical features of the adverse events and explore the biological basis for the adverse events using an in vitro model. Children presenting to a tertiary paediatric hospital in 2010 with adverse events within 72 h of TIV were retrospectively reviewed. Demographics, clinical features, physiological variables and outcomes were examined. Plasma cytokine and chemokine levels were examined in a subgroup of children with vaccine-related febrile convulsions. Peripheral blood mononuclear cells of age-matched children were stimulated with different TIV preparations. Inflammatory cytokine and chemokine analysis was performed on cultured supernatants. Vaccine-related febrile adverse events were identified in 190 children. Most occurred in healthy children (median age: 1.5 years) within 12 h of vaccination. Twenty-eight (14.7%) required hospital admission. High temperature ≥39.0 °C (101/190 53%), vomiting (120/190 63%) and convulsions (38/190 20%) were common. All children presenting had received Fluvax(®) or Fluvax Junior(®). In the in vitro model, IFN-α, IL-1β, IL-6, IL-10, IP-10 and MIP-1α levels were significantly higher when measured at 6 and 24 h in cultures stimulated with Fluvax(®) compared with alternative 2010 TIV preparations. Numerous febrile adverse events (including febrile seizures) were observed following Fluvax(®) or Fluvax Junior(®) in 2010. Clear differences in cytokine production were observed when peripheral blood mononuclear cells were stimulated with Fluvax(®) compared with alternate TIV preparations. Increased awareness of these potential adverse events is required to ensure earlier detection and prevention in the future.
Publisher: Wiley
Date: 10-11-2017
DOI: 10.1002/IID3.206
Publisher: American Society for Microbiology
Date: 04-2011
DOI: 10.1128/IAI.00535-10
Abstract: Group B streptococcus (GBS) is an important cause of early- and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBS-induced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.
Publisher: Informa UK Limited
Date: 09-2012
DOI: 10.4161/ONCI.20493
Publisher: Public Library of Science (PLoS)
Date: 22-08-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Elsevier BV
Date: 04-2004
Publisher: Springer Science and Business Media LLC
Date: 29-03-2012
DOI: 10.1038/PR.2012.48
Abstract: Staphylococcus epidermidis (SE) rarely causes infection in term infants but is a leading cause of late-onset sepsis in preterm infants. We hypothesized that the innate immune responses to SE in preterm infants are impaired in a gestational age (GA)-dependent manner. Cord and peripheral blood mononuclear cells (MNCs) were stimulated with SE bacteria, and a range of innate immune responses were assessed, including phagocytosis, intracellular killing, Toll-like receptor (TLR) pathway transcriptional activation, cytokine production, TLR2 and TLR4 expression, and cell signaling. Phagocytosis and intracellular killing of SE bacteria were similar in neonatal and adult monocytes. Cytokine gene expression and protein synthesis increased in a GA-dependent manner, which was confirmed at the single-cell level. These GA-related effects were not associated with differences in expression of TLR2 or TLR4, nor with downstream activation of nuclear factor-κB or mitogen-activated protein kinase pathways. The expression of TLRs, phagocytic capacity, and intracellular killing by monocytes develops early in fetal development, whereas the ability to mount a bacteria-induced cytokine response requires further maturation. The functional immaturity of monocyte activation pathways in the preterm infant may underpin their particular susceptibility to sepsis with commensal bacteria.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.JPEDS.2017.01.037
Abstract: To assess whether exposure to histologically confirmed chorioamnionitis (ie, histologic chorioamnionitis [HCA]) is associated with altered risk of infection-related hospitalization (IRH) during the first 24 months of life in very preterm infants. This single-center retrospective cohort study analyzed data on 1218 infants born at <30 weeks gestational age (GA). Semiquantitative placental histology, obstetric, and neonatal data were extracted from hospital databases and linked with discharge diagnoses on rehospitalization until age 24 months from statewide statutory data. The associations between HCA and overall and clinical categories of IRH were analyzed by Cox proportional hazards regression with left-truncated failure times. Mean GA was 27 weeks, and HCA was present in 577 placentas (47.4%). Among the 1088 infants surviving until the birth-related discharge, 684 (62.9%) of had at least 1 IRH by age 24 months, of whom 287 included a diagnosis of acute lower respiratory tract infection (ALRTI). Following adjustment for sex, birth weight z-score, GA, early-onset sepsis, late-onset sepsis, previous antibiotic use, age at birth-related discharge, and chronic lung disease, HCA was associated with a 32% increased risk of hospitalization with ALRTI (HR, 1.32 95% CI, 1.02-1.70 P = .033). There was no association with infection overall or with other infection categories. HCA is associated with a significantly increased risk of hospitalization with ALRTI that is independent of known risk factors, including chronic lung disease.
Publisher: Public Library of Science (PLoS)
Date: 20-07-2015
Publisher: Cambridge University Press (CUP)
Date: 19-02-2016
DOI: 10.1017/S0007114516000234
Abstract: There is a paucity of data on the effect of preterm birth on the immunological composition of breast milk throughout the different stages of lactation. We aimed to characterise the effects of preterm birth on the levels of immune factors in milk during the 1st month postpartum, to determine whether preterm milk is deficient in antimicrobial factors. Colostrum (days 2–5 postpartum), transitional milk (days 8–12) and mature milk (days 26–30) were collected from mothers of extremely preterm ( weeks of gestation, n 15), very preterm (28– weeks of gestation, n 15), moderately preterm (32– weeks of gestation, n 15) and term infants (37–41 weeks of gestation, n 15). Total protein, lactoferrin, secretory IgA, soluble CD14 receptor (sCD14), transforming growth factor- β 2 (TGF- β 2), α defensin 5 (HD5), β defensins 1 (HBD1) and 2, IL-6, IL-10, IL-13, interferon- γ , TNF- α and lysozyme (LZ) were quantified in milk. We examined the effects of lactation stage, gestational age, volume of milk expressed, mode of delivery, parity and maternal infection on milk immune factor concentrations using repeated-measures regression analysis. The concentrations of all factors except LZ and HD5 decreased over the 1st month postpartum. Extremely preterm mothers had significantly higher concentrations of HBD1 and TGF- β 2 in colostrum than term mothers did. After controlling for other variables in regression analyses, preterm birth was associated with higher concentrations of HBD1, LZ and sCD14 in milk s les. In conclusion, preterm breast milk contains significantly higher concentrations of some immune proteins than term breast milk.
Publisher: Springer Science and Business Media LLC
Date: 02-10-2019
Publisher: Wiley
Date: 07-02-2014
DOI: 10.1111/APA.12559
Abstract: To evaluate mononuclear cell expression and function of the cytosolic nucleotide-binding oligomerization domain-containing receptors, NOD1 and NOD2, in very preterm and full-term infants. NOD1 and NOD2 gene and protein expression in very preterm infants, term infants and healthy adult, cord and peripheral blood mononuclear cells (C/PBMC) were quantified using qPCR and flow cytometry. Cytokine responses of purified infant and adult monocytes to NOD1- and NOD2-specific agonists were assessed using a multiplex immunoassay (Bioplex). NOD1 and NOD2 were expressed by a range of infant and adult mononuclear cell types, including T- and B cells, with highest expression in classical (CD14(++) CD16(-) ) and intermediate (CD14(++) CD16(+) ) monocytes. NOD1 and NOD2 expression levels by monocytes from very preterm infant were similar to those in term infants or adults. Monocyte production of TNFα, IL-6 and IL-1β induced by activation of NOD1 and NOD2 was similar between very preterm infants, term infants and adults. Monocyte expression and function of NOD1 and NOD2 in very preterm infants are intact and comparable/equivalent to term infants and adults. Functional deficiencies in monocyte NOD signalling pathways are unlikely to contribute to the increased susceptibility to bacterial sepsis in preterm infants.
Publisher: Frontiers Media SA
Date: 26-07-2018
Publisher: American Society for Microbiology
Date: 21-02-2020
DOI: 10.1128/AAC.02003-19
Abstract: Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis , we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2005
DOI: 10.1158/0008-5472.CAN-05-0328
Abstract: Resection alone is rarely curative for advanced tumors, but the outcome generally improves with adjuvant therapy. We have previously shown that a combination of traditional chemotherapy (gemcitabine) and immunotherapy (anti-CD40/FGK-45) without surgery is synergistic and can lead to long-term cure when applied to small tumors. Such cured animals have immunologic memory and are protected from rechallenge. Here we investigate the effectiveness of combination chemotherapy and immunotherapy after partial or complete surgical debulking of large tumors. We found that complete resection followed by combination chemotherapy/immunotherapy led to a high rate of cure (& %) but failed to induce a long-term, tumor-specific memory. Partial debulking followed by combination therapy elicited the same proportion of cured animals but in contrast to complete resection, a memory response was invoked. We postulate that chemotherapy induced apoptosis of the residual tumor cells following incomplete resection is absolutely required for the induction of long-term immunologic memory.
Publisher: Oxford University Press (OUP)
Date: 21-01-2020
DOI: 10.1093/CID/CIAA063
Abstract: Late-onset sepsis (LOS) with Staphylococcus epidermidis is common in preterm infants, but the immunological mechanisms underlying heightened susceptibility are poorly understood. Our aim is to characterize the ontogeny of cytokine responses to live S. epidermidis in preterm infants with and without subsequent Gram-positive LOS. We conducted a prospective, observational cohort study of preterm infants (& weeks gestational age [GA]) with blood s ling on Days 1, 7, 14, 21, and 28 of life. Cytokine responses in peripheral whole blood stimulated with live S. epidermidis were analyzed by 11-plex immunoassay. Of 129 infants (mean GA, 26.2 weeks mean birth weight, 887g), 23 (17.8%) had confirmed LOS with Gram-positive organisms and 15 (11.6%) had clinical sepsis, with median onsets at 13 and 15 days, respectively. Blood cytokine responses to an in vitro S. epidermidis challenge were similar between infected and uninfected infants on Day 1, but erged thereafter. Infants with subsequent LOS displayed broadly reduced S. epidermidis–induced responses from Day 7 onwards, compared to those who did not develop LOS. This pattern was observed with chemokines (interleukin [IL]-8, monocyte chemotactic protein–1, and macrophage inflammatory protein–1α), pro-inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor–α) and the regulatory cytokine IL-10. Cytokine responses to a live S. epidermidis challenge are impaired in infants with LOS and precede the onset of clinical illness. Quantifying pathogen-specific cytokine responses at Day 7 may identify those high-risk preterm infants at the greatest risk of LOS, and prospective replication is warranted.
Publisher: Public Library of Science (PLoS)
Date: 10-05-2018
Publisher: Hindawi Limited
Date: 11-03-2004
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JPEDS.2016.04.083
Abstract: To compare rates of a composite outcome of mortality or major morbidity in very-preterm/very low birth weight infants between 8 members of the International Network for Evaluating Outcomes. We included 58 004 infants born weighing <1500 g at 24(0)-31(6) weeks' gestation from databases in Australia/New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. We compared a composite outcome (mortality or any of grade ≥3 peri-intraventricular hemorrhage, periventricular echodensity/echolucency, bronchopulmonary dysplasia, or treated retinopathy of prematurity) between each country and all others by using standardized ratios and pairwise using logistic regression analyses. Despite differences in population coverage, included neonates were similar at baseline. Composite outcome rates varied from 26% to 42%. The overall mortality rate before discharge was 10% (range: 5% [Japan]-17% [Spain]). The standardized ratio (99% CIs) estimates for the composite outcome were significantly greater for Spain 1.09 (1.04-1.14) and the United Kingdom 1.16 (1.11-1.21), lower for Australia/New Zealand 0.93 (0.89-0.97), Japan 0.89 (0.86-0.93), Sweden 0.81 (0.73-0.90), and Switzerland 0.77 (0.69-0.87), and nonsignificant for Canada 1.04 (0.99-1.09) and Israel 1.00 (0.93-1.07). The adjusted odds of the composite outcome varied significantly in pairwise comparisons. We identified marked variations in neonatal outcomes between countries. Further collaboration and exploration is needed to reduce variations in population coverage, data collection, and case definitions. The goal would be to identify care practices and health care organizational factors, which has the potential to improve neonatal outcomes.
Publisher: The American Association of Immunologists
Date: 15-12-2009
Abstract: Tumors have evolved multiple mechanisms to evade immune destruction. One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1 B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. However, PD-L1 blockade only marginally affected tumor growth and was associated with the emergence of activated programmed death-1+ ICOS+ CD4 T cells in tumor-draining lymph nodes, whereas few activated CD8 T cells were present. Full activation of antitumor CD8 T cells, characterized as programmed death-1+ ICOS+ Ki-67+ and displaying CTL activity, was only observed when CD4 T cells were depleted, suggesting that a population of suppressive CD4 T cells exists. ICOS+ foxp3+ regulatory T cells were found to be regulated through PD-L1, identifying one potentially suppressive CD4 T cell population. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies.
Publisher: Wiley
Date: 06-2010
Abstract: One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cell-associated tumor antigens to CD8(+) T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c(+) DC. Further analysis revealed that both CD8alpha(+) and CD8alpha(-) DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8alpha(-) DC subset. Therefore LN resident CD8alpha(+) DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2015
Publisher: Oxford University Press (OUP)
Date: 19-06-2017
Abstract: The extreme vulnerability of preterm infants to invasive microbial infections has been attributed to “immature” innate immune defenses. Monocytes are important innate immune sentinel cells critical in the defense against infection in blood. They achieve this via erse mechanisms that include pathogen recognition receptor- and inflammasome-mediated detection of microbes, migration into infected tissues, and differentiation into Mϕs and dendritic cells, initiation of the inflammatory cascade by free radicals and cytokine/chemokine production, pathogen clearance by phagocytosis and intracellular killing, and the removal of apoptotic cells. Relatively little is known about these cells in preterm infants, especially about how their phenotype adapts to changes in the microbial environment during the immediate postnatal period. Overall, preterm monocytes exhibit attenuated proinflammatory cytokine responses following stimulation by whole bacterial or specific microbial components in vitro. These attenuated cytokine responses cannot be explained by a lack of intracellular signaling events downstream of pattern recognition receptors. This hyporesponsiveness also contrasts with mature, term-like phagocytosis capabilities detectable even in the most premature infant. Finally, human data on the effects of fetal chorioamnionitis on monocyte biology are incomplete and inconsistent. In this review, we present an integrated view of human studies focused on monocyte functions in preterm infants. We discuss how a developmental immaturity of these cells may contribute to preterm infants’ susceptibility to infections.
Publisher: Informa UK Limited
Date: 05-2019
Publisher: Elsevier BV
Date: 04-2018
Start Date: 08-2020
End Date: 08-2021
Amount: $620,000.00
Funder: Australian Research Council
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