Prue Hart - Academia.edu (original) (raw)

Papers by Prue Hart

PubMed, Mar 1, 1989

There have been suggestions that the production of pro-inflammatory mediators by human monocytes ... more There have been suggestions that the production of pro-inflammatory mediators by human monocytes in response to interferon-gamma (IFN-gamma) may be controlled by changes in prostaglandins. Therefore we investigated tumour necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) activities and prostaglandin E2 (PGE2) levels in the supernatants of highly purified human monocytes cultured for 18 hr with recombinant human IFN-gamma. IFN-gamma (100 U/ml) did not stimulate monocytes isolated by counter-current centrifugal elutriation for detectable TNF alpha or IL-1 activities, or PGE2 production. However, IFN-gamma synergistically enhanced lipopolysaccharide (LPS)-induced TNF alpha and IL-1 activities. In contrast, there was no consistent change in PGE2 levels upon addition of IFN-gamma to LPS-treated monocyte cultures. The TNF alpha and IL-1 activities induced by LPS and by LPS with IFN-gamma were reduced by PGE2, and stimulated by indomethacin. As reported previously for IL-1 activities, the regulation by cyclo-oxygenase products of TNF alpha activities reflected predominantly a control of the production of immunoreactive TNF alpha, rather than the measurement of TNF alpha bio-activity. However, the addition of indomethacin or PGE2 to monocyte cultures did not change the extent of IFN-gamma synergy with LPS for increased TNF alpha and IL-1 activities. The results of this study suggest that, despite control by cyclo-oxygenase products of TNF alpha and IL-1 production in human monocytes, IFN-gamma may enhance TNF alpha and IL-1 activities independently of this regulatory mechanism. These findings are contrary to those suggested for the regulation by prostanoids of IL-1 production by murine macrophages.

Journal of Immunology, Sep 1, 1988

TNF-a and IL-1 activities and PGEz levels were investigated in the supernatants of highly purifie... more TNF-a and IL-1 activities and PGEz levels were investigated in the supernatants of highly purified human monocytes cultured for 18 h with recombinant human granulocyte-macrophage CSF (GM-CSF). GM-CSF alone did not stimulate I C 1 or TNF-a activities or the production of PGE2. GM-CSF with IFN-y, but not with LPS, consistently activated the monocytes for TNF-a activity. In contrast, for increased IL-1 activity, GM-CSF synergized weakly and irregularly with LPS. but not at all with IFN-y. For the third monocyte product investigated, GM-CSF was a weak and inconsistent inducer of PGEz and only in the co-presence of IFN-y. Thus, GM-CSF can elicit different responses in human monocytes depending both on the co-stimulus as well as the monocyte product being investigated. CSF control the proliferation and differentiation in vitro of hematopoietic progenitor cells (1, 2); GM-CSF3 stimulates the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages (1, 2). More recently, it has been reported that CSF can also functionally activate mature cells of the appropriate lineage and much attention has been paid to activation studies of human neutrophils by GM-CSF. Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to major physiologic chemoattractants (3). enhances neutrophil cytotoxic activity against antibody-coated targets (4). and increases their phagocytic properties (4). A receptor on human monocytes for GM-CSF has been identified and its binding characteristics reported (5). However, there have been few reports of activation of human monocytes by GM-CSF. Grabstein and co-workers (6) have shown increased tumoricidal activity by monocytes incubated with GM-CSF for 24 h; their report stressed that, unlike for IFN-y-induced tumoricidal activ

Proceedings of the National Academy of Sciences of the United States of America, May 1, 1989

Stimulated human monocytes/macrophages are a source of mediators such as tumor necrosis factor a ... more Stimulated human monocytes/macrophages are a source of mediators such as tumor necrosis factor a (TNF-a), interleukin 1 (IL-1), and prostaglandin E2 (PGE2), which can modulate inflammatory and immune reactions.

Nature Reviews Immunology, Aug 29, 2019

Fabis-Pedrini, M.J., Kuhle, J., Michalak, Z., Walters, S., Trend, S., Jones, A.P., Carroll, W.M., Lucas, R., Hart, P.H. and Kermode, A.G. <https://researchrepository.murdoch.edu.au/view/author/Kermode, Allan.html> (2019) Serum neurofilament light chain levels among patients with clinically isolat..., 2019

Clinical & translational immunology, 2020

Objectives. At the end of a 60-day course of narrowband UVB phototherapy, administered to individ... more Objectives. At the end of a 60-day course of narrowband UVB phototherapy, administered to individuals with early multiple sclerosis, there were changes in the relative proportions of circulating B-cell subsets. This study investigated phototherapyassociated changes to cytokine responses of B cells when exposed to a TLR7 ligand. Methods. PBMCs from participants of the PhoCIS (Phototherapy for Clinically Isolated Syndrome) trial taken before (day 1) and after phototherapy for 8 weeks (day 60) were incubated with, or without, the TLR7 ligand, R848, for 18 h. Production of TNF and IL-10 in seven B-cell subsets was examined, with cytokine responses in each individual at day 60, adjusted for responses at day 1. Paired PBMCs were from participants administered phototherapy (n = 7) or controls (n = 6). Results. At day 60, significantly fewer B cells, particularly marginal zone-like B cells (CD27 + /IgD +), from participants administered phototherapy produced TNF in response to TLR7 stimulation. When responses by seven B-cell subsets were analysed together using multivariate methods, a phototherapy-specific signature was observed. An increased responsiveness from day 1 to day 60 in IgM-only memory B cells (CD27 + /IgD À /IgM +) after TLR7 stimulation also predicted slower progression from CIS to MS. Phototherapy was without significant effect on B-cell IL-10 production. Conclusions. Reduced TNF responses after TLR7 stimulation in marginal zonelike B cells from participants administered phototherapy suggested treatment-associated priming effects that were detected upon subsequent polyclonal B-cell activation. Changes in responsiveness to TLR7 stimulation also suggested that IgM-only memory B cells may be important in conversion from CIS to MS.

Frontiers in digital health, Mar 23, 2021

Despite education about the risks of excessive sun exposure, teenagers in Australia are sun-seeki... more Despite education about the risks of excessive sun exposure, teenagers in Australia are sun-seeking, with sunburn common in summer. Conversely, some regular (time-limited) exposure to sunlight (that avoids sunburn) is necessary for vitamin D and healthy bones and other molecules important for immune and metabolic health. New interventions are thus required to better support teenagers to make healthy and balanced decisions about their sun behaviors. This paper describes the development of a prototype online tool-a smartphone app-that aimed to foster safe sun practices in teenagers. We recruited young adolescents (aged 12-13 years, n = 24) as "co-researchers" to provide ongoing input into the nature and design of the online tool. This age group was selected, as it is a critical time when young people transition from primary education, where "SunSmart" behaviors are entrenched in Australian schools, to high school, where risky behaviors emerge. Through a series of interviews and workshops, we codesigned an Apple iOS smartphone app with the co-researchers, leading health promotion professionals, researchers, and app designers. The developed app, Sun Safe, contains educational content relevant to teenagers about safe sun behaviors, complemented by other features requested by co-researchers and stakeholders to help engage young people, including gamified quizzes to test their sun health knowledge, real-time weather data on the UV Index and temperature, a sunscreen application timer, and reminders to check the UV Index. The developed prototype app was rated well by co-researchers, suggesting it is suitable for further feasibility and efficacy testing as an intervention tool to improve knowledge and promote safe sun behaviors by young adolescents.

Brain and behavior, Jan 27, 2022

ObjectiveTo determine whether serum neurofilament light chain (sNfL) levels are suppressed in pat... more ObjectiveTo determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB‐PT).MethodssNfL levels were measured using a sensitive single‐molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB‐PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes.ResultsBaseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7–161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2–212.2) than in HC (10.7 pg/ml [IQR] 4.9–21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB‐PT in the first 3 months (UVB‐PT −10.6% vs non‐UVB‐PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall.ConclusionsOur findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro‐axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB‐PT.

Clinical and Experimental Immunology, Nov 2, 2016

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmun... more Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MSassociated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4 1 and CD8 1 T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.

The Journal of Steroid Biochemistry and Molecular Biology, Nov 1, 2019

Highlights:  Saliva could be a non-invasive way to measure vitamin D status  Differences betwee... more Highlights:  Saliva could be a non-invasive way to measure vitamin D status  Differences between collection methods normalised by adjusting for VDBP  Centrifugation both prior to and following thawing samples is essential  Strongest correlation with serum 25(OH)D was via passive collection over 3 days  Adjusting for flow rate improves the linear correlation (serum and saliva 25(OH)D)

Immunology and Cell Biology, May 20, 2021

Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While i... more Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC)which give rise to DCsin bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the 'whitening' effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.

Annals of the American Thoracic Society, Oct 1, 2014

Frontiers in Neurology, Feb 3, 2022

The immunological mechanisms that contribute to multiple sclerosis (MS) differ between males and ... more The immunological mechanisms that contribute to multiple sclerosis (MS) differ between males and females. Females are 2-3 times more likely to develop MS compared to males, however the reason for this discrepancy is unknown. Once MS is established, there is a more inflammatory yet milder form of disease in females whereas males generally suffer from more severe disease and faster progression, neural degradation, and disability. Some of these differences relate to genetics, including genetic control of immune regulatory genes on the X-chromosome, as well as immune modulatory properties of sex hormones. Differences in MS development may also relate to how sex interacts with environmental risk factors. There are several environmental risk factors for MS including late-onset Epstein Barr virus infection, low serum vitamin D levels, low UV radiation exposure, smoking, obesity, and lack of physical activity. Most of these risk factors impact males and females differently, either due to biological or immunological processes or through behavioral differences. In this review, we explore these differences further and focus on how the interaction of environmental risk factors with sex hormones may contribute to significantly different prevalence and pathology of MS in males and females.

American Journal of Physiology-lung Cellular and Molecular Physiology, Sep 1, 2016

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophy... more Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

Experimental Hematology, Dec 1, 2017

Number of Tables: 1 Number of References: 21 Monocytes/macrophages differentiating from bone marr... more Number of Tables: 1 Number of References: 21 Monocytes/macrophages differentiating from bone marrow cells pulsed for 2 hours at 37 o C with a stabilised derivative of prostaglandin E 2 , 16,16-dimethyl PGE 2 (dmPGE 2), migrated less efficiently towards a chemoattractant than monocytes/macrophages differentiated from bone marrow cells pulsed with vehicle. To confirm that the effect on bone marrow cells was long-lasting and to replicate human bone marrow transplantation, chimeric mice were established with donor bone marrow cells pulsed for 2 hours with dmPGE 2 before injection into marrow-ablated congenic recipient mice. After 12 weeks and confirmed numericallysimilar engraftment of donor cells as 90% of haematopoietic cells in peripheral organs, monocytes/macrophages differentiating in vitro or in vivo from the bone marrow of reconstituted recipient mice migrated inefficiently towards the chemokines, CSF-1 and CCL2, or thioglycollate, respectively. Results suggest long lasting changes to progenitor cells of monocytes/macrophages by a 2 hour dmPGE 2 pulse that, in turn, limits the migration of their daughter cells to chemoattractants and inflammatory mediators.

PubMed, Sep 1, 1990

Urokinase-type plasminogen activator (u-PA), tumour necrosis factor-alpha (TNF-alpha) and interle... more Urokinase-type plasminogen activator (u-PA), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) activities were measured for highly purified human monocytes cultured for 18 hr with recombinant human interleukin-3 (IL-3). IL-3 alone stimulated monocyte u-PA activity, but not TNF-alpha or IL-1 activity. However, IL-3, together with interferon-gamma (IFN-gamma), stimulated the TNF-alpha, but not IL-1, activities of monocytes from several donors. In parallel cultures, granulocyte-macrophage colony-stimulating factor (GM-CSF) behaved similarly. IL-3, like GM-CSF, synergized weakly and sometimes irregularly with lipopolysaccharide (LPS) for increased TNF-alpha and IL-1 activities. Thus, IL-3 can selectively stimulate monocyte mediator production depending on the costimulus present; however, the stimulatory properties of IL-3 vary from those of IFN-gamma and IL-4. The similarities in activity between IL-3 and GM-CSF may be explained by a common or associated IL-3/GM-CSF receptor(s), as suggested by biochemical studies.

Journal of Gastroenterology and Hepatology, Sep 1, 1996

Very few women have professorial status in Australian medical schools. However, there are approxi... more Very few women have professorial status in Australian medical schools. However, there are approximately equal numbers of male and female PhD students in biomedical research at Australian universities. At Flinders University of South Australia, females comprise approximately 25% of academics in the School of Medicine, with 75% of general staff (including research staff without academic status, e.g. research assistants, research officers) being female. Females comprise 29% of Fellows in the highly competitive Career Awards Scheme of the National Health and Medical Research Council of Australia (NHMRC; 26% excluding those of the lowest rank, namely RD Wright Fellows). In both systems, a higher percentage of women are appointed to the lower levels. The statistics suggest that the main hurdle for women in medical research is the inability to progress in the postdoctoral ranks (e.g. appointment to, or promotion from, academic Level A/B positions (TutorLecturer) or appointment to the NHMRC Research Fellowships Scheme). This may reflect the conflicts that women face in their debate of the priorities of family (children and partner) versus career, or research versus teaching and professional activities. All medical research is time-demanding and continuing research funds are difficult to obtain. Women and men have similar success rates for obtaining funds from the NHMRC. However, a greater percentage of women academics do not apply for grants. Why? Can women be helped to play a larger role in medical research?

Immunology, Nov 6, 2019

The majority of human vaccines are administered above the deltoid muscle of the arm, a site that ... more The majority of human vaccines are administered above the deltoid muscle of the arm, a site that is chronically sun-exposed in many people. It is known that exposure of the skin to the UV wavelengths in sunlight stimulates systemic immunosuppression, an outcome that is associated with reduced immunity to microbial infections in animal models. Here we consider whether immunization of humans through a UV-irradiated skin site will lead to a less effective immune response compared with immunization through an unexposed site. Studies showing that the efficacy of vaccination can be reduced when surrogates of increased levels of sun exposure, such as latitude of residence and season of the year, are considered. Results from a limited number of intervention experiments in humans demonstrate a similar pattern. To provide an explanation for these findings, changes in the number and functional potential of immune cells in chronically sun-exposed compared with unexposed skin are outlined. UV radiation-induced changes to skin cells are also relevant when considering skin sites for administration of immune-tolerizing peptides. The review provides the basis for further research into the effects of acute and chronic UV radiation exposure on skin cells in the context of vaccination.

American Journal of Obstetrics and Gynecology, Dec 1, 2004

Preterm birth Polymorphism Cytokine Premature rupture of membranes Mannose-binding protein C Obje... more Preterm birth Polymorphism Cytokine Premature rupture of membranes Mannose-binding protein C Objective: The purpose of this study was to examine the relationship between preterm birth and 22 single nucleotide polymorphisms in genes that encode cytokines and mediators of apoptosis and host defense. Study design: Two hundred two white women with a spontaneous preterm birth of !35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and sequence specific primers. Multivariable analyses included demographic and genetic variables. Results: Alcohol (multivariable odds ratio, 2.3; P = .001] and substance use (multivariable odds ratio, 3.7; P = .01) were associated with preterm birth at !35 weeks of gestation. Smoking (multivariable odds ratio, 2.3; P = .03), haplotypes IL10 e1082A/e819T/e592A (multivariable odds ratio, 2.1; P = .04), tumor necrosis factor (TNF)C488A/e238G/e308G (multivariable odds ratio, 2.4; P = .04), and IL4 e509C/C (multivariable odds ratio, 3.4; P = .02), and the presence of MBL2 codon 54Asp (multivariable odds ratio, 2.3; P = .02) were associated independently with preterm birth at !29 weeks of gestation. Homozygosity for IL10 e1082G/ e819C/e592C haplotype (multivariable odds ratio, 1.9; P = .02) was more common in women with preterm premature rupture of membranes.