
Dr Steven Maltby
Research Academic
School of Nursing and Midwifery
- Email:steven.maltby@newcastle.edu.au
- Phone:(02) 404 20173
Down to the Marrow
Dr Steven Maltby is interested in the body’s response to infection and inflammation, with dual focusses on severe asthma, and the role of bone marrow in immune responses.
When it is working well, we don’t even notice it. But when the body’s immune system is improperly activated it leads to chronic disease, including asthma and osteoporosis.
Steven is looking at the mechanisms that shape the bone marrow response in the hope of magnifying the good and eliminating the bad.
Dividing his time between two roles, Steven spends three days a week as a Research Academic at the Centre of Research Excellence (CRE) in Severe Asthma.
Steven dedicates his time to communicating research results, translation of knowledge into practice, as well as Centre logistics.
For two days a week, he works as a Post-doctoral Research Fellow, with Laureate Professor Paul Foster’s research group.
“A lot of the focus in our lab is on asthma and exacerbations of asthma,” Steven explains.
“I look at viral infections because they worsen asthma, and whether any of that worsening is through bone marrow changes is an open question.”
Following function
Bone marrow, the soft tissue in the middle of your long bones, is the site of production of immune cells and blood cells, as well as cells that create bone itself.
Steven’s research sees him positioned in a relatively unique space.
“My work studying bone marrow cells sits at the junction of immunology, and the study of bones,” Steven explains.
“From the development side of things people study these cells making bone. From the immune side, people study these cells in their role of regulating stem cell space.”
“I am interested in how and why the marrow creates different cell types, and the mechanisms behind that.”
Steven points out that there has been a massive change in our understanding of bone marrow function in the last fifteen years.
“We believed that bone marrow was nicely isolated from most infections and inflammation and just kept ticking over, making new bone cells and immune cells everyday,” he says.
“Now there is more recognition that signals produced during infection go all the way back to the bone marrow, and actually change production and maybe the function of those cells.”
Bones of contention
“We are interested in looking at the responses in the bone marrow to short-term infections with a virus, and long-term inflammation with a disease such as asthma.”
During a virus infection, an immune response is required to kill the virus and infected cells.
“If you get a really bad infection, you actually get signals and communication back from the site of infection that change the production of immune cells,” Steven notes.
“You get signals back to the bone marrow that say look, we are not taking care of this, we need to increase the production of immune cells.”
“On the other side, we are finding that if you get that infection you also reduce the cells responsible for making bone.”
The bone marrow putting bone production on-hold production to focus on creating cells designed to defeat a infection makes sense in the short term, but what about the long term?
Too much of a good thing
Problems occur when the body’s defense system becomes confused or hyper-vigilant.
“In cases of chronic inflammation in diseases such as arthritis, inflammatory bowel disease, and asthma, the bone marrow seems to interpret this inflammation as infection,” Steven says.
“Whereas your immune response might be really positive when you want to deal with the flu in a week, it is really negative when you have got it going on constantly for 20 years of your life.”
“You are constantly making extra immune cells which make the inflammation worse, and taking energy away from making bone.”
Using model systems, Steven is trying to understand the basic molecular mechanisms related to different features of disease, in the hope of reversing harmful effects.
“If we understand the mechanisms we can develop drugs that target different parts of that pathway, or are upstream at beginning of the pathway. Or even find a master regulator that blocks the entire process altogether.”
New hope
Educating the public and healthcare practitioners regarding new medications that target specific pathways related to severe asthma is part of Steven’s role at the CRE in Severe Asthma.
A network of clinicians and researchers focused on severe asthma, the CRE has a clinical focus, prioritizing the translation of research outcomes into practice.
“Looking at patient samples is important, but looking at how you treat and manage severe asthma, and developing better mechanisms to handle it in the healthcare system are equally important,” Steven says.
Despite the common belief that asthma can be easily controlled by preventative medication, one percent of Australians have a form of asthma that does not respond to widely used treatments.
“We are still amongst the highest in the developed world for asthma deaths. People are still dying of asthma.”
Steven explains that new medications have provided hope for these extreme cases of treatment-refractory asthma.
Eosinophils are a type of white blood cell produced by the immune system that are involved in allergies, asthma, and defense against parasites.
One therapy reduces eosinophil production in severe asthmatics to normal levels, alleviating and repairing symptoms - such as inflammation of the airways.
Another new medication, anti-immunoglobulin E therapy, works by interfering with the development of allergic inflammation.
Knowledge into practice
Although excited by the potential of these new medications to relieve discomfort and symptoms for severe asthmatics, Steven is quick to point out that the specificity of these therapies mean they will not work for all patients.
The first step in introducing these new medications is to develop consensus on the process of assessing individual patients to see if the targeted pathways are important for their individual disease.
Future steps will be necessary with the availability of multiple therapies, requiring consensus on how to choose one drug over another.
“For some patients, biomarkers will be clear indicators of whether one or the other new therapy is likely to work,” says Steven.
“The tricky thing will be choosing one medication, when multiple options seem suitable in some patients.”
“We need discussion and consensus to get the best outcomes for people who have been living their lives with severe asthma.”
This research will continue to explore and target asthma, as well as other diseases caused by cell changes in the bone marrow.
“The idea is to work out the mechanisms, to identify what part of the process and what molecules are causing the changes.”
“Using model systems, we need to go in there and tinker with the different parts, and see what effect we have.”
“Then based on that data then we will get an understanding of what is good and what is bad and expand it from there.”
Down to the Marrow
Steven's research is focussed on characterizing changes in the bone marrow during disease and infection.
Career Summary
Biography
I currently work 3 days/week with the Centre of Excellence in Severe Asthma (www.severeasthma.org.au). In my role as a Research Academic, I am actively involved in science communications and logistics and administration of the research network.
My remaining 2 days/week, I work as a Post-doctoral Research Fellow, with Laureate Professor Paul Foster's research group. My current research is focussed on characterizing changes in the bone marrow during disease and infection. During a virus infection, an immune response is rapidly induced. This immune response is required to kill the virus and infected cells. However, the immune response often also causes a lot of the damage and pathology that is observed.
The aim of our studies is to characterise what happens when a virus is first detected by the immune system, including systemic changes in the bone marrow. The bone marrow houses immune cell progentors that give rise to mature immune cells, as well as structural cells that are important for maintaining mineral bone. Our second aim is to identify key molecules involved in feedback from sites of infection/inflammation to the bone marrow and the impacts of blocking these molecules on disease pathology.
Past Experience:
I completed my PhD studies with Dr Kelly McNagny at The Biomedical Research Centre, University of British Columbia in Vancouver, BC, Canada. My research focused on the role of CD34 (and the related molecule podocalyxin) in immune responses, using mouse models of disease. Those studies identified the importance of CD34 for efficient eosinophil and mast cell migration to sites of inflammation during disease. Further, I demonstrated that loss of CD34 expression (using transgenic Cd34-/- animals) resulted in reduced disease severity in mouse models of asthma and ulcerative colitis.
Research ExpertiseMain Research Focus Areas: Bone Marrow Responses MicroRNA Regulation Immune Cell Activation and Migration Virus Infections
Teaching Expertise
Immunology
Qualifications
- PhD, University of British Columbia - Canada
- Bachelor of Science, University of British Columbia - Canada
Keywords
- Asthma
- Bone Biology
- Bone Marrow
- Disease Models
- Hematopoiesis
- Immunology
- Infection
- Virus
Languages
- English (Fluent)
Fields of Research
Code | Description | Percentage |
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110799 | Immunology not elsewhere classified | 50 |
110309 | Infectious Diseases | 30 |
110316 | Pathology (excl. Oral Pathology) | 20 |
Professional Experience
UON Appointment
Title | Organisation / Department |
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Research Academic Science Communications & Research Academic (www.severeasthma.org.au) |
University of Newcastle School of Nursing and Midwifery Australia |
Academic appointment
Dates | Title | Organisation / Department |
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1/01/2012 - 5/05/2016 |
University of Newcastle Research Fellow University of Newcastle Research Fellowship |
University of Newcastle School of Biomedical Sciences and Pharmacy Australia |
1/07/2010 - 1/09/2011 | Post-doctoral fellow | University of British Columbia The Biomedical Research Centre Canada |
Awards
Research Award
Year | Award |
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2012 |
Postdoctoral Research Fellowship Canadian Institutes of Health Research |
2012 |
Postdoctoral Research Fellowship University of Newcastle |
Publications
For publications that are currently unpublished or in-press, details are shown in italics.
Chapter (2 outputs)
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2015 |
Maltby S, Plank M, Ptaschinski C, Mattes J, Foster PS, 'MicroRNA function in mast cell biology: Protocols to characterize and modulate MicroRNA expression', Mast Cells: Methods and Protocols, Springer, New York 287-304 (2015) [B1]
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2013 |
Maltby S, McNagny KM, Ackerman SJ, Du J, Mori Y, Iwasaki H, et al., 'Eosinophilopoiesis', Eosinophils in Health and Disease 73-119 (2013) [B2]
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Journal article (31 outputs)
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2018 |
Mateer SW, Mathe A, Bruce J, Liu G, Maltby S, Fricker M, et al., 'IL-6 Drives Neutrophil-Mediated Pulmonary Inflammation Associated with Bacteremia in Murine Models of Colitis', American Journal of Pathology, 188 1625-1639 (2018) [C1] © 2018 American Society for Investigative Pathology Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of a... [more] © 2018 American Society for Investigative Pathology Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of all IBD patients have some form of respiratory pathology, most commonly neutrophil-mediated diseases, such as bronchiectasis and chronic bronchitis. Using murine models of colitis, we aimed to identify the immune mechanisms driving pulmonary manifestations of IBD. We found increased neutrophil numbers in lung tissue associated with the pulmonary vasculature in both trinitrobenzenesulfonic acid¿ and dextran sulfate sodium¿induced models of colitis. Analysis of systemic inflammation identified that neutrophilia was associated with bacteremia and pyrexia in animal models of colitis. We further identified IL-6 as a systemic mediator of neutrophil recruitment from the bone marrow of dextran sulfate sodium animals. Functional inhibition of IL-6 led to reduced systemic and pulmonary neutrophilia, but it did not attenuate established colitis pathology. These data suggest that systemic bacteremia and pyrexia drive IL-6 secretion, which is a critical driver for pulmonary manifestation of IBD. Targeting IL-6 may reduce neutrophil-associated extraintestinal manifestations in IBD patients.
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2018 |
Maltby S, Lochrin AJ, Bartlett B, Tay HL, Weaver J, Poulton IJ, et al., 'Osteoblasts Are Rapidly Ablated by Virus-Induced Systemic Inflammation following Lymphocytic Choriomeningitis Virus or Pneumonia Virus of Mice Infection in Mice', Journal of Immunology, 200 632-642 (2018) [C1] Copyright © 2018 by The American Association of Immunologists, Inc. A link between inflammatory disease and bone loss is now recognized. However, limited data exist on the impact ... [more] Copyright © 2018 by The American Association of Immunologists, Inc. A link between inflammatory disease and bone loss is now recognized. However, limited data exist on the impact of virus infection on bone loss and regeneration. Bone loss results from an imbalance in remodeling, the physiological process whereby the skeleton undergoes continual cycles of formation and resorption. The specific molecular and cellular mechanisms linking virus-induced inflammation to bone loss remain unclear. In the current study, we provide evidence that infection of mice with either lymphocytic choriomeningitis virus (LCMV) or pneumonia virus of mice (PVM) resulted in rapid and substantial loss of osteoblasts from the bone surface. Osteoblast ablation was associated with elevated levels of circulating inflammatory cytokines, including TNF-a, IFN-g, IL-6, and CCL2. Both LCMV and PVM infections resulted in reduced osteoblast-specific gene expression in bone, loss of osteoblasts, and reduced serum markers of bone formation, including osteocalcin and procollagen type 1 N propeptide. Infection of Rag-1-deficient mice (which lack adaptive immune cells) or specific depletion of CD8+ T lymphocytes limited osteoblast loss associated with LCMV infection. By contrast, CD8+ T cell depletion had no apparent impact on osteoblast ablation in association with PVM infection. In summary, our data demonstrate dramatic loss of osteoblasts in response to virus infection and associated systemic inflammation. Further, the inflammatory mechanisms mediating viral infection-induced bone loss depend on the specific inflammatory condition.
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2018 |
Jones KA, Maltby S, Plank MW, Kluge M, Nilsson M, Foster PS, Walker FR, 'Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke', Brain, Behavior, and Immunity, 67 299-307 (2018) [C1] © 2017 Elsevier Inc. Experimental stroke leads to microglia activation and progressive neuronal loss at sites of secondary neurodegeneration (SND). These lesions are remote from, ... [more] © 2017 Elsevier Inc. Experimental stroke leads to microglia activation and progressive neuronal loss at sites of secondary neurodegeneration (SND). These lesions are remote from, but synaptically connected to, primary infarction sites. Previous studies have demonstrated that immune cells are present in sites of infarction in the first hours and days after stroke, and are associated with increased neurodegeneration in peri-infarct regions. However, it is not known whether immune cells are also present in more distal sites where SND occurs. Our study aimed to investigate whether immune cells are present in sites of SND and, if so, how these cell populations compare to those in the peri-infarct zone. Cells were isolated from the thalamus, the main site of SND, and remaining brain tissue 14 days post-stroke. Analysis was performed using flow cytometry to quantify microglia, myeloid cell and lymphocyte numbers. We identified a substantial infiltration of immune cells in the ipsilateral (stroked) compared to the contralateral (control) thalamus, with a significant increase in the percentage of CD4+ and CD8+ T cells. This result was further quantified using immunofluorescent labelling of fixed tissue. In the remaining ipsilateral hemisphere tissue, there were significant increases in the frequency of CD4+ and CD8+ T lymphocytes, B lymphocytes, Ly6G+ neutrophils and both Ly6G-Ly6CLO and Ly6G-Ly6CHI monocytes. Our results indicate that infiltrating immune cells persist in ischemic tissue after the acute ischemic phase, and are increased in sites of SND. Importantly, immune cells have been shown to play pivotal roles in both damage and repair processes after stroke. Our findings indicate that immune cells may also be involved in the pathogenesis of SND and further clinical studies are warranted to characterise the nature of inflammatory cell infiltrates in human disease.
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2018 |
Porsbjerg C, Sverrild A, Baines KJ, Searles A, Maltby S, Foster PS, et al., 'Advancing the management of obstructive airways diseases through translational research.', Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 48 493-501 (2018) [C1]
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2018 |
Nguyen TH, Maltby S, Tay HL, Eyers F, Foster PS, Yang M, 'Identification of IFN-¿ and IL-27 as Critical Regulators of Respiratory Syncytial Virus-Induced Exacerbation of Allergic Airways Disease in a Mouse Model', Journal of Immunology, 200 237-247 (2018) [C1] Copyright © 2017 by The American Association of Immunologists, Inc. Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical ... [more] Copyright © 2017 by The American Association of Immunologists, Inc. Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exacerbations are the main cause of morbidity and mortality associated with asthma, and significantly contribute to asthma-associated healthcare costs. Although glucocorticoids are used to manage exacerbations, some patients respond to them poorly. The underlying mechanisms associated with steroid-resistant exacerbations remain largely unknown. We have previously established a mouse model of RSV-induced exacerbation of allergic airways disease, which mimics hallmark clinical features of asthma. In this study, we have identified key roles for macrophage IFN-¿ and IL-27 in the regulation of RSV-induced exacerbation of allergic airways disease. Production of IFN-¿ and IL-27 was steroid-resistant, and neutralization of IFN-¿ or IL-27 significantly suppressed RSV-induced steroid-resistant airway hyperresponsiveness and airway inflammation. We have previously implicated activation of pulmonary macrophage by TNF-a and/or MCP-1 in the mechanisms of RSV-induced exacerbation. Stimulation of pulmonary macrophages with TNF-a and/or MCP-1 induced expression of both IFN-¿ and IL-27. Our findings highlight critical roles for IFN-¿ and IL-27, downstream of TNF-a and MCP-1, in the mechanism of RSV-induced exacerbation. Thus, targeting the pathways that these factors activate may be a potential therapeutic approach for virus-induced asthma exacerbations.
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2017 |
Foster PS, Maltby S, Rosenberg HF, Tay HL, Hogan SP, Collison AM, et al., 'Modeling T © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional... [more] © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+ T-helper type-2 lymphocytes (TH2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.
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2017 |
Maltby S, Tay HL, Yang M, Foster PS, 'Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation', Respirology, 22 874-885 (2017) [C1] © 2017 Asian Pacific Society of Respirology Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the major... [more] © 2017 Asian Pacific Society of Respirology Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/non-eosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.
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2017 |
McDonald VM, Maltby S, Reddel HK, King GG, Wark PAB, Smith L, et al., 'Severe asthma: Current management, targeted therapies and future directions¿A roundtable report', Respirology, 22 53-60 (2017) [C1] © 2016 Asian Pacific Society of Respirology Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper... [more] © 2016 Asian Pacific Society of Respirology Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and directly affects 10% of Australians, 1¿5% of adults in Asia and 300 million people worldwide. It is a heterogeneous disorder with many clinical, molecular, biological and pathophysiological phenotypes. Current management strategies successfully treat the majority of patients with asthma who have access to them. However, there is a subset of an estimated 5¿10% of patients with asthma who have severe disease and are disproportionately impacted by symptoms, exacerbations and overall illness burden. The care required for this relatively small proportion of patients is also significant and has a major impact on the healthcare system. A number of new therapies that hold promise for severe asthma are currently in clinical trials or are entering the Australian and international market. However, recognition of severe asthma in clinical practice is variable, and there is little consensus on the best models of care or how to integrate emerging and often costly therapies into current practice. In this article, we report on roundtable discussions held with severe asthma experts from around Australia, and make recommendations about approaches for better patient diagnosis and assessment. We assess current models of care for patient management and discuss how approaches may be optimized to improve patient outcomes. Finally, we propose mechanisms to assess new therapies and how to best integrate these approaches into future treatment.
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2017 |
Maltby S, Gibson PG, Powell H, McDonald VM, 'Omalizumab Treatment Response in a Population With Severe Allergic Asthma and¿Overlapping COPD', Chest, 151 78-89 (2017) [C1] © 2016 American College of Chest Physicians Background Asthma and COPD are common airway diseases. Individuals with overlapping asthma and COPD experience increased health impairm... [more] © 2016 American College of Chest Physicians Background Asthma and COPD are common airway diseases. Individuals with overlapping asthma and COPD experience increased health impairment and severe disease exacerbations. Efficacious treatment options are required for this population. Omalizumab (anti-IgE) therapy is effective in patients with severe persistent asthma, but limited data are available on efficacy in populations with overlapping asthma and COPD. Methods Data from the Australian Xolair Registry were used to compare treatment responses in individuals with asthma-COPD overlap with responses in patients with severe asthma alone. Participants were assessed at baseline and after 6¿months of omalizumab treatment. We used several different definitions of asthma-COPD overlap. First, we compared participants with a previous physician diagnosis of COPD to participants with no COPD diagnosis. We then made¿comparisons based on baseline lung function, comparing participants with an FEV1<¿80%¿predicted to those with an FEV1> 80%¿predicted after bronchodilator use. In the population with an FEV1< 80%, analysis was further stratified based on smoking history. Results Omalizumab treatment markedly improved asthma control and health-related quality of life in all populations assessed based on the Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. Omalizumab treatment did not improve lung function (FEV1, FVC, or FEV1/FVC ratio) in populations that were enriched for asthma-COPD overlap (diagnosis of COPD or FEV1¿< 80%/ever smokers). Conclusions Our study suggests that omalizumab improves asthma control and health-related quality of life in individuals with severe allergic asthma and overlapping COPD. These findings provide real-world efficacy data for this patient population and suggest that omalizumab is useful in the management of severe asthma with COPD overlap.
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2017 |
Tay HL, 'Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity.', JOURNAL OF IMMUNOLOGY, 198 2182-2190 (2017) [C1]
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2016 |
Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, et al., 'TNF-a and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease', Journal of Immunology, 196 3547-3558 (2016) [C1] Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation... [more] Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-a, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVAsensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-a, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-a levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-a and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-a and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.
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2016 |
Maltby S, Plank M, Tay HL, Collison A, Foster PS, 'Targeting MicroRNA function in respiratory diseases: Mini-review', Frontiers in Physiology, 7 (2016) [C1]
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2016 |
Wark PAB, Hew M, Maltby S, McDonald VM, Gibson PG, 'Diagnosis and investigation in the severe asthma clinic.', Expert Rev Respir Med, 10 491-503 (2016) [C1]
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2016 |
Thi HN, Maltby S, Eyers F, Foster PS, Yang M, 'Bromodomain and Extra Terminal (BET) Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation', PLOS ONE, 11 (2016) [C1]
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2015 |
Tay HL, Kaiko GE, Plank M, Li J, Maltby S, Essilfie A-T, et al., 'Correction: Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung.', PLoS pathogens, 11 e1004956 (2015) [O1]
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2015 |
Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, et al., 'MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity', Journal of Allergy and Clinical Immunology, 136 462-473 (2015) [C1] © 2015 American Academy of Allergy, Asthma & Immunology. Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells.... [more] © 2015 American Academy of Allergy, Asthma & Immunology. Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells. Levels of IFN-¿ and LPS are often increased in these patients. Cooperative signaling between IFN-¿/LPS induces macrophage-dependent steroid-resistant airway hyperresponsiveness (AHR) in mouse models. MicroRNAs (miRs) are small noncoding RNAs that regulate the function of innate immune cells by controlling mRNA stability and translation. Their role in regulating glucocorticoid responsiveness and AHR remains unexplored. Objective IFN-¿ and LPS synergistically increase the expression of miR-9 in macrophages and lung tissue, suggesting a role in the mechanisms of steroid resistance. Here we demonstrate the role of miR-9 in IFN-¿/LPS-induced inhibition of dexamethasone (DEX) signaling in macrophages and in induction of steroid-resistant AHR. Methods MiRNA-9 expression was assessed by means of quantitative RT-PCR. Putative miR-9 targets were determined in silico and confirmed in luciferase reporter assays. miR-9 function was inhibited with sequence-specific antagomirs. The efficacy of DEX was assessed by quantifying glucocorticoid receptor (GR) cellular localization, protein phosphatase 2A (PP2A) activity, and AHR. Results Exposure of pulmonary macrophages to IFN-¿/LPS synergistically induced miR-9 expression; reduced levels of its target transcript, protein phosphatase 2 regulatory subunit B (B56) d isoform; attenuated PP2A activity; and inhibited DEX-induced GR nuclear translocation. Inhibition of miR-9 increased both PP2A activity and GR nuclear translocation in macrophages and restored steroid sensitivity in multiple models of steroid-resistant AHR. Pharmacologic activation of PP2A restored DEX efficacy and inhibited AHR. MiR-9 expression was increased in sputum of patients with neutrophilic but not those with eosinophilic asthma. Conclusion MiR-9 regulates GR signaling and steroid-resistant AHR. Targeting miR-9 function might be a novel approach for the treatment of steroid-resistant asthma.
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2015 |
Plank MW, Maltby S, Tay HL, Stewart J, Eyers F, Hansbro PM, Foster PS, 'MicroRNA Expression Is Altered in an Ovalbumin-Induced Asthma Model and Targeting miR-155 with Antagomirs Reveals Cellular Specificity.', PloS one, 10 1-25 (2015) [C1]
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2015 |
Tay HL, Kaiko GE, Plank M, Li JJ, Maltby S, Essilfie AT, et al., 'Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung', PLoS Pathogens, 11 (2015) [C1] © 2015 Tay et al. Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to ... [more] © 2015 Tay et al. Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.
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2014 |
Maltby S, Hansbro NG, Tay HL, Stewart J, Plank M, Donges B, et al., 'Production and differentiation of myeloid cells driven by proinflammatory cytokines in response to acute pneumovirus infection in mice.', J Immunol, 193 4072-4082 (2014) [C1]
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2013 |
Plank M, Maltby S, Mattes J, Foster PS, 'Targeting translational control as a novel way to treat inflammatory disease: The emerging role of MicroRNAs', Clinical and Experimental Allergy, 43 981-999 (2013) [C1] Chronic inflammatory diseases (e.g. asthma and chronic obstructive pulmonary disease) are leading causes of morbidity and mortality world-wide and effective treatments are limited... [more] Chronic inflammatory diseases (e.g. asthma and chronic obstructive pulmonary disease) are leading causes of morbidity and mortality world-wide and effective treatments are limited. These disorders can often be attributed to abnormal immune responses to environmental stimuli and infections. Mechanisms leading to inflammation are complex, resulting from interactions of structural cells and activation of both the adaptive and innate arms of the immune system. The activation of structural and immune cells involves both temporary and permanent changes in gene expression in these cells, which underpin chronic inflammation and tissue dysfunction. miRNAs are small non-coding RNAs increasingly being recognized to play important roles in the post-transcriptional regulation of gene expression in mammalian cells by regulating translation. Individual miRNAs can exert their effects by directly inhibiting the translation or stability of multiple mRNAs simultaneously. Thus, the expression or blockade of function of a single miRNA (miR) can result in pronounced alterations in protein expression within a given cell. Dysregulation of miRNA expression may subsequently alter cellular function, and in certain situations predispose to disease. Our current understanding of the role of miRNA in the regulation of inflammatory disease (e.g. allergic diseases) remains limited. In this review, we provide an overview of the current understanding of miRNA biogenesis and function, the roles miRNA play in the regulation of immune cell function and their potential contribution to inflammatory diseases. We also highlight strategies to alter miRNA function for experimental or therapeutic gain, and discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies. © 2013 John Wiley & Sons Ltd.
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2013 |
Plank M, Maltby S, Mattes J, Foster PS, 'Targeting translational control as a novel way to treat inflammatory disease: the emerging role of microRNAs.', Clinical and Experimental Allergy, 43 981-999 (2013)
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Show 28 more journal articles |
Review (4 outputs)
Year | Citation | Altmetrics | Link | ||||||||
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2017 |
McDonald VM, Maltby S, Gibson PG, 'Severe asthma: Can we fix it? Prologue to seeking innovative solutions for severe asthma', RESPIROLOGY (2017)
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2016 |
Grainge CL, Maltby S, Gibson PG, Wark PAB, McDonald VM, 'Targeted therapeutics for severe refractory asthma: monoclonal antibodies', EXPERT REVIEW OF CLINICAL PHARMACOLOGY (2016)
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2015 |
Mateer SW, Maltby S, Marks E, Foster PS, Horvat JC, Hansbro PM, Keely S, 'Potential mechanisms regulating pulmonary pathology in inflammatory bowel disease.', J Leukoc Biol (2015) [C1]
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Show 1 more review |
Conference (17 outputs)
Year | Citation | Altmetrics | Link | |||||
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2017 |
Plank MW, Kaiko GE, Maltby S, Weaver J, Tay H, Shen W, et al., 'Th22 cells form a distinct th lineage from Th17 cells in vitro with unique transcriptional properties and Tbet-dependent Th1 plasticity', ALLERGY, Helsinki, FINLAND (2017)
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2017 |
Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, et al., 'MACROPHAGES REGULATE THE DEVELOPMENT OF RSV INDUCED ASTHMA EXACERBATIONS', RESPIROLOGY (2017)
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2017 |
Maltby S, Gibson PG, Powell H, Mcdonald VM, 'OMALIZUMAB TREATMENT RESPONSE IN A SEVERE ALLERGIC ASTHMA POPULATION WITH OVERLAPPING COPD', RESPIROLOGY (2017)
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2015 |
Plank M, Kaiko G, Maltby S, Tay H, Stewart J, Durum S, Foster P, 'Mapping the cellular source and role of IL-22 in murine lung infections', EUROPEAN RESPIRATORY JOURNAL (2015)
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2015 |
Tay H, Kaiko G, Plank M, Li J, Essilfie A, Maltby S, et al., 'THE ROLE OF MIR-328 IN RESPIRATORY DISEASES', RESPIROLOGY, Queensland, AUSTRALIA (2015) [E3]
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2015 |
Mateer S, Marks E, Maltby S, Goggins B, Horvat J, Hansbro P, Keely S, 'Pulmonary retention of PMN attracts primed intestinal lymphocytes in a mouse model of inflammatory bowel disease', FASEB JOURNAL (2015) [E3]
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2014 |
Mateer S, Maltby S, Marks E, Goggins B, Horvat J, Hansbro P, Keely S, 'Immune cell mis-homing drives secondary organ inflammation in inflammatory bowel disease; a focus on the respiratory system', JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY (2014) [E3]
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Show 14 more conferences |
Grants and Funding
Summary
Number of grants | 10 |
---|---|
Total funding | $500,635 |
Click on a grant title below to expand the full details for that specific grant.
20161 grants / $22,500
Exploring Novel Therapies for Cystic Fibrosis$22,500
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Hock Tay, Laureate Professor Paul Foster, Mr Max Plank, Doctor Steven Maltby |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2016 |
Funding Finish | 2016 |
GNo | G1600577 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
20151 grants / $1,500
Keystone Symposium: Hematopoiesis, Colorado USA, 22-27 February 2015$1,500
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Doctor Steven Maltby |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2015 |
Funding Finish | 2015 |
GNo | G1500324 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20143 grants / $44,216
Miltenyi Biotec GentleMACS Octo Dissociator with Heaters $23,566
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Phil Hansbro, Laureate Professor Paul Foster, Professor Darryl Knight, Professor Dirk Van Helden, Professor Joerg Mattes, Professor Jodie Simpson, Professor Lisa Wood, Professor Liz Milward, Dr NATHAN Bartlett, Associate Professor Simon Keely, Doctor Steven Maltby, Doctor Andrew Jarnicki, Doctor Malcolm Starkey, Doctor Adam Collison, Doctor Shaan Gellatly |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1500861 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
Virus Infections Change the Bone Marrow: Effects on Immunity, Bone Development and Inflammatory Disease$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Steven Maltby, Mr Max Plank, Doctor Hock Tay, Laureate Professor Paul Foster |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1401394 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
Inaugural Future of Experimental Medicine Conference: Inflammation in Disease and Ageing, Sydney Australia, 16-19 March 2014$650
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Doctor Steven Maltby |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1400166 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20132 grants / $21,500
DP73 Digital colour and monochrome camera + cellSens software + Xcite120 fluorescence lamp illuminator$20,000
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Laureate Professor Paul Foster, Doctor Alan Hsu, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Katie Baines, Professor Jodie Simpson, Professor Rakesh Kumar, Doctor Nicole Hansbro, Doctor Steven Maltby, Doctor Ming Yang, Doctor Gerard Kaiko, Associate Professor Jay Horvat, Associate Professor Simon Keely, Doctor Andrew Jarnicki, Doctor Michael Fricker |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2013 |
Funding Finish | 2013 |
GNo | G1201186 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
43rd Annual Scientific meeting of the Australasian Society for Immunology (ASI), Wellington New Zealand, 2 - 5 December 2013$1,500
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Doctor Steven Maltby |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2013 |
Funding Finish | 2014 |
GNo | G1300439 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20123 grants / $410,919
2011 Research Fellowship - DVCR Strategic Appointment (PRCARD)$240,550
Funding body: University of Newcastle
Funding body | University of Newcastle |
---|---|
Project Team | Doctor Steven Maltby |
Scheme | Research Fellowship |
Role | Lead |
Funding Start | 2012 |
Funding Finish | 2014 |
GNo | G1100534 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
Post-Doctoral Research Fellowship$150,000
Funding body: Canadian Institutes of Health Research (CIHR)
Funding body | Canadian Institutes of Health Research (CIHR) |
---|---|
Scheme | Health Research |
Role | Lead |
Funding Start | 2012 |
Funding Finish | 2015 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Fellowship Start-up Grant$20,369
Funding body: University of Newcastle
Funding body | University of Newcastle |
---|---|
Project Team | Doctor Steven Maltby |
Scheme | Fellowship Grant |
Role | Lead |
Funding Start | 2012 |
Funding Finish | 2012 |
GNo | G1200114 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
Research Supervision
Number of supervisions
Past Supervision
Year | Level of Study | Research Title | Program | Supervisor Type |
---|---|---|---|---|
2017 | PhD | Modeling of Respiratory Syncytial Virus-induced Exacerbation of Allergic Airways Disease | PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle | Co-Supervisor |
2017 | PhD | Understanding the Mechanisms of Bacterial-Induced Exacerbation of Allergic Airways Disease in a Mouse Model | PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle | Co-Supervisor |
2016 | Honours | The Systemic Impacts of Viral Inflammation on the Structural Integrity of Bone and Haematopoiesis | Medical Science, The University of Newcastle - Faculty of Health and Medicine | Co-Supervisor |
Dr Steven Maltby
Positions
Research Academic
School of Nursing and Midwifery
Faculty of Health and Medicine
Casual Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine
Casual Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine
Contact Details
steven.maltby@newcastle.edu.au | |
Phone | (02) 404 20173 |
Fax | (02) 404 20025 |
Links |
Research Networks |
Office
Room | HMRI Level 2 |
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Building | HMRI |
Location | NEWCASTLE , |