ORCID Profile
0000-0002-4550-1859
Current Organisation
University of Tasmania
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Zoology | Animal Immunology | Veterinary Immunology | Tumour Immunology | Veterinary Sciences | Biological Control | Veterinary Diagnosis and Diagnostics
Expanding Knowledge in the Biological Sciences | Flora, Fauna and Biodiversity at Regional or Larger Scales | Control of Pests, Diseases and Exotic Species at Regional or Larger Scales | Veterinary Biological Preventatives (e.g. Vaccines) | Veterinary Diagnostics |
Publisher: Informa UK Limited
Date: 02-06-2023
Publisher: Public Library of Science (PLoS)
Date: 07-10-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
Abstract: A simple cut-and-paste reagent development method applicable to any species reveals checkpoint molecules on transmissible cancers.
Publisher: Cold Spring Harbor Laboratory
Date: 16-12-2021
DOI: 10.1101/2021.12.14.472710
Abstract: Ethyl-Iophenoxic acid (Et-IPA) has been widely used as a bait biomarker to determine oral bait consumption by vertebrate wildlife species. Oral bait vaccines have been delivered to numerous wildlife species to protect them from disease. The Tasmanian devil ( Sarcophilis harrisii ), the largest extant carnivorous marsupial species, is threatened by the transmissible cancers known as devil facial tumour disease (DFTD). Development of a protective DFTD vaccine is underway, and an oral bait has been proposed to deliver the vaccine in the wild. The bait delivery system requires a biomarker that can be detected for several months post-consumption in Tasmanian devils. To determine the suitability of Et-IPA as a bait biomarker in the Tasmanian devil. Two Tasmanian devils were fed 50 mg Et-IPA (4.5 to 7.1 mg Et-IPA/kg bodyweight). Liquid chromatography with tandem mass spectrometry (LC-MS/-MS) was used to directly measure Et-IPA in baseline serum s les and s les collected on days 1, 14, 26 and 56 post-baiting. Both devils retained serum Et-IPA concentrations at two orders of magnitude above negative control sera when this study concluded. Et-IPA is a useful bait biomarker for Tasmanian devils and can be included in future DFTD bait vaccine field trials to determine bait vaccine uptake.
Publisher: Public Library of Science (PLoS)
Date: 11-06-2015
Publisher: Springer Science and Business Media LLC
Date: 16-07-2021
DOI: 10.1007/S11912-021-01095-X
Abstract: Immune checkpoint immunotherapies (ICI) are now approved for over 20 types of cancer and there are almost 6000 ongoing clinical trials investigating immuno-modulators as cancer therapies. This review investigated the effect of monoclonal antibody-based immune checkpoint immunotherapies when combined with cytokine therapy. We reviewed published clinical trial results from 2005 to 2020 for studies that used approved monoclonal antibody ICI in combination with the cytokines. Studies that met the search criteria were assessed for treatment efficacy and immunological changes associated with treatment. ICI often fails to result in improved clinical outcomes for patients and lasting protection from cancer recurrence. The use of pro-inflammatory cytokines alongside ICI has been shown to enhance the efficacy of these therapies in vitro and in animal studies. However, the results in human clinical trials are less clear and many clinical trials do not publish results at the end of the trial. A deeper understanding of the molecular interactions between cytokines, tumors, and immune cells is needed to improve overall ICI outcomes and design combination trials. Critical examination of the design and characteristics of previous clinical trials can provide insight into the lack of effective clinical translation for many immunotherapeutic drugs.
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2022
DOI: 10.1101/2022.04.03.486872
Abstract: Tasmanian Devils facial tumor disease is severely impacting the population of this wild animal. We developed a computational model of the population of Tasmanian Devils, and the change induced by DFTD. We use this model to test possible intervention strategies Tasmanian conservationists could do. We investigate bait drop vaccination programs, diseased animal removals programs, and evolution of natural immunity. We conclude that a combination of intervention strategies gives the most favorable outcome. An additional goal of this paper is for reproducibility of our results. Our StochSS software platform features the ability to share and reproduce the computational notebooks that created all of the results in the paper. We endeavor that all readers should be able to reproduce our results with minimum effort.
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2021
DOI: 10.1101/2021.07.12.21260394
Abstract: Some countries have been crippled by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic while others have emerged with few infections and fatalities the factors underscoring this macro-epidemiological variation is one of the mysteries of this global catastrophe. Variation in immune responses influence SARS-CoV-2 transmission and mortality, and factors shaping this variation at the country level, in addition to other socio-ecological drivers, may be important. Here, we construct spatially explicit Bayesian models that combine data on prevalence of endemic diseases and other socio-ecological characteristics to quantify patterns of confirmed deaths and cases across the globe before mass vaccination. We find that the prevalence of parasitic worms, human immunodeficiency virus and malaria play a surprisingly important role in predicting country-level SARS-CoV-2 patterns. When combined with factors such as population density, our models predict 63% (56-67) and 76% (69-81) of confirmed cases and deaths among countries, respectively. While our findings at this macro-scale are necessarily associative, they highlight a need for studies to consider factors, such as infection by other pathogens, on global SARS-CoV-2 dynamics. These relationships are vital for developing countries that already have the highest burden of endemic disease and are becoming the most affected by the SARS-CoV-2 pandemic.
Publisher: Oxford University Press (OUP)
Date: 2021
Abstract: Ecoimmunology is a rapidly developing field that explores how the environment shapes immune function, which in turn influences host–parasite relationships and disease outcomes. Host immune defence is a key fitness determinant because it underlies the capacity of animals to resist or tolerate potential infections. Importantly, immune function can be suppressed, depressed, reconfigured or stimulated by exposure to rapidly changing environmental drivers like temperature, pollutants and food availability. Thus, hosts may experience trade-offs resulting from altered investment in immune function under environmental stressors. As such, approaches in ecoimmunology can provide powerful tools to assist in the conservation of wildlife. Here, we provide case studies that explore the erse ways that ecoimmunology can inform and advance conservation efforts, from understanding how Galapagos finches will fare with introduced parasites, to using methods from human oncology to design vaccines against a transmissible cancer in Tasmanian devils. In addition, we discuss the future of ecoimmunology and present 10 questions that can help guide this emerging field to better inform conservation decisions and bio ersity protection. From better linking changes in immune function to disease outcomes under different environmental conditions, to understanding how in idual variation contributes to disease dynamics in wild populations, there is immense potential for ecoimmunology to inform the conservation of imperilled hosts in the face of new and re-emerging pathogens, in addition to improving the detection and management of emerging potential zoonoses.
Publisher: American Society of Hematology
Date: 04-2008
DOI: 10.1182/BLOOD-2007-11-123141
Abstract: B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell–mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1+ cancer cells also become refractory to apoptosis induced by Fas ligation or the protein kinase inhibitor Staurosporine. Our study reveals a new mechanism by which cancer cells use a receptor on immune cells as a ligand to induce resistance to therapy.
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2022
DOI: 10.1101/2022.04.13.486902
Abstract: Diseases are increasingly contributing to wildlife population declines. Tasmanian devil ( Sarcophilus harrisii ) populations have locally declined by 82% largely due to the morbidity and mortality associated with two independent transmissible devil facial tumours (DFT1 and DFT2). Toxic baits are often used as a management tool for controlling vertebrate pest populations in Australia, but in other areas of the world oral baits are also used to deliver vaccines or pharmaceuticals to wildlife. Oral vaccine bait products have been distributed for more than 50 years at a landscape scale to protect wildlife from rabies virus and contributed to the elimination of fox rabies from more than ten European nations. An oral bait vaccine to protect against devil facial tumours has been proposed as a management tool to improve the population health, resiliency and fitness of wild Tasmanian devils. Our goal was to evaluate the potential use of edible baits as vehicles for vaccine delivery to Tasmanian devils. We tested placebo versions of baits that are already used in Australia. Captive devils consumed all types of placebo baits but exhibited a preference for ruminant- and fish-based baits. Captive devils also consumed inert capsules inserted into placebo baits. Bait fate trials in the field revealed that baits were generally removed within 24 hours. Tasmanian pademelons ( Thylogale billardierii ), brushtail possums ( Trichosurus vulpecula ), and Eastern quolls ( Dasyurus viverrinus ) were the most common nontarget bait competitors at six private properties in southern Tasmania wild devils removed approximately 5% of ground baits at these sites. We also evaluated an automated bait dispenser, which reduced nontarget uptake and resulted in over 50% of the baits being removed by devils. This study demonstrates that captive and wild devils will accept and consume placebo versions of commercial baits. Bait dispensers or modified baits or baiting strategies are needed to increase bait uptake by devils. Bait dispensers can be used at a regional scale to deliver baits to Tasmanian devils. These could act as vehicles for preventive or therapeutic vaccines to mitigate the impacts of disease on devil populations. This study aimed to test oral baits as potential vaccine delivery vehicles for Tasmanian devils. Captive and wild devils consumed placebo versions of commercial baits used on mainland Australia. Abundant non-target species, such as brushtail possums, Tasmanian pademelons, and eastern quolls consumed most baits in the wild. Implementation of automated bait dispensers increased bait uptake by devils to over 50% at the same regional field sites.
Publisher: Wiley
Date: 28-11-2014
DOI: 10.1002/JBM.B.33336
Abstract: The aim of this study was to develop and characterize an injectable bone void filler by incorporating baghdadite (Ca3 ZrSi2 O9 ) particles (average size of 1.7 µm) into polycaprolactone (PCL). A series of PCL composites containing different volume percentages of baghdadite [1 (PCL-1%Bag), 5 (PCL-5%Bag), 10 (PCL-10%Bag), 20 (PCL-20%Bag), and 30 (PCL-30%Bag)] were prepared, and their injectability, setting time, mechanical properties, radiopacity, degradation, and cytocompatibility were investigated. PCL, PCL-1%Bag, PCL-5%Bag, and PCL-10%Bag were able to be injected through a stainless steel syringe (Length: 9.0 mm, nozzle diameter: 2.2 mm) at 75°C at injection forces of below 1.5 kN. The core temperature of the injected material at the nozzle exit ranged between 55 and 60°C and was shown to set after 2.5-3.5 min postinjection in a 37°C environment. Injection force, melt viscosity, and radiopacity of the composites increased with increasing baghdadite content. Incorporation of 10-30 vol % baghdadite into PCL increased the compressive strength of the composites from 36 to 47.1 MPa, compared with that for pure PCL (31.4 MPa). Similar trend was found for the compressive modulus of the composites, which increased from 203.8 to 741 MPa, compared with that for pure PCL (205 MPa). Flexural strain of PCL, PCL-5%Bag, and PCL-10%Bag exceeded 30%, and PCL-10%Bag showed the highest flexural strength (29.8 MPa). Primary human osteoblasts cultured on PCL-10%Bag showed a significant upregulation of osteogenic genes compared with pure PCL. In summary, our results demonstrated that PCL-10%Bag could be a promising injectable material for orthopedic and trauma application.
Publisher: Informa UK Limited
Date: 02-01-2020
Publisher: Frontiers Media SA
Date: 09-12-2016
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2022
DOI: 10.1101/2022.05.29.493930
Abstract: The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil ( Sarcophilus harrisii ) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100%. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2, and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as vaccine platform for devils and potentially other marsupials.
Publisher: Springer Science and Business Media LLC
Date: 03-01-2020
DOI: 10.1007/S00018-019-03435-4
Abstract: The Tasmanian devil (Sarcophilus harrisii) is the only mammalian species known to be affected by multiple transmissible cancers. Devil facial tumours 1 and 2 (DFT1 and DFT2) are independent neoplastic cell lineages that produce large, disfiguring cancers known as devil facial tumour disease (DFTD). The long-term persistence of wild Tasmanian devils is threatened due to the ability of DFTD cells to propagate as contagious allografts and the high mortality rate of DFTD. Recent studies have demonstrated that both DFT1 and DFT2 cancers originated from founder cells of the Schwann cell lineage, an uncommon origin of malignant cancer in humans. This unprecedented finding has revealed a potential predisposition of Tasmanian devils to transmissible cancers of the Schwann cell lineage. In this review, we compare the molecular nature of human Schwann cells and nerve sheath tumours with DFT1 and DFT2 to gain insights into the emergence of transmissible cancers in the Tasmanian devil. We discuss a potential mechanism, whereby Schwann cell plasticity and frequent wounding in Tasmanian devils combine with an inherent cancer predisposition and low genetic ersity to give rise to transmissible Schwann cell cancers in devils on rare occasions.
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2020
DOI: 10.1101/2020.06.11.145789
Abstract: Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil ( Sarcophilus harrisii ) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumours. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily ergent species. Key immune checkpoint receptor-ligand interactions are conserved in marsupials. Live cell-based assays show Tasmanian devil CD28 and CTLA4 can capture CD80 and CD86 in trans from adjacent cells. Mutation of the conserved CTLA4 MYPPPY ligand binding motif to CTLA4 MYPPPA reduces binding to CD80 and intercellular protein transfer. Removal of conserved CTLA4 YVKM protein recycling binding motif in CTLA4 results in bidirectional intercellular protein transfer between CTLA4 and CD80. Highly successful human immune checkpoint immunotherapies have the potential to be translated for veterinary and conservation medicine.
Publisher: Wiley
Date: 29-02-2016
Publisher: Elsevier BV
Date: 04-2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2020
DOI: 10.1101/831404
Abstract: Immune checkpoint immunotherapy has revolutionized medicine, but translational success for new treatments remains low. Around 40% of humans and Tasmanian devils ( Sarcophilus harrisii ) develop cancer in their lifetime, compared to less than 10% for most species. Additionally, devils are affected by two of the three known transmissible cancers in mammals. Unfortunately, little is known about of immune checkpoints in devils and other non-model species, largely due to a lack of species-specific reagents. We developed a simple cut-and-paste reagent development method applicable to any vertebrate species and show that immune checkpoint interactions are conserved across 160 million years of evolution. The inhibitory checkpoint molecule CD200 is highly expressed on devil facial tumor cells. We are the first to demonstrate that co-expression of CD200R1 can block CD200 expression. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can serve as models for understanding cancer and immunological tolerance.
Publisher: Frontiers Media SA
Date: 03-05-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-08-2018
Abstract: A “human phenomic science” approach could accelerate personalized medicine
Publisher: The American Association of Immunologists
Date: 11-2004
DOI: 10.4049/JIMMUNOL.173.9.5445
Abstract: B7-H3 is a B7 family molecule with T cell costimulatory function in vitro. The in vivo role of B7-H3 in the stimulation of tumor immunity is unclear. We report here that expression of B7-H3 by transfection of the mouse P815 tumor line enhances its immunogenicity, leading to the regression of tumors and lification of a tumor-specific CD8+ CTL response in syngeneic mice. Tumor cells engineered to express B7-H3 elicit a rapid clonal expansion of P1A tumor Ag-specific CD8+ CTL in lymphoid organs in vivo and acquire the ability to directly stimulate T cell growth, ision, and development of cytolytic activity in vitro. Our results thus establish a role for B7-H3 in the costimulation of T cell immune responses in vivo.
Publisher: American Society for Microbiology
Date: 13-07-2023
Abstract: Wildlife is the source of many emerging infectious diseases. Several viruses from the order Nidovirales have recently emerged in wildlife, sometimes with severe consequences for endangered species. The order Nidovirales is currently classified into eight suborders, three of which contain viruses of vertebrates. Vertebrate coronaviruses (suborder Cornidovirineae ) have been extensively studied, yet the other major suborders have received less attention. The aim of this minireview was to summarize the key findings from the published literature on nidoviruses of vertebrate wildlife from two suborders: Arnidovirineae and Tornidovirineae . These viruses were identified either during investigations of disease outbreaks or through molecular surveys of wildlife viromes, and include pathogens of reptiles and mammals. The available data on key biological features, disease associations, and pathology are presented, in addition to data on the frequency of infections among various host populations, and putative routes of transmission. While nidoviruses discussed here appear to have a restricted in vivo host range, little is known about their natural life cycle. Observational field-based studies outside of the mortality events are needed to facilitate an understanding of the virus-host-environment interactions that lead to the outbreaks. Laboratory-based studies are needed to understand the pathogenesis of diseases caused by novel nidoviruses and their evolutionary histories. Barriers preventing research progress include limited funding and the unavailability of virus- and host-specific reagents. To reduce mortalities in wildlife and further population declines, proactive development of expertise, technologies, and networks should be developed. These steps would enable effective management of future outbreaks and support wildlife conservation.
Publisher: American Society of Hematology
Date: 19-12-2006
DOI: 10.1182/BLOOD-2006-09-047332
Abstract: Decoy lymphotoxin β receptor (LTβR) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LTβ-LTβR and LIGHT-HVEM/LTβR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti–host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti–HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.
Publisher: American Society of Hematology
Date: 07-2007
DOI: 10.1182/BLOOD-2006-12-062422
Abstract: Expression of the PD-1 receptor on T cells has been shown to provide an important inhibitory signal that down-modulates peripheral effector responses in normal tissues and tumors. Furthermore, PD-1 up-regulation on chronically activated T cells can maintain them in a partially reversible inactive state. The function of PD-1 in the very early stages of T-cell response to antigen in vivo has not been fully explored. In this study, we evaluate the role of PD-1 and its 2 B7 family ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), in early fate decisions of CD8 T cells. We show that CD8 T cells specific for influenza hemagglutinin (HA) expressed as a self-antigen become functionally tolerized and express high levels of surface PD-1 by the time of their first cell ision. Blockade of PD-1 or B7-H1, but not B7-DC, at the time of self-antigen encounter mitigates tolerance induction and results in CD8 T-cell differentiation into functional cytolytic T lymphocytes (CTLs). These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell–fate decisions.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2023
Publisher: American Society of Hematology
Date: 07-2007
DOI: 10.1182/BLOOD-2006-11-060087
Abstract: Although self-reactive T-cell precursors can be eliminated upon recognition of self-antigen presented in the thymus, this central tolerance process is often incomplete, and additional mechanisms are required to prevent autoimmunity. Recent studies indicates that the interaction between B7-H1 and its receptor PD-1 on activated T cells plays an important role in the inhibition of T-cell responses in peripheral organs. Here, we show that, before their exit to the periphery, T cells in lymphoid organs rapidly up-regulate PD-1 upon tolerogen recognition. Ablation of the B7-H1 and PD-1 interaction when T cells are still in lymphoid organs prevents anergy. Furthermore, blockade of B7-H1 and PD-1 interaction could render anergic T cells responsive to antigen. Our results thus reveal previously unappreciated roles of B7-H1 and PD-1 interaction in the control of initiation and reversion of T-cell anergy.
Publisher: American Society of Hematology
Date: 06-2007
DOI: 10.1182/BLOOD-2006-10-043463
Abstract: CD137 has long been recognized as a costimulatory receptor for growth and functional maturation of recently activated T cells in the presence of T-cell receptor signal. In this report, we present the fact that, in the absence of MHC and antigen, triggering of CD137 by an agonist monoclonal antibody induces vigorous growth of both CD8+ and CD4+ T cells with memory phenotype, whereas it does not affect naive T cells. Moreover, T cells with memory phenotype accumulate progressively in transgenic mice overexpressing CD137 ligand. CD137-mediated proliferation of memory T cells is directly through CD137 on T cells and does not require IL-15 and IFN-γ. Our results define a new role of CD137 signal in the growth of memory T cells.
Publisher: CSIRO Publishing
Date: 09-12-2021
DOI: 10.1071/WR20210
Abstract: Abstract Context Disease is increasingly becoming a driver of wildlife population declines and an extinction risk. Vaccines are one of the most successful health interventions in human history, but few have been tested for mitigating wildlife disease. The transmissible cancer, devil facial tumour disease (DFTD), triggered the Tasmanian devil’s (Sarcophilus harrisii) inclusion on the international endangered species list. In 2016, 33 devils from a DFTD-free insurance population were given an experimental DFTD vaccination before their wild release on the Tasmanian northern coast. Aim To determine the efficacy of the vaccination protocol and the longevity of the induced responses. Method Six trapping trips took place over the 2.5 years following release, and both vaccinated and incumbent devils had blood s les and tumour biopsies collected. Key results In all, 8 of the 33 vaccinated devils were re-trapped, and six of those developed DFTD within the monitoring period. Despite the lack of protection provided by the vaccine, we observed signs of immune activation not usually found in unvaccinated devils. First, sera collected from the eight devils showed that anti-DFTD antibodies persisted for up to 2 years post-vaccination. Second, tumour-infiltrating lymphocytes were found in three of four biopsies collected from vaccinated devils, which contrasts with the ‘immune deserts’ typical of DFTs only 1 of the 20 incumbent devils with DFTD had a tumour biopsy exhibiting immune-cell infiltrate. Third, immunohistochemical analysis of the vaccinated devils’ tumour biopsies identified the functional immune molecules associated with antigen-presenting cells (MHC-II) and T-cells (CD3), and the immune checkpoint molecule PD-1, all being associated with anti-tumour immunity in other species. Conclusions These results correlate with our previous study on captive devils in which a prophylactic vaccine primed the devil immune system and, following DFTD challenge and tumour growth, immunotherapy induced complete tumour regressions. The field trial results presented here provide further evidence that the devil immune system can be primed to recognise DFTD cells, but additional immune manipulation could be needed for complete protection or induction of tumour regressions. Implications A protective DFTD vaccine would provide a valuable management approach for conservation of the Tasmanian devil.
Publisher: American Society for Clinical Investigation
Date: 23-03-2006
DOI: 10.1172/JCI27083
Publisher: American Society of Hematology
Date: 19-02-2009
DOI: 10.1182/BLOOD-2008-01-133223
Abstract: B7-H4 is an immunoglobulin superfamily molecule and shown to be inhibitory for T-cell responses. To explore physiologic roles of B7-H4, we created B7-H4–deficient (KO) mice by genetic targeting. B7-H4KO mice are healthy and their T- and B-cell responses to polyclonal antigens are in normal range. However, B7-H4KO mice are more resistant to infection by Listeria monocytogenes than their littermates. Within 3 days after infection, bacterial colonies in livers and spleens are significantly lower than the controls, suggesting a role of B7-H4 in enhancing innate immunity. Further studies demonstrate that neutrophils increase in peripheral organs of B7-H4KO mice more so than their littermates but their bactericidal functions remain unchanged. Augmented innate resistance is completely dependent on neutrophils, even in the absence of adaptive immunity. In vitro B7-H4 inhibits the growth of bone marrow–derived neutrophil progenitors, suggesting an inhibitory function of B7-H4 in neutrophil expansion. Our results identify B7-H4 as a negative regulator of the neutrophil response to infection and provide a new target for manipulation of innate immunity.
Publisher: Cold Spring Harbor Laboratory
Date: 07-12-2020
DOI: 10.1101/2020.12.06.408963
Abstract: Disease is increasingly becoming a driver of wildlife population declines and extinction risk. Vaccines have been one of the most successful health interventions in human history, but few have been tested for mitigating wildlife disease. The transmissible cancer, devil facial tumour disease (DFTD), triggered the Tasmanian devil’s ( Sarcophilus harrisii ) inclusion on the international endangered species list. Development of a protective DFTD vaccine would provide a valuable management approach for conservation of the species. In 2016, 33 devils from a DFTD-free insurance population were given an experimental DFTD vaccination prior to their release on the north coast of Tasmania. The release site was already home to an incumbent population of devils, including some in iduals with DFTD. To determine the efficacy of the vaccination protocol and the longevity of the response it induced, six trapping trips took place at the site over the 2.5 years following release. Eight of the 33 vaccinated devils were re-trapped, and six of those developed DFTD within the monitoring period. Despite the apparent lack of protection provided by the vaccine for the re-trapped devils, we observed several signs of immune activation not usually found in unvaccinated devils. Firstly, sera collected from the eight devils showed that anti-DFTD antibodies persisted for up to two years post vaccination. Secondly, tumour infiltrating lymphocytes were found in three out of four biopsies collected from vaccinated devils which contrasts with the “immune deserts” typical of DFT’s only one out of twenty incumbent devils with DFTD trapped during the same period had a tumour biopsy exhibiting immune cell infiltrate. Thirdly, immunohistochemical analysis of tumour biopsies from the vaccinated devils identified the functional immune molecules associated with antigen presenting cells (MHC-II) and T cells (CD3), and the immune checkpoint molecule PD-1, all associated with anti-tumour immunity in other species. These results correlate with our previous study on captive devils in which a prophylactic vaccine primed the devil immune system and, following DFTD challenge and tumour growth, immunotherapy induced complete tumour regressions. The field trial results presented here provide further evidence that the devil immune system can be primed to recognise DFTD cells, but additional immune manipulation could be needed for complete protection or induction of tumour regressions.
Publisher: Cold Spring Harbor Laboratory
Date: 07-09-2020
DOI: 10.1101/2020.09.06.274720
Abstract: Downregulation of major histocompatibility complex I (MHC-I) on tumor cells is a primary means of immune evasion by many types of cancer. Additionally, MHC-I proteins are a primary target of immune-mediated transplant rejection. Transmissible tumors that overcome allograft rejection mechanisms and evade anti-tumor immunity have killed thousands of wild Tasmanian devils ( Sarcophilus harrisii ). Interferon gamma (IFNG) upregulates surface MHC-I expression on devil facial tumor (DFT) cells but is not sufficient to induce tumor regressions. Transcriptome analysis of IFNG-treated DFT cells revealed strong upregulation of NLRC5 , a master regulator of MHC-I in humans and mice. To explore the role of NLRC5 in transmissible cancers, we developed DFT cell lines that constitutively overexpress NLRC5. Transcriptomic results suggest that the role of NLRC5 as a master regulator of MHC-I is conserved in devils. Furthermore, NLRC5 was shown to drive the expression of many components of the antigen presentation pathway. To determine if MHC-I is a target of allogeneic immune responses, we tested serum from devils with anti-DFT responses including natural DFT regressions against DFT cells. Antibody binding occurred with cells treated with IFNG and overexpressed NLRC5. However, CRISPR/Cas9-mediated knockout of MHC-I subunit beta-2-microglobulin ( B2M ) eliminated antibody binding to DFT cells. Consequently, MHC-I could be identified as a target for anti-tumor and allogeneic immunity and provides mechanistic insight into MHC-I expression and antigen presentation in marsupials. NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
Publisher: Frontiers Media SA
Date: 30-01-2019
Publisher: Microbiology Society
Date: 11-2022
DOI: 10.1099/JGV.0.001812
Abstract: The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil ( Sarcophilus harrisii ) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100 %. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2 and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as a vaccine platform for devils and potentially other marsupials.
Publisher: CSIRO Publishing
Date: 2022
DOI: 10.1071/WR22070
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
Abstract: Integrating comparative immunology can improve human, animal, and ecosystem health
Publisher: Bio-Protocol, LLC
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 02-02-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-2022
DOI: 10.1101/2022.10.31.513798
Abstract: The wild Tasmanian devil ( Sarchophilus harrisii ) population has suffered a devastating decline due to two clonal transmissible cancers. Devil facial tumor 1 (DFT1) was first observed in 1996, followed by a second genetically distinct transmissible tumor, devil facial tumor 2 (DFT2), in 2014. DFT1/2 frequently metastasize, with lymph nodes being common metastatic sites. Downregulation of MHC-I by DFT1 cells is a primary means of evading allograft immunity aimed at polymorphic MHC-I proteins. DFT2 cells constitutively express MHC-I, and MHC-I is upregulated on DFT1/2 cells by interferon gamma, suggesting other immune evasion mechanisms may contribute to overcoming allograft and anti-tumor immunity. Human clinical trials have demonstrated PD1/PDL1 blockade effectively treats patients showing increased expression of PD1 in tumor draining lymph nodes, and PDL1 on peritumoral immune cells and tumor cells. The effects of DFT1/2 on systemic immunity remain largely uncharacterized. This study applied the open-access software QuPath to develop a semiautomated pipeline for whole slide analysis of stained tissue sections to quantify PD1/PDL1 expression in devil lymph nodes. The QuPath protocol provided strong correlations to manual counting. PD-1 expression was approximately 10-fold higher than PD-L1 expression in lymph nodes and was primarily expressed in germinal centers, whereas PD-L1 expression was more widely distributed throughout the lymph nodes. The density of PD1 positive cells was increased in lymph nodes containing DFT2 metastases, compared to DFT1. This suggests PD1/PDL1 exploitation may contribute to the poorly immunogenic nature of transmissible tumors in some devils and could be targeted in therapeutic or prophylactic treatments.
Publisher: Frontiers Media SA
Date: 14-01-2019
Publisher: Cold Spring Harbor Laboratory
Date: 14-07-2021
DOI: 10.1101/2021.07.14.452299
Abstract: MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that constitutive expression of NLRC5 can induce stable upregulation of MHC-I on DFT1 and DFT2 cells, but unlike IFNG-treated cells, NLRC5 does not upregulate PDL1. MHC-II expression is crucial for CD4 + T cell activation and is primarily confined to haematopoietic antigen presenting cells. Transcriptomic analysis of DFT1 and DFT2 cell lines showed that several genes of the MHC-I and MHC-II pathways were upregulated in response to constitutive overexpression of the class II transactivator (CIITA) gene. This was further supported by upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only on DFT1 cells. The functional significance of the MHC upregulation on DFT cells was shown using serum from devils with natural or immunotherapy-induced DFT1 regressions binding of serum IgG was stronger in CIITA-transfected cells than wild type cells, but was less than binding to NLRC5 transfected cells. This new insight into regulation of MHC-I and MHC-II in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy, and tissue transplant strategies for human and veterinary medicine.
Publisher: Oxford University Press (OUP)
Date: 26-10-2018
DOI: 10.1093/ICB/ICY118
Abstract: The Tasmanian devil, a marsupial carnivore, has been restricted to the island state of Tasmania since its extinction on the Australian mainland about 3000 years ago. In the past two decades, this species has experienced severe population decline due to the emergence of devil facial tumor disease (DFTD), a transmissible cancer. During these 20 years, scientists have puzzled over the immunological and evolutionary responses by the Tasmanian devil to this transmissible cancer. Targeted strategies in population management and disease control have been developed as well as comparative processes to identify variation in tumor and host genetics. A multi-disciplinary approach with multi-institutional teams has produced considerable advances over the last decade. This has led to a greater understanding of the molecular pathogenesis and genomic classification of this cancer. New and promising developments in the Tasmanian devil’s story include evidence that most immunized, and some wild devils, can produce an immune response to DFTD. Furthermore, epidemiology combined with genomic studies suggest a rapid evolution to the disease and that DFTD will become an endemic disease. Since 1998 there have been more than 350 publications, distributed over 37 Web of Science categories. A unique endemic island species has become an international curiosity that is in the spotlight of integrative and comparative biology research.
Publisher: Wiley
Date: 31-05-2023
DOI: 10.1111/JEB.14181
Abstract: Driven by co‐evolution with pathogens, host immunity continuously adapts to optimize defence against pathogens within a given environment. Recent advances in genetics, genomics and transcriptomics have enabled a more detailed investigation into how immunogenetic variation shapes the ersity of immune responses seen across domestic and wild animal species. However, a deeper understanding of the erse molecular mechanisms that shape immunity within and among species is still needed to gain insight into—and generate evolutionary hypotheses on—the ultimate drivers of immunological differences. Here, we discuss current advances in our understanding of molecular evolution underpinning jawed vertebrate immunity. First, we introduce the immunome concept, a framework for characterizing genes involved in immune defence from a comparative perspective, then we outline how immune genes of interest can be identified. Second, we focus on how different selection modes are observed acting across groups of immune genes and propose hypotheses to explain these differences. We then provide an overview of the approaches used so far to study the evolutionary heterogeneity of immune genes on macro and microevolutionary scales. Finally, we discuss some of the current evidence as to how specific pathogens affect the evolution of different groups of immune genes. This review results from the collective discussion on the current key challenges in evolutionary immunology conducted at the ESEB 2021 Online Satellite Symposium: Molecular evolution of the vertebrate immune system, from the lab to natural populations.
Publisher: Wildlife Disease Association
Date: 07-2013
DOI: 10.7589/2011-09-262
Abstract: Beginning in 1997 Michigan State University Mara Hyena Project investigators observed waxing and waning progression of oral and genital masses during long-term behavioral observations of a population of wild spotted hyenas (Crocuta crocuta) from the Masai Mara Game Reserve, Kenya. From 1999-2000, we darted adult spotted hyenas to obtain routine physiologic and hematologic data and collected small, raised, lobulated, pigmented masses from the oral or genital areas of eight animals. Microscopically, masses consisted of variably thickened epidermis with thick elongate rete pegs, prominent stratum spinosum, and few koilocytes, consistent with papillomavirus-induced lesions. Immunohistochemistry on formalin-fixed, paraffin-embedded papilloma tissue revealed positive intranuclear labeling for papillomavirus antigen in the superficial stratum granulosum and in sloughing keratin layers of multiple s les. Polymerase chain reaction on DNA extracts from tumor tissue lified a papillomavirus-specific 418 base pair licon in the E1 ORF. Basic Local Alignment Search Tool analysis of the sequenced licon suggests a novel hyaenid papillomavirus. Confirmatory complete genomic sequencing was performed later by the Rega Institute in Belgium. To our knowledge, this is the first report of a papillomavirus in a Hyaenidae species. Spotted hyena social behavior might facilitate oral-genital transmission of papillomavirus in this population.
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.DCI.2020.103882
Abstract: Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily ergent species.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2019
DOI: 10.1007/S00018-019-03259-2
Abstract: Devil facial tumour disease (DFTD) comprises two genetically distinct transmissible cancers (DFT1 and DFT2) endangering the survival of the Tasmanian devil (Sarcophilus harrisii) in the wild. DFT1 first arose from a cell of the Schwann cell lineage however, the tissue-of-origin of the recently discovered DFT2 cancer is unknown. In this study, we compared the transcriptome and proteome of DFT2 tumours to DFT1 and normal Tasmanian devil tissues to determine the tissue-of-origin of the DFT2 cancer. Our findings demonstrate that DFT2 expresses a range of Schwann cell markers and exhibits expression patterns consistent with a similar origin to the DFT1 cancer. Furthermore, DFT2 cells express genes associated with the repair response to peripheral nerve damage. These findings suggest that devils may be predisposed to transmissible cancers of Schwann cell origin. The combined effect of factors such as frequent nerve damage from biting, Schwann cell plasticity and low genetic ersity may allow these cancers to develop on rare occasions. The emergence of two independent transmissible cancers from the same tissue in the Tasmanian devil presents an unprecedented opportunity to gain insight into cancer development, evolution and immune evasion in mammalian species.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2021
Publisher: Elsevier BV
Date: 2012
Publisher: The Royal Society
Date: 10-2022
DOI: 10.1098/RSOB.220208
Abstract: MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4 + T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.
Publisher: Informa UK Limited
Date: 2012
Location: United States of America
Start Date: 2017
End Date: 2017
Funder: Department of Industry and Science
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: University of Tasmania Foundation Inc
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: University of Tasmania Foundation Inc
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 12-2020
Amount: $365,058.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2018
End Date: 12-2021
Amount: $303,931.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2023
End Date: 06-2025
Amount: $204,900.00
Funder: Australian Research Council
View Funded Activity