Melbourne Dental School - Research Publications
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ItemSAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis(MDPI, 2022-06)Most patients with colorectal cancer (CRC) develop metastases, predominantly in the liver (CLM). Targeted therapies are being investigated to improve current CLM treatments. This study tested the effectiveness of SAR131675, a selective VEGFR-3 tyrosine kinase inhibitor, to inhibit CLM in a murine model. Following intrasplenic induction of CLM, mice were treated daily with SAR131675. Tumor growth and immune infiltrates into tumor and liver tissues were assessed at 10-, 16- and 22-days post tumor induction by stereology, IHC and flow cytometry. SAR151675 treatment significantly reduced tumor burden and F4/80+ macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45+ leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b+ CD45+) indicated that the proportion of F4/80- Ly6Clow was significantly reduced, including a predominate PD-L1+ subset, while CD3+ T cells increased, particularly CD8+ PD1+, reflected by an increase in the CD8+:CD4+ T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80+ Ly6Clo and increased CD4+ T cells. These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth.
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ItemAdolescent temperament dimensions as stable prospective risk and protective factors for salivary C-reactive protein(WILEY, 2018-02)OBJECTIVE: Temperament has associations with later physical health outcomes, yet there is a dearth of research exploring the connection between temperament and mechanisms that have known associations with these health outcomes. Recent research has delineated a connection between personality and inflammation during adulthood, but this association has not yet been studied in adolescent samples. DESIGN: We investigated whether stable adolescent temperament (averaged over two years), specifically effortful control and negative emotionality, provided a more robust prediction of inflammation as measured by salivary C-reactive protein (sCRP), than depressive symptoms. METHODS: Temperament and depressive symptoms were measured in a sample of sixty-three adolescents (37 males) when they were approximately 12 years old (mean age = 12.30, SD = 0.69) and again when they were approximately 14 years old (mean age = 14.84, SD = 0.49). Levels of sCRP were determined approximately 7 months later (mean = 6.77, SD = 2.99) when participants were approximately 15 years old (mean age = 15.49, SD = 0.49). RESULTS: Regression analyses revealed that effortful control (EC) was significantly associated with lower sCRP levels, while higher negative emotionality (NE) was significantly associated with higher sCRP levels. Furthermore, these associations were larger than those for depressive symptoms and were differentially impacted by the addition of covariates. Implications for the role of stable risk and protective factors in inflammatory processes are discussed. CONCLUSIONS: These findings are the first to show associations between adolescent temperament and inflammation. Furthermore, these findings extend previous personality research to temperamental research in a younger sample of adolescents. Statement of contribution What is already known? There is a large extant literature on the association between depressive symptoms and inflammation. There is a smaller extant literature on the association between personality and inflammation. No studies have examined how adolescent temperament traits may relate to inflammation. What does this study add? Longitudinal data collection over the course of 3 years in an adolescent sample. Addresses the question of whether temperament factors relate to inflammation. Temperament provides a more robust predictor of later inflammation than depressive symptoms.
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ItemPeripheral memory T-cell profile is modified in patients undergoing periodontal management(WILEY, 2021-02)AIMS: T-cells are known to have a role in periodontitis, however, the effect of periodontal therapy on peripheral memory T-cells is unclear. This study evaluated variation in peripheral memory T-cells and red complex bacteria in sub-gingival plaque in patients undergoing periodontal management. METHODS: Peripheral blood mononuclear cells and sub-gingival plaque were collected from 54 periodontitis patients at baseline, 3-, 6- and 12-months post-therapy and 40 healthy controls. Periodontitis patients were divided into treatment outcome (TxO) groups based on prevalence of sites with probing depth ≥5 mm as good (<10% of sites), moderate (10-20%) or poor (>20%) at study conclusion. Naïve (TN -CCR7+ CD45RA+ ), central memory (TCM -CCR7+ CD45RA- ), effector memory (TEM -CCR7- CD45RA- ) and effector memory T-cells re-expressing CD45RA (TEMRA -CCR7- CD45RA+ ) were phenotyped using flow cytometry in CD4+ , CD8+ , CD4+ CD8+ and CD4- CD8- T-cells and red complex bacteria were quantified using qPCR. RESULTS: At baseline, periodontitis subjects had significantly greater mean probing depths and Porphyromonas gingivalis proportions, lower TN but higher CD4+ TCM , CD8+ TCM , CD4+ CD8+ TEM and CD4- CD8- TEM cell proportions compared to health. Periodontal therapy decreased mean probing depths, P. gingivalis proportions, TEM and CD4+ and CD8+ TCM cells, but increased TN and CD4+ and CD8+ TEMRA cells. The T-cell profile in the good TxO group showed therapy-related changes in CD4+ TEM , and CD8+ TN and TEM cells, whereas, no changes were observed in the poor TxO group. CONCLUSION: Management and the reduction in red complex bacteria were associated with changes in peripheral memory T-cells in periodontitis.
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ItemPeripheral T helper cell profiles during management of periodontitis(WILEY, 2021-01)AIM: Periodontitis has been associated with other systemic diseases with underlying inflammation responsible for the shared link. This study evaluated longitudinal variation in peripheral T helper cells in periodontitis patients undergoing management over 1 year. MATERIALS AND METHODS: Periodontal parameters and peripheral blood mononuclear cells (PBMCs) were collected from 54 periodontitis patients at baseline, and 3-, 6- and 12-months post-treatment and 40 healthy controls. IFN-γ+ , IL-4+ , IL-17+ and Foxp3+ and their double-positive expression were identified in CD4+ and TCRαβ+ cells using flow cytometry. PBMCs were incubated with P. gingivalis, and IFN-γ, IL-4, IL-17 and IL-10 in cell supernatant were measured by ELISA. Cells and cytokines were also assessed based on clinical response to treatment where good (<10% of sites), moderate (10-20%) and poor (>20%) treatment outcome (TxO) groups had probing depths of ≥5 mm at study conclusion. RESULTS: IFN-γ+ cells were lower at baseline, and 3- and 6-months compared to health, whereas Foxp3+ cells were increased at 12-months compared to all preceding timepoints and health. The good TxO group showed treatment-related variation in IFN-γ+ and Foxp3+ cells, whereas the poor TxO group did not. IFN-γ and IL-17 cytokine expression in cell supernatants was significantly lower at baseline compared to health, and IFN-γ and IL-10 showed treatment-related decrease. CONCLUSION: This study suggests that IFN-γ+ and Foxp3+ cells may have a role in the systemic compartment in periodontitis. Periodontal management has local and systemic effects, and thus, assessment and management of periodontitis should form an integral part of overall systemic health.
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ItemPeripheral neutrophil phenotypes during management of periodontitis(WILEY, 2021-01)BACKGROUND AND OBJECTIVES: Neutrophils are emerging as a key player in periodontal pathogenesis. The surface expression of cellular markers enables functional phenotyping of neutrophils which have distinct roles in disease states. This study aimed to evaluate the effect of periodontal management on neutrophil phenotypes in peripheral blood in periodontitis patients over one year. MATERIALS AND METHODS: Peripheral blood and the periodontal parameters, mean probing depth and percentage of sites with bleeding on probing (%BOP), were collected from 40 healthy controls and 54 periodontitis patients at baseline and 3-, 6- and 12- months post-treatment. Flow cytometry was used to identify CD11b+ , CD16b+ , CD62L- and CD66b+ expression on neutrophils, neutrophil maturation stages as promyelocytes (CD11b- CD16b- ), metamyelocytes (CD11b+ CD16b- ) and mature neutrophils (CD11b+ CD16b+ ), and suppressive neutrophil phenotype as bands (CD16dim CD62Lbright ), normal neutrophils (CD16bright CD62Lbright ) and suppressive neutrophils (CD16bright CD62Ldim ). RESULTS: CD62L- expression decreased with treatment. No differences were observed in neutrophil maturation stages in health or disease upon treatment. Suppressive and normal neutrophils showed a reciprocal relationship, where suppressive neutrophils decreased with treatment and normal neutrophils increased with treatment. In addition, %BOP was associated with suppressive neutrophils. CONCLUSION: This study demonstrates that management of periodontitis significantly modifies distinct neutrophil phenotypes in peripheral blood. Suppressive neutrophils may play a role in the pathogenesis of periodontitis. However, their exact role is unclear and requires further investigation.
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ItemImmunomodulatory effects of renin-angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases(BMJ PUBLISHING GROUP, 2020)BACKGROUND: It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin-angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin-angiotensin system inhibitors (RASi). AIM: To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases. METHODS: Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC). RESULTS: Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets . CONCLUSION: Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.
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ItemMEK-ERK signaling diametrically controls the stimulation of IL-23p19 and EBI3 expression in epithelial cells by IL-36(WILEY, 2018-07)Interleukin (IL)-36 cytokines are important regulators of mucosal homeostasis and inflammation. We previously established that oral epithelial cells strongly upregulate IL-36γ expression in response to the bacterial pathogen Porphyromonas gingivalis. Here, we have established that IL-36γ stimulates the expression of the IL-12 cytokine family members, IL-23p19 and Epstein-Barr Virus-Induced Gene 3 (EBI3), by oral epithelial cells; their expression was also selectively stimulated by IL-36α. Notably, IL-23p19 and EBI3 expression was not stimulated by P. gingivalis, thus suggesting that their expression by the oral epithelium in response to P. gingivalis is likely to be mediated in an autocrine manner by IL-36γ. The IL-36γ-inducible expression of IL-23p19 and EBI3 was found to be diametrically regulated by the mitogen-activated protein kinase/extracellular signal regulated kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereby the activation of MEK-ERK signaling likely functions as a negative feedback mechanism to limit EBI3 expression. Furthermore, epidermal growth factor receptor (EGFR) signaling, which is important for mucosal homeostasis, was demonstrated to modulate, in a MEK-ERK-dependent manner, the stimulation of IL-23p19 and EBI3 expression by IL-36γ. IL-23p19 and EBI3 have recently been shown to heterodimerize to form the novel cytokine IL-39 and promote neutrophil expansion. EBI3 has been shown to also have IL-12 cytokine family independent functions (e.g. mediating IL-6 trans-signaling). Thus, this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function.
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ItemAssociations Between Observed Parenting Behavior and Adolescent Inflammation Two and a Half Years Later in a Community Sample(AMER PSYCHOLOGICAL ASSOC, 2017-07)OBJECTIVE: Family environments have an effect on physical health during adolescence, and a possible underlying mechanism is inflammation. However, little is known about the association between observed parenting behaviors and immune system functioning. The current study examined whether positive and negative emotional parental behaviors observed during family interactions were associated with inflammation in adolescents. METHOD: Sixty-one parent-adolescent dyads (37 male adolescents, 60.6%; 15 male parents, 24.6%) were observed during 2 laboratory-based interaction tasks designed to elicit positive and conflictual emotional behaviors, respectively. Frequency of aggressive and positive parental behavior was coded. Adolescents were followed up approximately 2.5 years later and salivary concentrations of the inflammatory biomarker C-reactive protein (sCRP) were measured. RESULTS: Controlling for BMI and depressive symptoms, lower sCRP was associated both with greater frequency of positive parental behaviors, t = -3.087, p = .003 and less frequency of aggressive parental behavior (t = 2.087, p = .041) in the conflictual task. Trend associations between positive behavior during the positive task and lower sCRP were also found. CONCLUSIONS: This is the first study to show that observed positive parenting is associated with lower levels of inflammation in adolescents. (PsycINFO Database Record
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ItemNo Preview AvailableBacterial Fluorescent-dextran Diffusion Assay(Bio-Protocol, LLC, 2014)
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ItemOxantel Disrupts Polymicrobial Biofilm Development of Periodontal Pathogens(AMER SOC MICROBIOLOGY, 2014-01)Bacterial pathogens commonly associated with chronic periodontitis are the spirochete Treponema denticola and the Gram-negative, proteolytic species Porphyromonas gingivalis and Tannerella forsythia. These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation. Here, we demonstrate that oxantel inhibited P. gingivalis Frd activity with a 50% inhibitory concentration (IC50) of 2.2 μM and planktonic growth of T. forsythia with a MIC of 295 μM, but it had no effect on the growth of T. denticola. Oxantel treatment caused the downregulation of six P. gingivalis gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that P. gingivalis may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of P. gingivalis, T. forsythia, and T. denticola in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of T. denticola on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of P. gingivalis-infected mice reduced bone loss to the same level as the uninfected control.