ARDC Research Link Australia

Publication

An HLA-based approach to the design of a CTL-inducing vaccine against Plasmodium falciparum

Publisher: Elsevier BV

Date: 1994

DOI: 10.1016/S0923-2494(94)80177-0

Publication

Publisher: Elsevier BV

Date: 08-1999

DOI: 10.1074/JBC.274.34.24113

Publication

Promising particle-based vaccines in cancer therapy

Publisher: Informa UK Limited

Date: 09-2008

DOI: 10.1586/14760584.7.7.1103

Abstract: Immunotherapy and preventative cancer vaccines offer the hope of controlling cancer in humans with few of the undesirable side effects associated with current chemotherapy-based methods. Particulate vaccines are effectively taken up by dendritic cells, inducing both T-cell and antibody responses. Virus-like particles (VLPs) have shown preventive efficacy against cervical cancer. Herein we review a range of leading particle-based vaccine approaches: VLPs, immunostimulating complexes, liposomes, synthetic nanoparticles and microparticles (both biocompatible and biodegradable, such as polylactide-co-glycolides and poly[D,L-lactic-co-glycolic] acid). Immune efficacy, regulatory and safety issues, as well the application of immunotherapeutics to immunosuppressed patients with high levels of Tregs are also discussed. We argue that developmental issues (cost and intellectual property lifespan) and the lack of reliable preclinical animal models, rather than the lack of innovative vaccine approaches, currently present a major obstacle to rapid and effective vaccine development.

Publication

Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor-An Opportunity for Cancer Treatment.

Publisher: MDPI AG

Date: 20-12-2019

DOI: 10.3390/CELLS9010033

Abstract: Tumor necrosis factor receptor 2 (TNFR2) is expressed on some tumor cells, such as myeloma, Hodgkin lymphoma, colon cancer and ovarian cancer, as well as immunosuppressive cells. There is increasingly evidence that TNFR2 expression in cancer microenvironment has significant implications in cancer progression, metastasis and immune evasion. Although nanomedicine has been extensively studied as a carrier of cancer immunotherapeutic agents, no study to date has investigated TNFR2-targeting nanomedicine in cancer treatment. From an epigenetic perspective, previous studies indicate that DNA demethylation might be responsible for high expressions of TNFR2 in cancer models. This perspective review discusses a novel therapeutic strategy based on nanomedicine that has the capacity to target TNFR2 along with inhibition of DNA demethylation. This approach may maximize the anti-cancer potential of nanomedicine-based immunotherapy and, consequently, markedly improve the outcomes of the management of patients with malignancy.

Publication

Insights into endotoxin-mediated lung inflammation and future treatment strategies

Publisher: Informa UK Limited

Date: 03-10-2018

DOI: 10.1080/17476348.2018.1523009

Abstract: Airway inflammatory disorders are prevalent diseases in need of better management and new therapeutics. Immunotherapies offer a solution to the problem of corticosteroid resistance. Areas covered: The current review focuses on lipopolysaccharide (Gram-negative bacterial endotoxin)-mediated inflammation in the lung and the animal models used to study related diseases. Endotoxin-induced lung pathology is usually initiated by antigen presenting cells (APC). We will discuss different subsets of APC including lung dendritic cells and macrophages, and their role in responding to endotoxin and environmental challenges. Expert commentary: The pharmacotherapeutic considerations to combat airway inflammation should cost-effectively improve quality of life with sustainable and safe strategies. Selectively targeting APCs in the lung offer the potential for a promising new strategy for the better management and treatment of inflammatory lung disease.

Publication

Publisher: MDPI AG

Date: 29-10-2015

DOI: 10.3390/VACCINES3040894

Publication

A flowcytometric analysis to efficiently quantify multiple innate immune cells and T Cell subsets in human blood

Publisher: Wiley

Date: 06-03-2017

DOI: 10.1002/CYTO.A.23080

Abstract: The balance of inflammation and immunosuppression driven by changed ratios in erse myeloid and T cell subsets, as well as their state of activation and ability to migrate to lymphoid compartments or inflammatory sites, has emerged as a highly active area of study across clinical trials of vaccines and therapies against cancer, trauma, as well as autoimmune and infectious diseases. There is a need for effective protocols which maximally use the possibilities offered by modern flow cytometers to characterize such immune cell changes in peripheral blood using small volumes of human blood. Additionally, longitudinal clinical studies often use cryopreserved s les, which can impact flow cytometric results. To efficiently gauge both the innate and the adaptive immune response, two novel 15-color antibody panels to identify key myeloid and T cell subsets and their functional potential were established. This approach was used to compare cellular immune profiles in fresh whole blood and in matched cryopreserved peripheral blood mononuclear cells (PBMCs). Cocktail I was designed to identify and characterize myeloid cell populations including dendritic cells (DCs), monocytic monocyte-derived suppressor cells (MO-MDSC), and monocytes, determining further core aspects of their state of maturity, T cell stimulatory (or inhibitory) potential, and migration capability. Cocktail II was used for phenotyping erse T cells subsets, and their key migration and functional regulatory capabilities. The two 15-color antibody panels for the evaluation of both immune-stimulating and immunosuppressive processes presented herein allowed for efficient evaluation of the balance of immune activation versus immunosuppression across key blood cells, with good resolution for all 15 markers stained for in each panel. Gating strategies for the myeloid and T cells are presented to further support specific subset identification. This protocol was shown to be reproducible across donors and useful to study both RBC-lysed whole blood and cryopreserved PBMCs. © 2017 International Society for Advancement of Cytometry.

Publication

Publisher: Springer Science and Business Media LLC

Date: 06-2006

DOI: 10.1186/BCR1505

Publication

Keratin-14 (KRT14) positive leader cells mediate mesothelial clearance and invasion by ovarian cancer cells

Publisher: MDPI AG

Date: 22-08-2019

DOI: 10.3390/CANCERS11091228

Abstract: Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a “snapshot” of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer “leader cell” phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies.

Publication

The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development

Publisher: Springer Science and Business Media LLC

Date: 08-09-2013

DOI: 10.1007/S00125-013-3038-2

Abstract: Type 1 diabetes is characterised by early peri-islet insulitis and insulin autoantibodies, followed by invasive insulitis and beta cell destruction. The immunological events that precipitate invasive insulitis are not well understood. We tested the hypothesis that B cells in diabetes-prone NOD mice drive invasive insulitis through elevated expression of CD19 and consequent enhanced uptake and presentation of beta cell membrane-bound antigens to islet invasive T cells. CD19 expression and signalling pathways in B cells from NOD and control mice were compared. Expansion of CD8(+) T cells specific for insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were compared in CD19-deficient and wild-type NOD mice and this was correlated with insulitis severity. The therapeutic potential of anti-CD19 treatment during the period of T cell activation was assessed for its ability to block invasive insulitis. CD19 expression and signalling in B cells was increased in NOD mice. CD19 deficiency significantly diminished the expansion of CD8(+) T cells with specificity for the membrane-bound beta cell antigen, IGRP. Conversely the reduction in CD8(+) T cells with specificity for the soluble beta cell antigen, insulin, was relatively small and not significant. Elevated CD19 on NOD B cells promotes presentation of the membrane-bound antigen, IGRP, mediating the expansion of autoreactive T cells specific for antigens integral to beta cells, which are critical for invasive insulitis and diabetes. Downregulating the CD19 signalling pathway in insulin autoantibody-positive in iduals before the development of type 1 diabetes may prevent expansion of islet-invasive T cells and preserve beta cell mass.

Publication

Publisher: Frontiers Media SA

Date: 06-11-2017

DOI: 10.3389/FIMMU.2017.01482

Publication

Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system

Publisher: Frontiers Media SA

Date: 09-09-2022

DOI: 10.3389/FGENE.2022.886170

Abstract: High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/ 2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through erse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.

Publication

CD38 identifies a hypo-proliferative IL-13-secreting CD4+ T-cell subset that does not fit into existing naive and memory phenotype paradigms

Publisher: Wiley

Date: 13-04-2011

DOI: 10.1002/EJI.201040726

Abstract: CD38 is commonly regarded as an activation marker for human T cells. Herein, we show that CD38 expression identifies a hypo-proliferative CD4(+) T-cell subset that, following TCR stimulation, retains expression of naive cell surface markers including CD45RA, CD62L and CCR7. Hypo-proliferation was mediated by reduced CD25 up-regulation upon TCR stimulation compared to CD4(+) CD38(-) cells and lack of responsiveness to exogenous IL-2. Instead, CD4(+) CD38(+) T cells expressed CD127, and hypo-proliferation was reversed by addition of IL-7, further associated with increased STAT5 phosphorylation. This phenotype was exacerbated by addition of an agonistic CD38-binding antibody, suggesting that signaling through CD38 promotes this cell profile. Activated CD4(+) CD38(+) cells had a bias towards IL-13 secretion, but not other Th2 cytokines such as IL-4 or IL-5. In comparison, the CD4(+) CD38(-) cells had a clear bias towards secretion of Th1-associated cytokines IFN-γ and TNF. The existence of such CD4(+) CD38(+) T cells may play an important role in pathologies such as asthma, which are associated with IL-13, but not IL-4 and IL-5. Coupled with responsiveness to IL-7 but not IL-2, and the involvement of CD38 ligation, our results highlight a unique T-cell subpopulation that does not fit into existing naive and memory cell paradigms.

Publication

Comparison of numerous delivery systems for the induction of cytotoxic T lymphocytes by immunization

Publisher: Wiley

Date: 08-1996

DOI: 10.1002/EJI.1830260841

Abstract: A variety of vaccine delivery systems including peptides with various adjuvants, recombinant particles, live recombinant viruses and bacteria and plasmid DNA were tested for their ability to induce CD8+ cytotoxic T lymphocytes (CTL) against a well-defined epitope (amino acids 252-260) from the circumsporozoite (CS) protein of Plasmodium berghei. We compared routes of immunization that would be applicable for the administration of a malaria vaccine in humans. The majority of these vaccines did not induce high CTL responses in the spleens of immunized mice. However, both a yeast-derived Ty virus-like particle expressing the optimal nine-amino acid epitope SYIPSAEKI from the CS protein (CSP-VLP) and a lipid-tailed peptide of this same sequence induced high levels of the major histocompatibility complex (MHC) class I-restricted CTL with one and three subcutaneous immunizations, respectively. Moreover, these CTL were able to recognize naturally processed antigen expressed by a recombinant vaccinia virus. The levels of CTL induced by CSP-VLP could be augmented by co-immunization with certain cytokines. Target cells pulsed with CSP-VLP were recognized and lysed, showing that the particles were effectively processed and presented through MHC class I presentation pathway. The levels of CTL induced using CSP-VLP and lipopeptides are comparable to those observed after immunization with multiple doses of irradiated sporozoites.

Publication

Publisher: Oxford University Press (OUP)

Date: 15-04-2011

DOI: 10.1093/INFDIS/JIQ166

Publication

Antibodies against Spike protein correlate with broad autoantigen recognition 8 months post SARS-CoV-2 exposure, and anti-calprotectin autoantibodies associated with better clinical outcomes

Publisher: Frontiers Media SA

Date: 11-08-2022

DOI: 10.3389/FIMMU.2022.945021

Abstract: Autoantibodies to multiple targets are found during acute COVID-19. Whether all, or some, persist after 6 months, and their correlation with sustained anti-SARS-CoV-2 immunity, is still controversial. Herein, we measured antibodies to multiple SARS-CoV-2 antigens (Wuhan-Hu-1 nucleoprotein (NP), whole spike (S), spike subunits (S1, S2 and receptor binding domain (RBD)) and Omicron spike) and 102 human proteins with known autoimmune associations, in plasma from healthcare workers 8 months post-exposure to SARS-CoV-2 (n=31 with confirmed COVID-19 disease and n=21 uninfected controls (PCR and anti-SARS-CoV-2 negative) at baseline). IgG antibody responses to SARS-CoV-2 antigens were significantly higher in the convalescent cohort than the healthy cohort, highlighting lasting antibody responses up to 8 months post-infection. These were also shown to be cross-reactive to the Omicron variant spike protein at a similar level to lasting anti-RBD antibodies (correlation r=0.89). In iduals post COVID-19 infection recognised a common set of autoantigens, specific to this group in comparison to the healthy controls. Moreover, the long-term level of anti-Spike IgG was associated with the breadth of autoreactivity post-COVID-19. There were further moderate positive correlations between anti-SARS-CoV-2 responses and 11 specific autoantigens. The most commonly recognised autoantigens were found in the COVID-19 convalescent cohort. Although there was no overall correlation in self-reported symptom severity and anti-SARS-CoV-2 antibody levels, anti-calprotectin antibodies were associated with return to healthy normal life 8 months post infection. Calprotectin was also the most common target for autoantibodies, recognized by 22.6% of the overall convalescent cohort. Future studies may address whether, counter-intuitively, such autoantibodies may play a protective role in the pathology of long-COVID-19.

Publication

Genetic analysis of host–parasite coevolution in human malaria

Publisher: The Royal Society

Date: 29-09-1997

DOI: 10.1098/RSTB.1997.0116

Abstract: Recent twin studies of clinical malaria and immune responses to malaria antigens have underscored the importance of both MHC and non–MHC genes in determining variable susceptibility and immune responsiveness. By using a combination of whole genome genetic linkage studies of families and candidate gene analysis, non–MHC genes are being mapped and identified. HLA genotype was found to affect susceptibility to severe malaria in a large study of West African children. T lymphocytes that may mediate such resistance have been identified and their target antigens and epitopes characterized. Some of these epitopes show substantial polymorphism, which appears to result from immune selection pressure. Natural variant epitopes have been found to escape T–cell recognition in cytolytic and other T–cell assays. More recently a novel immune escape mechanism has been described in viral infections, altered peptide ligand antagonism, whereby variants of a T–cell epitope can downregulate or ablate a T cell response to the index peptide. The likely implications of such immune escape mechanisms for the population structure of malaria parasites, for HLA associations with malaria infection and disease, and for the design of new malaria vaccines, are discussed. The evolutionary consequences of such molecular interactions can be assessed by using mathematical models that capture the dynamic interplay of variable host and parasite molecules. Combined genetic, immunological and mathematical analysis of host and parasite variants in natural populations can identify some mechanisms driving host–parasite coevolution.

Publication

A Perspective Review on the Role of Nanomedicine in the Modulation of TNF-TNFR2 Axis in Breast Cancer Immunotherapy

Publisher: Hindawi Limited

Date: 23-05-2019

DOI: 10.1155/2019/6313242

Abstract: In the past decade, nanomedicine research has provided us with highly useful agents (nanoparticles) delivering therapeutic drugs to target cancer cells. The present review highlights nanomedicine applications for breast cancer immunotherapy. Recent studies have suggested that tumour necrosis factor (TNF) and its receptor 2 (TNFR2) expressed on breast cancer cells have important functional consequences. This cytokine/receptor interaction is also critical for promoting highly immune-suppressive phenotypes by regulatory T cells (Tregs). This review generally provides a background for nanoparticles as potential drug delivery agents for immunomodulators and further discusses in depth the potential of TNF antagonists delivery to modulate TNF-TNFR2 interactions and inhibit breast cancer progression.

Publication

Publisher: Elsevier

Date: 2017

DOI: 10.1016/B978-0-323-46144-3.00012-X

Publication

Publisher: Frontiers Media SA

Date: 14-08-2017

DOI: 10.3389/FIMMU.2017.00921

Publication

Crystal structure of a non-canonical low-affinity peptide complexed with MHC class I: A new approach for vaccine design

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S0022-2836(02)00196-1

Abstract: Peptides bind with high affinity to MHC class I molecules by anchoring certain side-chains (anchors) into specificity pockets in the MHC peptide-binding groove. Peptides that do not contain these canonical anchor residues normally have low affinity, resulting in impaired pMHC stability and loss of immunogenicity. Here, we report the crystal structure at 1.6 A resolution of an immunogenic, low-affinity peptide from the tumor-associated antigen MUC1, bound to H-2Kb. Stable binding is still achieved despite small, non-canonical residues in the C and F anchor pockets. This structure reveals how low-affinity peptides can be utilized in the design of novel peptide-based tumor vaccines. The molecular interactions elucidated in this non-canonical low-affinity peptide MHC complex should help uncover additional immunogenic peptides from primary protein sequences and aid in the design of alternative approaches for T-cell vaccines.

Publication

Publisher: Frontiers Media SA

Date: 14-02-2017

DOI: 10.3389/FIMMU.2017.00115

Publication

Effect of Vitamin D supplementation on inflammation and nuclear factor kappa-B activity in overweight/obese adults: A randomized placebo-controlled trial

Publisher: Springer Science and Business Media LLC

Date: 09-11-2017

DOI: 10.1038/S41598-017-15264-1

Abstract: In-vitro studies suggest that vitamin D reduces inflammation by inhibiting nuclear factor kappa-B (NFκB) activity. Yet, no trials have examined the effects of vitamin D supplementation on NFκB activity in-vivo in humans. We conducted a double-blind randomized trial (RCT) examining effects of vitamin D supplementation on inflammatory markers and NFκB activity in peripheral blood mononuclear cells (PBMCs). Sixty-five overweight/obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 50 nmol/L) adults were randomized to a single 100,000 IU bolus followed by 4,000 IU daily cholecalciferol or matching placebo for 16 weeks. We measured BMI, % body fat, serum 25(OH)D, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ), several interleukins, and NFκB activity in PBMCs. Fifty-four participants completed the study. Serum 25(OH)D concentrations increased with vitamin D supplementation compared to placebo (p 0.001). Vitamin D and placebo groups did not differ in any inflammatory markers or NFκB activity (all p 0.05). Results remained non-significant after adjustment for age, sex, and % body fat, and after further adjustment for sun exposure, physical activity, and dietary vitamin D intake. Although in-vitro studies report anti-inflammatory effects of vitamin D, our RCT data show no effect of vitamin D supplementation on inflammatory markers or NFκB activity in-vivo in humans.

Publication

Association of Malaria Parasite Population Structure, HLA, and Immunological Antagonism

Publisher: American Association for the Advancement of Science (AAAS)

Date: 20-02-1998

DOI: 10.1126/SCIENCE.279.5354.1173

Abstract: Host-parasite coevolution has been likened to a molecular arms race, with particular parasite genes evolving to evade specific host defenses. Study of the variants of an antigenic epitope of Plasmodium falciparum that induces a cytotoxic T cell response supports this view. In African children with malaria, the variants present are influenced by the presence of a human leukocyte antigen (HLA) type that restricts the immune response to this epitope. The distribution of parasite variants may be further influenced by the ability of cohabiting parasite strains to facilitate each other's survival by down-regulating cellular immune responses, using altered peptide ligand antagonism.

Publication

Carnosine supplementation improves serum resistin concentrations in overweight or obese otherwise healthy adults: A pilot randomized trial

Publisher: MDPI AG

Date: 07-09-2018

DOI: 10.3390/NU10091258

Abstract: Adipokines play an important role in the regulation of glucose metabolism. We have previously shown that carnosine supplementation in overweight or obese non-diabetic in iduals improves glucose metabolism but does not change adiponectin concentrations. However, its effect on other adipokines has not been investigated. Herein we further determined the effect of carnosine supplementation on serum adipsin, resistin and leptin. Twenty-two overweight or obese otherwise healthy adults were randomly assigned to receive either 2 g of carnosine (n = 13) or identically looking placebo (n = 9) for 12 weeks. Serum adipsin, leptin and resistin were analyzed using a bead-based multiplex assay. Carnosine supplementation decreased serum resistin concentrations compared to placebo (mean change from baseline: −35 ± 83 carnosine vs. 35 ± 55 ng/mL placebo, p = 0.04). There was a trend for a reduction in serum leptin concentrations after carnosine supplementation (−76 ± 165 ng/mL carnosine vs. 20 ± 28 ng/mL placebo, p = 0.06). The changes in leptin and resistin concentrations were inversely related to the change in concentration for urinary carnosine (r = −0.72, p = 0.0002 r = −0.67, p = 0.0009, respectively), carnosine-propanal (r = −0.56, p = 0.005 r = −0.63, p = 0.001, respectively) and carnosine-propanol (r = −0.61, p = 0.002 r = −0.60, p = 0.002, respectively). There were no differences between groups in change in adipsin concentrations. Our findings show carnosine supplementation may normalize some, but not all, of the serum adipokine concentrations involved in glucose metabolism, in overweight and obese in iduals. Further clinical trials with larger s les are needed to confirm these results.

Publication

Inert 50-nm polystyrene nanoparticles that modify pulmonary dendritic cell function and inhibit allergic airway inflammation

Publisher: The American Association of Immunologists

Date: 02-2012

DOI: 10.4049/JIMMUNOL.1100156

Abstract: Nanoparticles are being developed for erse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c+MHCIIhi DCs in the lung and draining LN and allergen-laden CD11bhiMHCIIhi DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11bhi DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4+ T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.

Publication

Publisher: Oxford University Press (OUP)

Date: 03-12-2015

DOI: 10.1093/TRSTMH/TRU184

Publication

Sperm protein 17 expression by murine epithelial ovarian cancer cells and its impact on tumor progression

Publisher: MDPI AG

Date: 20-08-2018

DOI: 10.3390/CANCERS10080276

Abstract: The cancer testis antigen sperm protein 17 (Sp17) is a promising antigenic target in epithelial ovarian cancer (EOC) vaccine development. However, its role in ovarian cancer is unclear. We isolated and expanded Sp17+ and Sp17− clones from the murine EOC cell line ID8, and compared their in-vitro cell growth characteristics and in-vivo tumorigenicity. We also examined the potential co-expression of molecules that may influence cancer cell survival and interaction with immune cells. These include stimulatory and immunosuppressive molecules, such as major histocompatibility class I molecules (MHC I), MHC II, cytotoxic T lymphocyte associated antigen-4 (CTLA-4), CD73, CD39, tumor necrosis factor receptor II (TNFRII), signal transducer and activator of transcription 3 (STAT3) and programmed death-ligand 1 (PD-L1). Whilst the presence of Sp17 was not correlated with the ID8 cell proliferation/growth capacity in vitro, it was critical to enable progressive tumor formation in vivo. Flow cytometry revealed that Sp17+ ID8 cells displayed higher expression of both STAT3 and PD-L1, whilst MHC II expression was lower. Moreover, Sp17high (PD-L1+MHCII−) cell populations showed significantly enhanced resistance to Paclitaxel-induced cell death in vitro compared to Sp17low (PD-L1−MHCII+) cells, which was associated in turn with increased STAT3 expression. Together, the data support Sp17 as a factor associated with in-vivo tumor progression and chemo-resistance, validating it as a suitable target for vaccine development.

Publication

Higher Adherence to a Mediterranean Diet Is Associated with Improved Insulin Sensitivity and Selected Markers of Inflammation in Individuals Who Are Overweight and Obese without Diabetes

Publisher: MDPI AG

Date: 21-10-2022

DOI: 10.3390/NU14204437

Abstract: Insulin resistance (IR) and chronic low-grade inflammation are risk factors for chronic diseases including type 2 diabetes (T2D) and cardiovascular disease. This study aimed to investigate two dietary indices: Mediterranean Diet Score (MDS) and Dietary Inflammatory Index (DII®), and their associations with direct measures of glucose metabolism and adiposity, and biochemical measures including lipids, cytokines and adipokines in overweight/obese adults. This cross-sectional study included 65 participants (males = 63% age 31.3 ± 8.5 years). Dietary intake via 3-day food diaries was used to measure adherence to MDS (0–45 points) higher scores indicating adherence. Energy-adjusted DII (E-DII) scores were calculated with higher scores indicating a pro-inflammatory diet. IR was assessed using hyperinsulinemic euglycemic cl s, insulin secretion by intravenous glucose tolerance test, adiposity by dual-energy X-ray absorptiometry, and circulating cytokine and adipokine concentrations by multiplex assays. Higher MDS was associated with greater insulin sensitivity (β = 0.179 95%CI: 0.39, 0.318) after adjusting for age, sex and % body fat, and lower NF-κB, higher adiponectin and adipsin in unadjusted and adjusted models. Higher E-DII score was associated with increased total cholesterol (β = 0.364 95%CI: 0.066, 0.390) and LDL-cholesterol (β = 0.305 95%CI: 0.019, 0.287) but not with adiposity, glucose metabolism, cytokines or adipokines. Greater MDS appears to be associated with decreased IR and inflammatory markers in overweight/obese adults.

Publication

The Development of Surface-Modified Liposomes as an Intranasal Delivery System for Group A Streptococcus Vaccines

Publisher: MDPI AG

Date: 30-01-2023

DOI: 10.3390/VACCINES11020305

Abstract: Intranasal vaccine administration can overcome the disadvantages of injectable vaccines and present greater efficiency for mass immunization. However, the development of intranasal vaccines is challenged by poor mucosal immunogenicity of antigens and the limited availability of mucosal adjuvants. Here, we examined a number of self-adjuvanting liposomal systems for intranasal delivery of lipopeptide vaccine against group A Streptococcus (GAS). Among them, two liposome formulations bearing lipidated cell-penetrating peptide KALA and a new lipidated chitosan derivative (oleoyl-quaternized chitosan, OTMC) stimulated high systemic antibody titers in outbred mice. The antibodies were fully functional and were able to kill GAS bacteria. Importantly, OTMC was far more effective at stimulating antibody production than the classical immune-stimulating trimethyl chitosan formulation. In a simple physical mixture, OTMC also enhanced the immune responses of the tested vaccine, without the need for a liposome delivery system. The adjuvanting capacity of OTMC was further confirmed by its ability to stimulate cytokine production by dendritic cells. Thus, we discovered a new immune stimulant with promising properties for mucosal vaccine development.

Publication

Publisher: American Chemical Society (ACS)

Date: 27-06-2022

DOI: 10.1021/ACSNANO.2C04543

Publication

Vaccination against foot-and-mouth disease virus using peptides conjugated to nano-beads

Publisher: Elsevier BV

Date: 05-2008

DOI: 10.1016/J.VACCINE.2008.03.025

Abstract: Vaccination against foot-and-mouth disease virus (FMDV) is a major problem as current vaccines do not allow easy differentiation between infected and vaccinated animals. Furthermore, large scale production of inactivated virus poses significant risks. To address this we investigated the feasibility of using inert nano-beads that target antigen to dendritic cells (DCs) to induce immune responses against FMDV-specific synthetic peptides in sheep. Our results demonstrate that while single peptides induce responses in most sheep, the combination of multiple peptides either conjugated separately to in idual nano-beads or conjugated as a mixture induce significant cell-mediated (CM) and humoral immune responses.

Publication

Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells

Publisher: Springer Science and Business Media LLC

Date: 07-1999

DOI: 10.1038/21900

Abstract: The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes to the venular endothelium has been associated with some of the syndromes of severe disease. Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.

Publication

Publisher: Walter de Gruyter GmbH

Date: 1999

DOI: 10.1515/BC.1999.041

Publication

Morphology and Composition of Immunodiffusion Precipitin Complexes Evaluated via Microscopy and Proteomics

Publisher: American Chemical Society (ACS)

Date: 06-04-2021

DOI: 10.1021/ACS.JPROTEOME.0C01042

Publication

Selectively Impaired CD8+ but Not CD4+ T Cell Cycle Arrest during Priming as a Consequence of Dendritic Cell Interaction with Plasmodium-Infected Red Cells

Publisher: The American Association of Immunologists

Date: 15-09-2005

DOI: 10.4049/JIMMUNOL.175.6.3525

Abstract: In iduals living in malaria-endemic areas show generally low T cell responses to malaria Ags. In this study, we show murine dendritic cell (DC) interaction with parasitized erythrocytes (pRBC) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall T cell responses in vitro and in vivo. Moreover, within the naive T cell population, pRBC-treated DC were selectively deficient in priming CD8+ but not CD4+ T cells. Indeed, DC that had taken up pRBC were shown for the first time to efficiently prime CD4+ T cell responses to a known protective merozoite Ag, MSP4/5. In contrast, impaired priming resulted in decreases in both proliferation and cytokine production by CD8+ T cells. Deficient priming was observed to both a model and a Plasmodium berghei-specific CD8+ T cell epitope. The mechanisms underlying the inability of parasite-treated DC to prime CD8+ T cells were explored. pRBC treatment of DC from wild-type C57BL/6, but not from IL-10 knockout animals, suppressed DC-mediated T cell priming across a Transwell, suggesting active IL-10-dependent suppression. CD8+ T cells were arrested at the G0 stage of the cell cycle after two cell isions post-Ag stimulation. The proliferation arrest was partially reversible by the addition of IL-2 or IL-7 to responder cultures. These results suggest that in malaria-endemic areas, priming of CD8+ T cell responses may be more difficult to induce via vaccination than the priming of CD4+ T cells. Moreover, pathogens may selectively target the CD8+ T cell arm of protective immunity for immune evasion.

Publication

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1016/S0140-6736(16)00661-9

Publication

Polymorphism in liver-stage malaria vaccine candidate proteins: Immune evasion and implications for vaccine design

Publisher: Informa UK Limited

Date: 23-12-2016

DOI: 10.1586/14760584.2016.1125785

Abstract: The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.

Publication

Nanoparticles, immunomodulation and vaccine delivery

Publisher: WORLD SCIENTIFIC

Date: 25-12-2013

DOI: 10.1142/9789814390262_0015

Publication

Publisher: Frontiers Media SA

Date: 21-12-2018

DOI: 10.3389/FIMMU.2018.02968

Publication

Induction of peptide‐specific primary cytotoxic T lymphocyte responses from human peripheral blood

Publisher: Wiley

Date: 06-1995

DOI: 10.1002/EJI.1830250645

Abstract: Various protocols were developed and compared for eliciting specific cytotoxic T lymphocyte (CTL) cell lines from the unselected human peripheral blood mononuclear cells of naive donors. Interleukin-7 and CD4+ T cells primed in vitro by keyhole limpet hemocyanin were shown to act together in the generation of these responses. Primary responses were consistently induced with a variety of different HLA class I-binding malarial peptides. Primary CTL responses could be induced from unselected CD8+ and from CD45RA+CD8+ T cells. The CTL lines derived from these naive donors were CD8+ and demonstrated a high level of HLA class I-restricted killing for > 3 months after priming in vitro. They were also able to recognize and kill targets infected with a recombinant vaccinia virus containing the full-length antigen. In addition, this same protocol enhanced up to fourfold the levels of secondary CTL responses induced. The optimal method presented for naive cytotoxic T cell stimulation is simple, rapid and generally applicable and should provide a useful tool for both basic research and human therapy.

Publication

Abstract 5547: Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy

Publisher: American Association for Cancer Research (AACR)

Date: 15-08-2020

DOI: 10.1158/1538-7445.AM2020-5547

Abstract: Ovarian cancer is the most lethal gynecological malignancy and treatment options have not improved in decades. Whilst ovarian tumors have an immune-mediated component, emerging immunotherapies (e.g. anti-PD-1, anti-PD-L1) have failed to achieve robust clinical response for ovarian cancer patients. There is an urgent need to develop new therapeutic strategies to improve survival rates in women, particularly those with recurrent, chemoresistant disease. In an ongoing study we are investigating the repurposing of sitagliptin, an anti-diabetes drug, as a novel immunomodulatory therapy in ovarian cancer. Ovarian tumors were generated in C57BL/6 wild-type mice by intrabursal implantation of ID8 murine ovarian cancer cells. Following the formation of primary tumors (~2 weeks), mice received a daily oral dose of sitagliptin (50mg/kg) until ethical endpoint. Anti-tumor immune responses were examined by flow cytometry and immunohistochemical staining according to tumor stage. Mice were assessed for overall survival compared to paclitaxel chemotherapy as standard-of-care. Daily sitagliptin treatment increased circulating Teff:Treg cell ratios in the blood, peritoneal fluid and tumor tissue at an early stage, and this was sustained throughout disease. Sitagliptin also enhanced T effector cell activation and proliferation, indicating that increased Teff:Treg ratios were a positive indicator of the anti-tumor immune response. Treatment with sitagliptin alone increased median survival time by 27% compared to both untreated controls and paclitaxel as standard-of-care, suggesting a beneficial effect mediated by anti-tumor immune responses. Of particular interest, sitagliptin treatment specifically increased the percentage of CXCR3+ T effector cells in the peritoneal cavity. Recent data has suggested that CXCR3+ T cells are functionally required for immune checkpoint inhibitors to exert efficacy. Thus, we hypothesize that sitagliptin may enhance the efficacy of immune checkpoint inhibitor therapies in ovarian cancers. Our ongoing studies are investigating the combination of sitagliptin with anti-PD-1 and anti-PD-L1 antibodies, as a rational approach to improving their efficacy in ovarian cancers. These studies will identify a clinically relevant and directly translatable approach to improve prognosis for ovarian cancer patients. Citation Format: Laura R. Moffitt, Amy L. Wilson, Bashirah Basri, Kirsty L. Wilson, Magdalena Plebanski, Andrew N. Stephens. Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR Cancer Res 2020 (16 Suppl):Abstract nr 5547.

Publication

Pathogen recognition and development of particulate vaccines: Does size matter?

Publisher: Elsevier BV

Date: 09-2006

DOI: 10.1016/J.YMETH.2006.05.016

Abstract: The use of particulate carriers holds great promise for the development of effective and affordable recombinant vaccines. Rational development requires a detailed understanding of particle up-take and processing mechanisms to target cellular pathways capable of stimulating the required immune responses safely. These mechanisms are in turn based on how the host has evolved to recognize and process pathogens. Pathogens, as well as particulate vaccines, come in a wide range of sizes and biochemical compositions. Some of these also provide 'danger signals' so that antigen 'senting cells (APC), usually dendritic cells (DC), acquire specific stimulatory activity. Herein, we provide an overview of the types of particles currently under investigation for the formulation of vaccines, discuss cellular uptake mechanisms (endocytosis, macropinocytosis, phagocytosis, clathrin-dependent and/or caveloae-mediated) for pathogens and particles of different sizes, as well as antigen possessing and presentation by APC in general, and DC in particular. Since particle size and composition can influence the immune response, inducing humoral and/or cellular immunity, activating CD8 T cells and/or CD4 T cells of T helper 1 and/or T helper 2 type, particle characteristics have a major impact on vaccine efficacy. Recently developed methods for the formulation of particulate vaccines are presented in this issue of Methods, showcasing a range of "cutting edge" particulate vaccines that employ particles ranging from nano to micro-sized. This special issue of Methods further addresses practical issues of production, affordability, reproducibility and stability of formulation, and also includes a discussion of the economic and regulatory challenges encountered in developing vaccines for veterinary use and for common Third World infectious diseases.

Publication

Methods for nano-particle based vaccine formulation and evaluation of their immunogenicity

Publisher: Elsevier BV

Date: 09-2006

DOI: 10.1016/J.YMETH.2006.05.018

Abstract: Nano- and microparticles have long been used for the delivery of drugs and are currently being evaluated as vaccine delivery systems. Particulates can elicit potent immune responses, either by direct immuno-stimulation of antigen presenting cells (APC) or/and by delivering antigen to specific cellular compartments and promoting antigen uptake by appropriate stimulatory cell types. Herein, we describe a detailed method for the preparation of a novel nanoparticle-based antigen delivery system which induces strong cellular and humoral immune responses in mice and sheep. This simple system is based on the use of 40 nanometer (nm) inert solid carrier beads to which antigen is covalently coupled before injection. Covalent conjugation of antigen to the nanobeads, assessment of conjugation efficiency, characterisation and measurement of in vivo immunogenicity by cytokine ELISPOT (to measure antigen-specific T-cell responses) and ELISA (to measure antibody titers), are described. Emphasis is placed on providing trouble-shooting advice to enable the reproducible production of soluble nano-size formulations that do not suffer from common problems such as aggregation, as well as understanding the causes and thus avoiding a range of prevalent technical problems that occur when using immune response detection assays, such as the cytokine ELISPOT assay and ELISA.

Publication

Plasmodium falciparum–Mediated Induction of Human CD25hiFoxp3hi CD4 T Cells Is Independent of Direct TCR Stimulation and Requires IL-2, IL-10 and TGFβ

Publisher: Public Library of Science (PLoS)

Date: 14-08-2009

DOI: 10.1371/JOURNAL.PPAT.1000543

Publication

Intercomparison of micro- and nanodosimetry Monte Carlo simulations: An approach to assess the influence of different cross-sections for low-energy electrons on the dispersion of results

Publisher: Elsevier BV

Date: 2022

DOI: 10.1016/J.RADMEAS.2021.106675

Publication

Unique T Cell Effector Functions Elicited by Plasmodium falciparum Epitopes in Malaria-Exposed Africans Tested by Three T Cell Assays

Publisher: The American Association of Immunologists

Date: 15-10-2001

DOI: 10.4049/JIMMUNOL.167.8.4729

Abstract: Natural immunity to malaria is characterized by low level CD4 T cell reactivity detected by either lymphoproliferation or IFN-γ secretion. Here we show a doubling in the detection rate of responders to the carboxyl terminus of circumsporozoite protein (CS) of Plasmodium falciparum by employing three T cell assays simultaneously: rapid IFN-γ secretion (ex vivo ELISPOT), IFN-γ secretion after reactivation of memory T cells and expansion in vitro (cultured ELISPOT), and lymphoproliferation. Remarkably, for no in idual peptide did a positive response for one T cell effector function correlate with any other. Thus these CS epitopes elicited unique T cell response patterns in malaria-exposed donors. Novel or important epitope responses may therefore be missed if only one T cell assay is employed. A borderline correlation was found between anti-CS Ab levels and proliferative responses, but no correlation was found with ex vivo or cultured IFN-γ responses. This suggested that the proliferating population, but not the IFN-γ-secreting cells, contained cells that provide help for Ab production. The data suggest that natural immunity to malaria is a complex function of T cell subgroups with different effector functions and has important implications for future studies of natural T cell immunity.

Publication

Publisher: Frontiers Media SA

Date: 25-01-2019

DOI: 10.3389/FIMMU.2018.03109

Publication

Regulatory T Cells in Ovarian Carcinogenesis and Future Therapeutic Opportunities

Publisher: MDPI AG

Date: 08-11-2022

DOI: 10.3390/CANCERS14225488

Abstract: Regulatory T cells (Tregs) have been shown to play a role in the development of solid tumors. A better understanding of the biology of Tregs, immune suppression by Tregs, and how cancer developed with the activity of Tregs has facilitated the development of strategies used to improve immune-based therapy. In ovarian cancer, Tregs have been shown to promote cancer development and resistance at different cancer stages. Understanding the various Treg-mediated immune escape mechanisms provides opportunities to establish specific, efficient, long-lasting anti-tumor immunity. Here, we review the evidence of Treg involvement in various stages of ovarian cancer. We further provide an overview of the current and prospective therapeutic approaches that arise from the modulation of Treg-related tumor immunity at those specific stages. Finally, we propose combination strategies of Treg-related therapies with other anti-tumor therapies to improve clinical efficacy and overcome tumor resistance in ovarian cancer.

Publication

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.HUMIMM.2020.07.006

Publication

Publisher: Oxford University Press (OUP)

Date: 08-2016

DOI: 10.1093/TRSTMH/TRW054

Publication

Induction of T helper type 1 and 2 responses to 19-kilodalton merozoite surface protein 1 in vaccinated healthy volunteers and adults naturally exposed to malaria

Publisher: American Society for Microbiology

Date: 03-2002

DOI: 10.1128/IAI.70.3.1417-1421.2002

Abstract: Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein 1 (MSP-1 19 ), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-1 19 , immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1 19 induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1 19 immune responses in endemic populations can be boosted by vaccination.

Publication

Alveolar macrophage function is altered in patients with lung cancer

Publisher: Oxford University Press (OUP)

Date: 20-12-2006

DOI: 10.1111/J.1365-2249.2006.02998.X

Abstract: The alveolar macrophage (AM) is believed to be of central importance in the immune response against infection and tumour. We examined patients with lung cancer in order to evaluate the immuno-stimulatory potential of AM in lung cancer. Bronchoalveolar lavage fluid s les were obtained from patients with adenocarcinoma, squamous cell carcinoma, large cell undifferentiated lung carcinoma, small cell carcinoma and control subjects. AM were isolated and phagocytic function, flow cytometry and cytokine analysis were assessed. AM from patients with small and squamous cell carcinoma had impaired uptake in vitro of 40 nm fluorescent polystyrene beads. AM from patients with small, squamous and large cell undifferentiated carcinoma showed impaired uptake of 1000 nm fluorescent polystyrene beads. Secreted levels of TNF-α and IL-1 from AM of patients with small, squamous, and large cell undifferentiated carcinoma were decreased compared to controls. Secreted AM IL-6 levels were decreased in small and large cell undifferentiated carcinoma. AM from adenocarcinoma patients showed similar levels of IL-10, IL-6, IL-1 and TNF-α compared to controls. Phenotypic analysis demonstrated that patients with small cell carcinoma were the only group that showed a decrease in MHC class II surface expression. Surface expression of ICAM-1 and CD83 was decreased on AM from patients with large, squamous and small cell carcinoma compared to controls but not adenocarcinoma. Mannose receptor levels were only decreased on AM from patients with squamous and small cell carcinoma but not adenocarcinoma and large cell undifferentiated carcinoma. We conclude that there are type-specific alterations in uptake ability, cytokine secretion and phenotype of AM from lung cancer patients, which may result in an inability to stimulate anti-tumour immunity. The observed differences between lung cancer subgroups may explain previously reported inconsistencies in descriptions of AM characteristics in lung cancer.

Publication

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis.

Publisher: Elsevier BV

Date: 12-2019

DOI: 10.1111/JTH.14603

Abstract: Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild-type and plasminogen-deficient (plg Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme-linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D-dimer and plasmin-antiplasmin complex levels. Plg In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen-presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.

Publication

Synthesis of the surface glycoprotein of rotavirus SA11 in the aroA strain of Salmonella typhimurium SL3261

Publisher: Elsevier BV

Date: 09-1990

DOI: 10.1016/0923-2508(90)90125-A

Publication

Understanding CD8⁺ T‐cell responses toward the native and alternate HLA‐A∗02:01‐restricted WT1 epitope

Publisher: Wiley

Date: 03-2017

DOI: 10.1038/CTI.2017.4

Publication

Nanoparticles, immunomodulation and vaccine delivery

Publisher: WORLD SCIENTIFIC

Date: 2016

DOI: 10.1142/9677

Publication

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

Publisher: Wiley

Date: 25-04-2006

DOI: 10.1002/EJI.200526010

Abstract: The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-gamma secretion as well as proliferation of CD4+ T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive in iduals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.

Publication

Publisher: Frontiers Media SA

Date: 11-03-2016

DOI: 10.3389/FMICB.2016.00303

Publication

A complementary role for the tetraspanins CD37 and Tssc6 in cellular immunity

Publisher: The American Association of Immunologists

Date: 15-09-2010

DOI: 10.4049/JIMMUNOL.0902867

Abstract: The cooperative nature of tetraspanin–tetraspanin interactions in membrane organization suggests functional overlap is likely to be important in tetraspanin biology. Previous functional studies of the tetraspanins CD37 and Tssc6 in the immune system found that both CD37 and Tssc6 regulate T cell proliferative responses in vitro. CD37−/− mice also displayed a hyper-stimulatory dendritic cell phenotype and dysregulated humoral responses. In this study, we characterize “double knockout” mice (CD37−/−Tssc6−/−) generated to investigate functional overlap between these tetraspanins. Strong evidence for a cooperative role for these two proteins was identified in cellular immunity, where both in vitro T cell proliferative responses and dendritic cell stimulation capacity are significantly exaggerated in CD37−/−Tssc6−/− mice when compared with single knockout counterparts. Despite these exaggerated cellular responses in vitro, CD37−/−Tssc6−/− mice are not more susceptible to autoimmune induction. However, in vivo responses to pathogens appear poor in CD37−/−Tssc6−/− mice, which showed a reduced ability to produce influenza-specific T cells and displayed a rapid onset hyper-parasitemia when infected with Plasmodium yoelii. Therefore, in the absence of both CD37 and Tssc6, immune function is further altered when compared with CD37−/− or Tssc6−/− mice, demonstrating a complementary role for these two molecules in cellular immunity.

Publication

Identification of conserved antigenic components for a cytotoxic T lymphocyte-inducing vaccine against malaria

Publisher: Elsevier BV

Date: 04-1995

DOI: 10.1016/S0140-6736(95)90754-8

Abstract: Several cellular and humoral mechanisms probably play a role in natural immunity to Plasmodium falciparum malaria, but the development of an effective vaccine has been impeded by uncertainty as to which antigens are targeted by protective immune responses. Experimental models of malaria have shown that cytotoxic T lymphocytes (CTL) which kill parasite-infected hepatocytes can provide complete protective immunity against certain species of Plasmodium in mice, and studies in The Gambia have provided indirect evidence that CTL play a protective role against P falciparum in humans. By using an HLA-based approach, termed reverse immunogenetics, we have previously identified peptide epitopes for CTL in liver-stage antigen-1 and the circumsporozoite protein of P falciparum. We have extended this work to identify CTL epitopes for HLA class I antigens that are found in most in iduals from Caucasian and African populations. Most of these epitopes are in conserved regions of P falciparum. CTL peptide epitopes were found in a further two antigens, thrombospondin-related anonymous protein and sporozoite threonine and asparagine rich protein, indicating that a subunit vaccine designed to induce a protective CTL response may need to include parts of several parasite antigens. However, CTL levels in both children with malaria and in semi-immune adults from an endemic area were low suggesting that boosting these low levels by immunisation might provide substantial or even complete protection against infection and disease.

Publication

Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin

Publisher: Public Library of Science (PLoS)

Date: 07-2015

DOI: 10.1371/JOURNAL.PONE.0131216

Publication

Publisher: Wiley

Date: 06-1999

DOI: 10.1002/(SICI)1521-4141(199906)29:06<1943::AID-IMMU1943>3.0.CO;2-1

Publication

Publisher: Frontiers Media SA

Date: 05-06-2020

DOI: 10.3389/FIMMU.2020.01083

Publication

Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.CLIM.2013.07.003

Abstract: Ovarian cancer is a prevalent gynecological malignancy with potent immune-suppression capabilities regulatory T cells (Tregs) are significant contributors to this immune-suppression. As ovarian cancer patients present with high levels of TNF and Tregs expressing TNFR2 are associated with maximal suppressive capacity, we investigated TNFR2+ Tregs within these patients. Indeed, TNFR2+ Tregs from tumor-associated ascites were the most potent suppressor T cell fraction. They were abundantly present within the ascites and more suppressive than peripheral blood TNFR2+ Tregs in patients. The increased suppressive capacity can be explained by a distinct cell surface expression profile, which includes high levels of CD39, CD73, TGF-β and GARP. Additionally, CD73 expression level on TNFR2+ Tregs was inversely correlated with IFN-γ production by effector T cells. This Treg fraction can be selectively recruited into the ascites from the peripheral blood of patients. Targeting TNFR2+ Tregs may offer new approaches to enhance the poor survival rates of ovarian cancer.

Publication

Nanotechnology and vaccine development: Methods to study and manipulate the interaction of nanoparticles with the immune system

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.YMETH.2013.05.018

Publication

Potent Induction of Focused Th1‐Type Cellular and Humoral Immune Responses by RTS,S/SBAS2, a RecombinantPlasmodium falciparumMalaria Vaccine

Publisher: Oxford University Press (OUP)

Date: 11-1999

DOI: 10.1086/315074

Abstract: The RTS,S/SBAS2 vaccine confers sterile protection against Plasmodium falciparum sporozoite challenge. The mechanisms underlying this are of great interest, yet little is known about the immune effector mechanisms induced by this vaccine. The immune responses induced by RTS,S/SBAS2 were characterized in 10 malaria-naive volunteers. Several epitopes in the circumsporozoite protein (CSP) were identified as targets of cultured interferon (IFN)-gamma-secreting CD4+ T cells. RTS,S-specific IFN-gamma-secreting effector T cells were induced in 8 subjects this ex vivo response mapped to a single peptide in Th2R. CSP-specific CD8+ cytotoxic T lymphocytes were not detected. RTS, S-specific IFN-gamma production was universal, whereas interleukin-4 and -5 production was rare. RTS,S-specific lymphoproliferative responses and antibodies to CSP were strongly induced in all volunteers. Responses waned with time but were boostable. Thus, RTS, S/SBAS2 is a potent inducer of Th1-type cellular and humoral immunity. These results highlight possible immune mechanisms of protection and have important implications for vaccine design in general.

Publication

Publisher: American Society for Clinical Investigation

Date: 08-2002

DOI: 10.1172/JCI0216163

Publication

Interleukin-13 regulates secretion of the tumor growth factor - β superfamily cytokine activin A in allergic airway inflammation

Publisher: American Thoracic Society

Date: 06-2010

DOI: 10.1165/RCMB.2008-0429OC

Publication

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.10097

Publication

Panobinostat in combination with azacitidine reduces the frequency of TNFR2+ regulatory T cells in acute myeloid leukemia patients. (P2048)

Publisher: The American Association of Immunologists

Date: 05-2013

DOI: 10.4049/JIMMUNOL.190.SUPP.132.14

Abstract: Panobinostat (LBH) and azacitidine (Aza) are currently being evaluated in the therapy of AML. The effect of this drug combination on T cells, particularly on regulatory T cells (Tregs) has not been previously investigated. The presence of Tregs in AML is detrimental, as these cells suppress anti-tumor immunity. Tregs expressing Tumor Necrosis Factor Receptor 2 (TNFR2) are associated with maximal immune suppressor activity. Here, we investigated the combined effect of LBH and Aza on effector T cells (Teff), and TNFR2+ and TNFR2- Tregs in newly diagnosed AML patients. Patients were treated with Aza on days 1-5 for each 28-day cycle combined with 7 doses of LBH on days 5-19. T cells within peripheral blood (PB) and bone marrow (BM) were analyzed via flow cytometry, at baseline and at the end of cycle 1 (EOC1). Specifically, TNFR2+ Tregs were present at high levels within patient PB when compared to controls and were significantly reduced by EOC1 of treatment. Interestingly, only patients who responded to treatment had this reduction in their BM. Mechanistic studies adding LBH alone or with Aza to PB cells during T cell activation in vitro indicated LBH might primarily drive the reduction in Tregs. Concomitant with Treg reduction, IFNγ and IL2 production by CD4 Teff and the ratio of CD4 Teff to TNFR2+ Tregs were enhanced by EOC1 in the BM of responder, but not non-responder patients. AML patients who responded to Aza and LBH treatment have a beneficial immunological outcome.

Publication

Differential uptake of nanoparticles and microparticles by pulmonary APC subsets induces discrete immunological imprints

Publisher: The American Association of Immunologists

Date: 15-11-2013

DOI: 10.4049/JIMMUNOL.1203131

Abstract: There is increasing interest in the use of engineered particles for biomedical applications, although questions exist about their proinflammatory properties and potential adverse health effects. Lung macrophages and dendritic cells (DC) are key regulators of pulmonary immunity, but little is known about their uptake of different sized particles or the nature of the induced immunological imprint. We investigated comparatively the immunological imprints of inert nontoxic polystyrene nanoparticles 50 nm in diameter (PS50G) and 500 nm in diameter (PS500G). Following intratracheal instillation into naive mice, PS50G were preferentially taken up by alveolar and nonalveolar macrophages, B cells, and CD11b+ and CD103+ DC in the lung, but exclusively by DC in the draining lymph node (LN). Negligible particle uptake occurred in the draining LN 2 h postinstillation, indicating that particle translocation does not occur via lymphatic drainage. PS50G but not PS500G significantly increased airway levels of mediators that drive DC migration/maturation and DC costimulatory molecule expression. Both particles decreased frequencies of stimulatory CD11b+MHC class IIhi allergen-laden DC in the draining LN, with PS50G having the more pronounced effect. These distinctive particle imprints differentially modulated induction of acute allergic airway inflammation, with PS50G but not PS500G significantly inhibiting adaptive allergen-specific immunity. Our data show that nanoparticles are taken up preferentially by lung APC stimulate cytokine/chemokine production and pulmonary DC maturation and translocate to the lung-draining LN via cell-associated transport. Collectively, these distinctive particle imprints differentially modulate development of subsequent lung immune responses. These findings support the development of lung-specific particulate vaccines, drug delivery systems, and immunomodulators.

Publication

Antibodies toPlasmodium falciparumandPlasmodium vivaxMerozoite Surface Protein 5 in Indonesia: Species‐Specific and Cross‐Reactive Responses

Publisher: Oxford University Press (OUP)

Date: 07-2008

DOI: 10.1086/588711

Magdalena Plebanski

Researcher

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Publications

An HLA-based approach to the design of a CTL-inducing vaccine against Plasmodium falciparum

Synthetic nanoparticles that promote tumor necrosis factor receptor 2 expressing regulatory T cells in the lung and resistance to allergic airways inflammation

Hot, sweet and sticky: the glycobiology of Plasmodium falciparum

Nanoparticles and Gut Microbiota in Colorectal Cancer

A Novel Approach for Non-Invasive Lung Imaging and Targeting Lung Immune Cells

Malaria vaccines in the eradication era: current status and future perspectives

Hypoxia Regulates DPP4 Expression, Proteolytic Inactivation, and Shedding from Ovarian Cancer Cells

On the efficacy of malaria DNA vaccination with magnetic gene vectors

Naturally Exposed Populations Differ in Their T1 and T2 Responses to the Circumsporozoite Protein ofPlasmodium falciparum

Sex-Differential Impact of Human Cytomegalovirus Infection on In Vitro Reactivity to Toll-Like Receptor 2, 4 and 7/8 Stimulation in Gambian Infants

Dendritic Cells and Myeloid Derived Suppressor Cells Fully Responsive to Stimulation via Toll-Like Receptor 4 Are Rapidly Induced from Bone-Marrow Cells by Granulocyte-Macrophage Colony-Stimulating Factor

Inducible Expression of the Cell Surface Heparan Sulfate Proteoglycan Syndecan-2 (Fibroglycan) on Human Activated Macrophages Can Regulate Fibroblast Growth Factor Action

Promising particle-based vaccines in cancer therapy

Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor-An Opportunity for Cancer Treatment.

Insights into endotoxin-mediated lung inflammation and future treatment strategies

A synthetic nanoparticle based vaccine approach targeting MSP4/5 is immunogenic and induces moderate protection against murine blood-stage malaria

Pre-operative sera interleukin-6 in the diagnosis of high-grade serous ovarian cancer

Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism

Systemic immune responses in sheep, induced by a novel nano-bead adjuvant

The Use of Synthetic Carriers in Malaria Vaccine Design

A flowcytometric analysis to efficiently quantify multiple innate immune cells and T Cell subsets in human blood

Correlation of Memory T Cell Responses against TRAP with Protection from Clinical Malaria, and CD4+ CD25high T Cells with Susceptibility in Kenyans

Poly-l-lysine-coated nanoparticles: A potent delivery system to enhance DNA vaccine efficacy

The good, the bad and the ugly: How altered peptide ligands modulate immunity

Low dose cyclophosphamide: Mechanisms of T cell modulation

Regulatory T-cells: Immunomodulators in health and disease

Modeling COVID-19 disease processes by remote elicitation of causal Bayesian networks from medical experts.

Methods to measure T-cell responses

Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis.

Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]

Keratin-14 (KRT14) positive leader cells mediate mesothelial clearance and invasion by ovarian cancer cells

The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development

Montanide, Poly I:C and nanoparticle based vaccines promote differential suppressor and effector cell expansion: A study of induction of CD8 T cells to a minimal Plasmodium berghei epitope

Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia

Size-Dependent Immunogenicity: Therapeutic and Protective Properties of Nano-Vaccines against Tumors

Interleukin 6 Present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells

Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system

CD38 identifies a hypo-proliferative IL-13-secreting CD4+ T-cell subset that does not fit into existing naive and memory phenotype paradigms

Comparison of numerous delivery systems for the induction of cytotoxic T lymphocytes by immunization

Investigation of a novel approach to scoring Giemsa-stained malaria-infected thin blood films

Sex-Differential Non-Vaccine-Specific Immunological Effects of Diphtheria-Tetanus-Pertussis and Measles Vaccination

Phenotypic analysis of ovine antigen presenting cells loaded with nanoparticles migrating from the site of vaccination

The immunology of malaria infection

The signalling imprints of nanoparticle uptake by bone marrow derived dendritic cells

Malaria vaccines: into a mirror, darkly?

Induction of CD8+ T cells using heterologous prime‐boost immunisation strategies

Two-dimensional single-cell patterning with one cell per well driven by surface acoustic waves

The challenge of assessing infant vaccine responses in resource-poor settings

Glycine microparticles loaded with functionalized nanoparticles for pulmonary delivery

Poly(amino acids) as a potent self-adjuvanting delivery system for peptide-based nanovaccines.

Abstract 6338: High-throughput screening program to target ovarian cancer leader cells

Methods of effective conjugation of antigens to nanoparticles as non-inflammatory vaccine carriers

Homologous and heterologous β-adrenergic desensitization in hepatocytes. Additivity and effect of pertussis toxin

Failure of immune homeostasis - The consequences of under and over reactivity

Mapping Epitopes Recognised by Autoantibodies Shows Potential for the Diagnosis of High-Grade Serous Ovarian Cancer and Monitoring Response to Therapy for This Malignancy

The Economics of Malaria Vaccine Development

DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model

Differential Cellular Recognition of Antigens During Acute Plasmodium falciparum and Plasmodium vivax Malaria

Antibodies against Spike protein correlate with broad autoantigen recognition 8 months post SARS-CoV-2 exposure, and anti-calprotectin autoantibodies associated with better clinical outcomes

Genetic analysis of host–parasite coevolution in human malaria

A Perspective Review on the Role of Nanomedicine in the Modulation of TNF-TNFR2 Axis in Breast Cancer Immunotherapy

A nanoparticle based Sp17 peptide vaccine exposes new immuno-dominant and species cross-reactive B cell epitopes

Pullulan-Coated Iron Oxide Nanoparticles for Blood-Stage Malaria Vaccine Delivery

Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

Active Ratio Test (ART) as a Novel Diagnostic for Ovarian Cancer

Biodegradable PLGA-b-PEG Nanoparticles Induce T Helper 2 (Th2) Immune Responses and Sustained Antibody Titers via TLR9 Stimulation

Synthesis of the outer-capsid glycoprotein of the simian rotavirus SA11 in Escherichia coli

Design of nanoparticle structures for cancer immunotherapy

REZOLVE (ANZGOG-1101): A phase 2 trial of intraperitoneal (IP) bevacizumab (bev) for recurrent ascites in advanced, chemotherapy-resistant, epithelial ovarian cancer (CR-EOC).

Immunotherapeutic interleukin-6 or interleukin-6 receptor blockade in cancer: Challenges and opportunities

Dependency on interleukin‐1 of primary human in vitro T cell responses to soluble antigens

Negative correlation between circulating Cd4+Foxp3+Cd127− regulatory T Cells and subsequent antibody responses to infant measles vaccine but not diphtheria–tetanus–pertussis vaccine implies a regulatory role

Induction of CD8⁺ T cells using heterologous prime‐boost immunisation strategies

Negative correlation between circulating Cd4⁺Foxp3⁺Cd127⁻ regulatory T Cells and subsequent antibody responses to infant measles vaccine but not diphtheria–tetanus–pertussis vaccine implies a regulatory role

Influenza‐specific IgG1⁺ memory B‐cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

Direct processing and presentation of antigen from malaria sporozoites by professional antigen‐presenting cells in the induction of CD8⁺ T‐cell responses

Design of Peptide-Based Nanovaccines Targeting Leading Antigens From Gynecological Cancers to Induce HLA-A2.1 Restricted CD8⁺ T Cell Responses