ORCID Profile
0000-0003-3551-6982
Current Organisation
The University of Auckland
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Publisher: American Association for Cancer Research (AACR)
Date: 08-2020
DOI: 10.1158/2326-6066.CIR-19-0796
Abstract: Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90+ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90+ podoplanin+ CD105+ CD146+ CD271+ VCAM-1+ ICAM-1+ α-SMA+) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90+ CD34+ CD105+ CD271+) represents a novel population of CD34+ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90+ CD146+ CD36+ NG2− pericytes in the walls of high endothelial venules and other small vessels, and CD90+ CD146+ NG2+ CD36− pericytes in the walls of larger vessels. Distinguishing between these CD90+ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.
Publisher: Georg Thieme Verlag KG
Date: 26-07-2013
Publisher: Oxford University Press (OUP)
Date: 10-02-2015
Abstract: Contact between T cells and APCs and activation of an effective immune response trigger cellular polarization and the formation of a structured interface known as the immunological synapse. Interactions across the synapse and secretion of T cell and APC-derived factors into the perisynaptic compartment regulate synapse formation and activation of T cells. We report that the serine protease inhibitor neuroserpin, an axonally secreted protein thought to play roles in the formation of the neuronal synapse and refinement of synaptic activity, is expressed in human nai¨ve effector memory and central memory subsets of CD4+ and CD8+ T cells, as well as monocytes, B cells, and NK cells. Neuroserpin partially colocalized with a TGN38/LFA-1-positive vesicle population in T cells and translocates to the immunological synapse upon activation with TCR antibodies or antigen-pulsed APCs. Activation of T cells triggered neuroserpin secretion, a rapid, 8.4-fold up-regulation of the serine protease tissue plasminogen activator, the protease target for neuroserpin, and a delayed, 6.25-fold down-regulation of neuroserpin expression. Evidence of polarization and regulated neuroserpin expression was also seen in ex vivo analyses of human lymph nodes and blood-derived T cells. Increased neuroserpin expression was seen in clusters of T cells in the paracortex of human lymph nodes, with some showing polarization to areas of cell:cell interaction. Our results support a role for neuroserpin and tissue plasminogen activator in activation-controlled proteolytic cleavage of proteins in the synaptic or perisynaptic space to modulate immune cell function.
Publisher: American Society for Microbiology
Date: 15-10-2013
DOI: 10.1128/JVI.03099-12
Abstract: Nonstructural protein 4 (NSP4), encoded by rotavirus, exhibits various properties linked to viral pathogenesis, including enterotoxic activity. A recent study (O. V. Kavanagh et al., Vaccine 28:3106-3111, 2010) indicated that NSP4 also has adjuvant properties, suggesting a possible role in the innate immune response to rotavirus infection. We report here that NSP4 purified from the medium of rotavirus-infected Caco-2 cells triggers the secretion of proinflammatory cytokines from macrophage-like THP-1 cells and nitric oxide from murine RAW 264.7 cells. Secretion is accompanied by the stimulation of p38 and JNK mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB. NSP4 triggered the secretion of cytokines from murine macrophages derived from wild-type but not MyD88 −/− or Toll-like receptor 2 (TLR2 −/− ) mice and induced secretion of interleukin-8 (IL-8) from human embryonic kidney cells transfected with TLR2 but not TLR4. Our studies identify NSP4 as a pathogen-associated molecular pattern (PAMP) encoded by rotavirus and provide a mechanism for the production of proinflammatory cytokines associated with the clinical symptoms of infection in humans and animals.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC00952A
Abstract: Convergent chemo-enzymatic synthesis of mannosylated glycopeptides enhances uptake by human antigen presenting cells whilst preserving the immunogenicity of peptide epitopes.
Publisher: Wiley
Date: 12-06-2014
Abstract: Lymph nodes (LNs) form the intersection between the vascular and lymphatic systems. Lymphocytes and antigen-presenting cells (APCs) traffic between these systems, but the barriers crossed during this trafficking in human LNs are poorly defined. We identified a population of cells in human LNs that lines the boundary between the parenchyma and lymphatic sinuses, consistent with descriptions of marginal reticular cells (MRCs) in murine LNs. Human MRCs are CD141(high) podoplanin(+), CD90(+), ICAM1(+), and VCAM1(+) but lack endothelial and hematopoietic cell markers, or alpha-smooth muscle actin. We then examined expression of the enzyme sphingosine-1-phosphate (S1P) lyase (SGPL1) relative to the boundary defined by MRCs. SGPL1 expression was almost exclusively restricted to cells on the parenchymal side of MRCs, consistent with a role in maintaining the S1P gradient between the sinuses and the parenchyma. Surprisingly the cells expressing SGPL1 in the parenchyma were CD68(+) APCs. CD68(+) APCs generated from human monocytes were able to internalize and irreversibly degrade S1P, and this activity was inhibited by the S1P analogue FTY720. This work provides a map of the key structures at the boundary where human lymphocytes egress into sinuses, and identifies a novel potential mechanism for the activity of S1P analogues in humans.
Publisher: Wiley
Date: 2016
DOI: 10.1038/CTI.2015.40
Publisher: Wiley
Date: 04-2016
DOI: 10.1038/CTI.2016.5
Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
DOI: 10.1038/S41366-019-0355-7
Abstract: Excessive adipose tissue macrophage accumulation in obesity has been implicated in mediating inflammatory responses that impair glucose homeostasis and promote insulin resistance. Colony-stimulating factor 1 (CSF1) controls macrophage differentiation, and here we sought to determine the effect of a CSF1 receptor inhibitor, PLX3397, on adipose tissue macrophage levels and understand the impact on glucose homeostasis in mice. A Ten-week-old mice were fed a chow or high-fat diet for 10 weeks and then treated with PLX3397 via oral gavage (50 mg/kg) every second day for 3 weeks, with subsequent monitoring of glucose tolerance, insulin sensitivity and assessment of adipose tissue immune cells. PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization. Our results indicate that macrophage infiltration of adipose tissue induced by a high-fat diet may not be the trigger for impairments in whole body glucose homeostasis, and that anti-CSF1 therapies are not likely to be useful as treatments for insulin resistance.
Publisher: Wiley
Date: 12-08-2013
Abstract: A radical lipidation: Application of a novel thiol-ene lipidation enables the one-step synthesis of self-adjuvanting antigenic peptides as vaccine candidates. The resultant monoacyl lipopeptides are shown to activate monocytes in a robust manner.
Publisher: Wiley
Date: 02-08-2016
DOI: 10.1038/ICB.2016.56
Abstract: The homeostatic chemokine CCL21 has a pivotal role in lymphocyte homing and compartment localisation within the lymph node, and also affects adhesion between immune cells. The effects of CCL21 are modulated by its mode of presentation, with different cellular responses seen for surface-bound and soluble forms. Here we show that plasmin cleaves surface-bound CCL21 to release the C-terminal peptide responsible for CCL21 binding to glycosaminoglycans on the extracellular matrix and cell surfaces, thereby generating the soluble form. Loss of this anchoring peptide enabled the chemotactic activity of CCL21 and reduced cell tethering. Tissue plasminogen activator did not cleave CCL21 directly but enhanced CCL21 processing through generation of plasmin from plasminogen. The tissue plasminogen activator inhibitor neuroserpin prevented processing of CCL21 and blocked the effects of soluble CCL21 on cell migration. Similarly, the plasmin-specific inhibitor α
Publisher: Elsevier BV
Date: 05-2019
Publisher: Wiley
Date: 28-10-2013
Publisher: Springer Science and Business Media LLC
Date: 21-10-2014
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JHEP.2019.06.028
Abstract: To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au/) number: ACTRN12615001133527.
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Publisher: SAGE Publications
Date: 14-09-2021
DOI: 10.1177/19476035211044822
Abstract: Mesenchymal stem/stromal cells (MSCs) are a well-established cell source for cartilage engineering, but challenges remain as differentiation often results in chondrocyte hypertrophy. Chondrogenic potential also varies with MSC source and donor age. We assessed the chondrogenic potential of first-trimester and term placental MSCs and compared their response to commonly used bone marrow MSCs (BM-MSCs). MSCs were isolated from first-trimester and term placentae. BM-MSCs were commercially obtained. Chondrogenesis was induced by micromass culture in commercial chondrogenic media for 7, 14, or 21 days. Pellets were assessed for glycosaminoglycan (GAG) content, and types I, II, and X collagen. Gene expression was profiled using Qiagen RT2 human MSC arrays. At day 0, first-trimester and term MSCs expression levels of many chondrogenic genes to BM-MSC after 21 days of culture. Only first trimester MSCs showed significant changes in chondrogenic gene expression during induction compared to day 0 undifferentiated MSCs (greater BMP4, KAT2B, and reduced GDF6 expression). Additionally, first-trimester MSCs showed significantly greater expression of ABCB1 (at days 14 and 21) and BMP4 (at days 7, 14, 21) compared with term MSCs. Both first-trimester and term pellets showed increased GAG content over time and term MSCs had significantly GAG greater compared with BM-MSCs at days 7 and 14. Type II collagen was present in all pellets but unlike BM-MSCs, type I collagen was not observed in first-trimester or term MSC pellets. These data highlight differences in BM-MSC and placental MSC chondrogenesis and demonstrate that placental MSCs may be an alternative cell source.
Publisher: American Vacuum Society
Date: 07-2021
DOI: 10.1116/6.0001124
Abstract: Plastic waste is ubiquitously spread across the world and its smaller analogs-microplastics and nanoplastics-raise particular health concerns. While biological impacts of microplastics and nanoplastics have been actively studied, the chemical and biological bases for the adverse effects are sought after. This work explores contributory factors by combining results from in vitro and model mammalian membrane experimentation to assess the outcome of cell/nanoplastic interactions in molecular detail, inspecting the in idual contribution of nanoplastics and different types of protein coronae. The in vitro study showed mild cytotoxicity and cellular uptake of polystyrene (PS) nanoplastics, with no clear trend based on nanoplastic size (20 and 200 nm) or surface charge. In contrast, a nanoplastic size-dependency on bilayer disruption was observed in the model system. This suggests that membrane disruption resulting from direct interaction with PS nanoplastics has little correlation with cytotoxicity. Furthermore, the level of bilayer disruption was found to be limited to the hydrophilic headgroup, indicating that transmembrane diffusion was an unlikely pathway for cellular uptake-endocytosis is the viable mechanism. In rare cases, small PS nanoplastics (20 nm) were found in the vicinity of chromosomes without a nuclear membrane surrounding them however, this was not observed for larger PS nanoplastics (200 nm). We hypothesize that the nanoplastics can interact with chromosomes prior to nuclear membrane formation. Overall, precoating PS particles with protein coronae reduced the cytotoxicity, irrespective of the corona type. When comparing the two types, the extent of reduction was more apparent with soft than hard corona.
Publisher: Wiley
Date: 15-09-2020
DOI: 10.1111/IMCB.12386
No related grants have been discovered for Anna Brooks.