ORCID Profile
0000-0003-3132-4924
Current Organisations
Perron Institute for Neurological and Translational Science
,
University of Western Australia
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Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.NEURON.2018.01.021
Abstract: Multiple sclerosis (MS) is an autoimmune disease triggered by environmental factors that act on a genetically susceptible host. It features three clinical stages: a pre-clinical stage detectable only by MRI a relapsing-remitting (RRMS) stage characterized by episodes of neurologic dysfunction followed by resolution and a progressive stage, which usually evolves from the relapsing stage. Advances in our understanding of the immune mechanisms that contribute to MS have led to more than ten FDA-approved immunotherapeutic drugs that target effector T cells, regulatory cells, B cells, and cell trafficking into the nervous system. However, most drugs for relapsing MS are not effective in treating progressive disease. Progressive MS features a compartmentalized immune response in the central nervous system, involving microglia cells and astrocytes, as well as immune-independent processes that drive axonal dysfunction. Major challenges for MS research involve understanding the mechanisms of disease progression, developing treatment for progressive MS, and determining the degree to which progressive disease can be prevented by early treatment. Key priorities for MS research include developing biomarkers, personalized medicine and advanced imaging, and a better understanding of the microbiome. With a better understanding of the genetic and epidemiological aspects of this disease, approaches to prevent MS are now also being considered.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
DOI: 10.1038/S41598-017-17981-Z
Abstract: While human Tregs hold immense promise for immunotherapy, their biologic variability poses challenges for clinical use. Here, we examined clinically-relevant activities of defined subsets of freshly-isolated and culture-expanded human PBMC-derived Tregs. Unlike highly suppressive but plastic memory Tregs (memTreg), naïve Tregs (nvTreg) exhibited the greatest proliferation, suppressive capacity after stimulation, and Treg lineage fidelity. Yet, unlike memTregs, nvTregs lack Fucosyltransferase VII and display low sLe X expression, with concomitant poor homing capacity. In vitro nvTreg expansion augmented their suppressive function, but did not alter the nvTreg sLe X-l ° w glycome. However, exofucosylation of the nvTreg surface yielded high sLe X expression, promoting endothelial adhesion and enhanced inhibition of xenogeneic aGVHD. These data indicate that the immature Treg glycome is under unique regulation and that adult PBMCs can be an ideal source of autologous-derived therapeutic Tregs, provided that subset selection and glycan engineering are engaged to optimize both their immunomodulation and tropism for inflammatory sites.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2017
DOI: 10.1212/NXI.0000000000000414
Abstract: To study the influence of the Abelson helper integration site 1 ( AHI1 ) locus associated with MS susceptibility on CD4 + T cell function. We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10 −13 ), overlaps with strong enhancer regions that are present in human naive and memory CD4 + T cells. Relative to the rs4896153 A protective allele, the rs4896153 T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4 + T cells ( p = 1.73 × 10 −74 , n = 213), and we replicate this effect in an independent set of subjects ( p = 2.5 × 10 −9 , n = 32). Functional studies then showed that the rs4896153 T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4 + T cell proliferation and a specific differentiation into interferon gamma (IFNγ)–positive T cells when compared with the protective rs4896153 A allele. This T cell phenotype was also observed in murine CD4 + T cells with genetic deletion of Ahi1 . Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ + T cells that have previously been implicated in MS and its mouse models.
Publisher: Cold Spring Harbor Laboratory
Date: 28-02-2018
DOI: 10.1101/273789
Abstract: Accumulation of tau and amyloid-β are two pathologic hallmarks of Alzheimer’s disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-β, tau protein burden had a broad effect on the epigenome, affecting 5,590 out of 26,384 H3K9Ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segment’s nuclear lamina association. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.
Publisher: Cold Spring Harbor Laboratory
Date: 12-07-2020
DOI: 10.1101/2020.07.11.198721
Abstract: We establish a genome-wide map of DNA methylation quantitative trait locus (mQTL) effects in CD4 + T cells isolated from multiple sclerosis (MS) patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both MS susceptibility and local ( cis -) DNA methylation. We also identify two distant ( trans -) mQTL effects of MS susceptibility loci: (1) a chromosome 16 MS locus affects PRDM8 methylation (a chromosome 4 region not previously associated with MS susceptibility), and (2) the aggregate effect of MS variants in the major histocompatibility complex (MHC, chromosome 6) influences DNA methylation near PRKCA on chromosome 17. Both effects are replicated in independent s les. Overall, we present a new methylome-wide mQTL resource for a key cell type in inflammatory disease research, uncover functional consequences of MS susceptibility variants, including the convergence of MHC risk alleles onto a new gene target involved in predisposition to MS.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2018
Publisher: Elsevier BV
Date: 10-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-12-2017
DOI: 10.1126/SCITRANSLMED.AAI7635
Abstract: A microglial-like cellular model can be used to identify functional consequences of genetic variants associated with neurodegenerative disease.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
Publisher: Elsevier BV
Date: 2012
Publisher: Elsevier BV
Date: 06-2012
Publisher: Frontiers Media SA
Date: 23-11-2022
DOI: 10.3389/FIMMU.2022.956907
Abstract: Parenteral anti-CD3 Mab (OKT3) has been used to treat transplant rejection and parental administration of a humanized anti-CD3 Mab (Teplizumab) showed positive effects in diabetes. Nasal administration of anti-CD3 Mab has not been carried out in humans. Nasal anti-CD3 Mab suppresses autoimmune diseases and central nervous system (CNS) inflammation in animal models. We investigated the safety and immune effects of a fully humanized, previously uncharacterized nasal anti-CD3 Mab (Foralumab) in humans and its in vitro stimulatory properties. In vitro , Foralumab were compared to UCHT1 anti-human CD3 mAb. For human administration, 27 healthy volunteers (9 per group) received nasal Foralumab or placebo at a dose of 10ug, 50ug, or 250ug daily for 5 days. Safety was assessed and immune parameters measured on day 1 (pre-treatment), 7, 14, and 30 by FACS and by scRNAseq. In vitro , Foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. Foralumab induced LAP, TIGIT, and KLRG1 immune checkpoint molecules on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. In vivo , nasal Foralumab did not modulate CD3 from the T cell surface at any dose. Immune effects were primarily observed at the 50ug dose and consisted of reduction of CD8+ effector memory cells, an increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T cell granzyme B and perforin expression. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ TEMRA population there was induction of TIGIT, TGFB1 and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed, and no subjects developed human anti-mouse antibodies. These findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3OB42333F
Abstract: Antroc hin A and B, and (±)- epi -antrodioxolanone have been synthesised from a common precursor. Antroc hin A displays anti-inflammatory activity but is also cytotoxic.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1MD00184A
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4MD00070F
Abstract: 24 compounds were synthesized and their immunomodulation of TNF-α and IL-1β was evaluated.
Publisher: Cold Spring Harbor Laboratory
Date: 22-01-2018
Publisher: Springer Science and Business Media LLC
Date: 06-12-2021
DOI: 10.1038/S41467-021-27427-W
Abstract: Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4 + T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.
Location: Australia
No related grants have been discovered for Belinda Kaskow.