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- Karnevi, Emelie, et al.
(author)
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Tumour-educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion.
- 2014
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In: Immunology and Cell Biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 92:6, s. 543-552
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Journal article (peer-reviewed)abstract
- At the time of diagnosis, almost 80% of pancreatic cancer patients present with new-onset type 2 diabetes (T2D) or impaired glucose tolerance. T2D and pancreatic cancer are both associated with low-grade inflammation. Tumour-associated macrophages (TAMs) have a key role in cancer-related inflammation, immune escape, matrix remodelling and metastasis. In this study, the interplay between tumour cells and immune cells under the influence of different glucose levels was investigated. Human peripheral blood mononuclear cells were exposed in vitro to conditioned medium from BxPC-3 human pancreatic cancer cells, in normal (5 mM) or high (25 mM) glucose levels. Flow cytometry analyses demonstrated that tumour-derived factors stimulated differentiation of macrophages, with a mixed classical (M1-like) and alternatively activated (M2-like) phenotype polarisation (CD11c(+)CD206(+)). High-glucose conditions further enhanced the tumour-driven macrophage enrichment and associated interleukin (IL)-6 and IL-8 cytokine levels. In addition, hyperglycaemia enhanced the responsiveness of tumour-educated macrophages to lipopolysaccharide, with elevated cytokine secretion compared with normal glucose levels. Tumour-educated macrophages were found to promote pancreatic cancer cell invasion in vitro, which was significantly enhanced at high glucose. The anti-diabetic drug metformin shifted the macrophage phenotype polarisation and reduced the tumour cell invasion at normal, but not high, glucose levels. In conclusion, this study demonstrates that pancreatic cancer cells stimulate differentiation of macrophages with pro-tumour properties that are further enhanced by hyperglycaemia. These findings highlight important crosstalk between tumour cells and TAMs in the local tumour microenvironment that may contribute to disease progression in pancreatic cancer patients with hyperglycaemia and T2D.Immunology and Cell Biology advance online publication, 25 March 2014; doi:10.1038/icb.2014.22.
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- Liu, Yawei, et al.
(author)
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Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE.
- 2010
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In: Immunology and Cell Biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 88, s. 468-476
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Journal article (peer-reviewed)abstract
- IFN-beta is anticipated to have an important function in mucosal tolerance, as it is one of the major cytokines produced by plasmacytoid dendritic cells, and has recently been suggested as central to the maintenance of mucosal homeostasis. Here, we have investigated whether oral tolerance is dependent on endogenous IFN-beta by feeding low-dose self-antigen myelin basic protein to IFN-beta(-/-) mice with subsequent induction of experimental autoimmune encephalomyelitis (EAE). Our study shows that oral tolerance was readily induced in IFN-beta(-/-) mice compared with their wild-type littermates (IFN-beta(+/+)). The non-self-antigen ovalbumin induced oral tolerance in both groups. These data indicate that endogenous IFN-beta is not required for induction of oral tolerance, whereas delivery of recombinant IFN-beta results in significant reduction in clinical score of EAE. Oral tolerance induction was associated with lower production of antigen-specific IFN-gamma, no shift toward antigen-specific Th2, Th17 or TGF-beta response was observed. Oral tolerance in IFN-beta(-/-) mice was also associated with the induction of regulatory and memory T cells in the mucosal-associated immune organs, however this was not a prerequisite for establishment of oral tolerance.Immunology and Cell Biology advance online publication, 12 January 2010; doi:10.1038/icb.2009.111.
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- O'Meara, Connor P, et al.
(author)
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Immunity against a Chlamydia infection and disease may be determined by a balance of IL-17 signaling.
- 2014
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In: Immunology and cell biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 92:3, s. 287-297
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Journal article (peer-reviewed)abstract
- Most vaccines developed against Chlamydia using animal models provide partial protection against a genital tract infection. However, protection against the oviduct pathology associated with infertility is highly variable and often has no defining immunological correlate. When comparing two adjuvants (CTA1-DD and a combination of Cholera toxin plus CpG-oligodeoxynucleotide-CT/CpG) combined with the chlamydial major outer membrane protein (MOMP) antigen and delivered via the intranasal (IN), sublingual (SL) or transcutaneous (TC) routes, we identified two vaccine groups with contrasting outcomes following infection. SL immunization with MOMP/CTA1-DD induced a 70% reduction in the incidence of oviduct pathology, without significantly altering the course of infection. Conversely, IN immunization with MOMP/CT/CpG prevented an ascending infection, but not the oviduct pathology. This anomaly presented a unique opportunity to study the mechanisms by which vaccines can prevent oviduct pathology, other than by controlling the infection. The IL-17 signaling in the oviducts was found to associate with both the enhancement of immunity to infection and the development of oviduct pathology. This conflicting role of IL-17 may provide some explanation for the discordance in protection between infection and disease and suggests that controlling immunopathology, as opposed to the rapid eradication of the infection, may be essential for an effective human chlamydial vaccine that prevents infertility.Immunology and Cell Biology advance online publication, 24 December 2013; doi:10.1038/icb.2013.92.
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- Rydnert, Frida, et al.
(author)
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Circulating CD1c(+) DCs are superior at activating Th2 responses upon Phl p stimulation compared with basophils and pDCs.
- 2014
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In: Immunology and Cell Biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 92:6, s. 557-560
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Journal article (peer-reviewed)abstract
- The contributing role of circulating human dendritic cell (DC) populations and basophils in the presentation and augmentation of Th2 responses remains to be determined. The present study aimed at elucidating the functional role of CD1c(+) myeloid DCs (mDCs), CD123(+) plasmacytoid DCs (pDCs), monocyte-derived DCs and basophils in allergen presentation and Th2 activation. By coculturing Phleum pratense (Phl p)-pulsed CD1c(+) mDCs, CD123(+) pDCs, monocyte-derived DCs and basophils with autologous CD4(+) effector memory T cells, we assessed T-cell proliferation as well as the frequency of interleukin-4- and interferon-γ-producing T cells. Interestingly, a Th2-stimulating ability was observed for Phl p-challenged CD1c(+) mDCs and monocyte-derived DCs, while CD123(+) pDCs and basophils did not affect the Th-balance. In addition, both Phl p-pulsed CD1c(+) mDCs and monocyte-derived DCs stimulated increased T-cell proliferation compared to basophils and CD123(+) pDCs. Together, these results point to a prominent role for circulating CD1c(+) mDCs in allergen presentation and augmentation of Th2 responses, making them promising therapeutic targets for Type I hypersensitivity reactions.Immunology and Cell Biology advance online publication, 1 April 2014; doi:10.1038/icb.2014.23.
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- Saksida, Tamara, et al.
(author)
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Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis
- 2012
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In: Immunology and Cell Biology. - : Wiley. - 0818-9641 .- 1440-1711. ; 90:7, s. 688-698
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Journal article (peer-reviewed)abstract
- As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators beta-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for beta-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect beta-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued beta-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, beta-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondria! membrane. In conclusion, the observed considerable preservation of beta-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.
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