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Article ; Online: Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B4 receptors.

Admyre, Charlotte / Axelsson, Lars-Göran / von Stein, Oliver / Zargari, Arezou

2014 Volume 144, Issue 2, Page(s) 206–217

Abstract: Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4 ) constitute key mediators by ... ...

Abstract	Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4 ) constitute key mediators by binding to the surface receptors CXCR1/2 and BLT1, respectively. Oligonucleotides (ODN) containing CpG motifs mediate potent immunomodulatory effects through binding to Toll-like receptor 9. So far, knowledge on how ODN can affect neutrophil migration during inflammation is lacking. This study demonstrates that several novel CpG ODN significantly down-regulate the surface expression of CXCR1/2 and BLT1. In addition, the ODN significantly blocked IL-8-induced and LTB4 -induced neutrophil migration in vitro, as well as leucocyte migration in vivo demonstrated in mice by intravital microscopy and in a model of airway inflammation. The down-regulation of CXCR1 is rapid, occurring 15 min after ODN stimulation, and can be mediated through an endosomally independent mechanism. Inhibition of the IL-8 and LTB4 pathways may provide new opportunities of therapeutic intervention using ODN to reduce neutrophil infiltration during inflammation.
MeSH term(s)	Animals ; Chemotaxis, Leukocyte/drug effects ; Chemotaxis, Leukocyte/immunology ; CpG Islands/genetics ; Down-Regulation/immunology ; Female ; Humans ; Immunologic Factors/pharmacology ; Immunomodulation ; Inflammation/drug therapy ; Inflammation/immunology ; Interleukin-8/antagonists & inhibitors ; Interleukin-8/biosynthesis ; Interleukin-8/immunology ; Macrophage-1 Antigen/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophil Infiltration/drug effects ; Neutrophil Infiltration/immunology ; Neutrophils/drug effects ; Neutrophils/immunology ; Oligonucleotides/pharmacology ; Ovalbumin ; Receptors, Interleukin-8A/biosynthesis ; Receptors, Interleukin-8B/biosynthesis ; Receptors, Leukotriene B4/antagonists & inhibitors ; Receptors, Leukotriene B4/biosynthesis ; Receptors, Leukotriene B4/immunology ; Toll-Like Receptor 9/immunology ; Tumor Necrosis Factor-alpha/immunology
Chemical Substances	Immunologic Factors ; Interleukin-8 ; Macrophage-1 Antigen ; Oligonucleotides ; Receptors, Interleukin-8A ; Receptors, Interleukin-8B ; Receptors, Leukotriene B4 ; Toll-Like Receptor 9 ; Tumor Necrosis Factor-alpha ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2014-08-07
Publishing country	England
Document type	Journal Article
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.12368
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Article ; Online: Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis.

Atreya, Raja / Reinisch, Walter / Peyrin-Biroulet, Laurent / Scaldaferri, Franco / Admyre, Charlotte / Knittel, Thomas / Kowalski, Jan / Neurath, Markus Friedrich / Hawkey, Christopher

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver

2018 Volume 50, Issue 10, Page(s) 1019–1029

Abstract: Background: The Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct: Aims: The objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes ...

Abstract	Background: The Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct Aims: The objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes (PRO) defined endpoints. Methods: Dual topical administration of cobitolimod was studied in a randomised, multicentre clinical trial named COLLECT in moderate-to-severe UC patients. Symptomatic remission (SR) was studied in 104 patients based on their e-diary records and was defined as absence of blood in stool and a mean daily stool frequency (SF) < 4. Results: SR was achieved at week 4 in 17.1% of cobitolimod vs. 5.9% of placebo treated patients (p = 0.13), at week 8 in 35.7% vs. 17.6% (p = 0.07), and at week 12 in 38.6% vs. 17.6% (p = 0.04) of the patients, respectively. SR rates with cobitolimod and placebo in anti-TNFα experienced patients were smaller but with a broadly similar relative effect-size to anti-TNFα naïve patients. Clinical efficacy was higher in patients with moderate compared to severe disease. Conclusions: Application of the Toll-like-receptor 9 (TLR-9) agonist cobitolimod is able to induce remission as assessed by PRO measures in UC patients with moderate-to-severe activity as well as in anti-TNFα experienced and naïve patients supporting the overall efficacy of the substance.
MeSH term(s)	Administration, Topical ; Adult ; Aged ; Colitis, Ulcerative/drug therapy ; DNA/administration & dosage ; Female ; Humans ; Internationality ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Patient Reported Outcome Measures ; Retrospective Studies ; Severity of Illness Index ; Toll-Like Receptor 9/agonists ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Young Adult
Chemical Substances	DIMS0150 ; Toll-Like Receptor 9 ; Tumor Necrosis Factor-alpha ; DNA (9007-49-2)
Language	English
Publishing date	2018-06-22
Publishing country	Netherlands
Document type	Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	1459373-7
ISSN	1878-3562 ; 1125-8055
ISSN (online)	1878-3562
ISSN	1125-8055
DOI	10.1016/j.dld.2018.06.010
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Article ; Online: Differences in exosome populations in human breast milk in relation to allergic sensitization and lifestyle.

Torregrosa Paredes, P / Gutzeit, C / Johansson, S / Admyre, C / Stenius, F / Alm, J / Scheynius, A / Gabrielsson, S

Allergy

2014 Volume 69, Issue 4, Page(s) 463–471

Abstract: Background: Breast-feeding has many beneficial effects on the developing immune system of the newborn. Breast milk contains immunoregulatory factors, such as nano-sized vesicles named exosomes. This study aimed at characterizing breast milk exosomes ... ...

Abstract	Background: Breast-feeding has many beneficial effects on the developing immune system of the newborn. Breast milk contains immunoregulatory factors, such as nano-sized vesicles named exosomes. This study aimed at characterizing breast milk exosomes from human early milk and mature milk and to investigate whether allergic sensitization and an anthroposophic lifestyle could influence the exosome profile. Methods: Breast milk was collected from 22 mothers at day 3-8 and from 61 mothers at 2 months postpartum, all part of the ALADDIN birth cohort. Isolated exosomes were captured on anti-MHC-class II- or anti-CD63 beads and analyzed by flow cytometry. Exosomal phenotype was related to lifestyle and allergic sensitization of the mothers, and sensitization of the child at 2 years of age. Results: We found a higher content of exosomes in early milk compared with mature milk. Early milk exosomes were enriched in HLA-DR molecules and displayed significantly lower levels of HLA-ABC compared with those in mature milk. Phenotypically different subpopulations of exosomes were found in mature milk. Significantly lower levels of MUC1 were detected on CD63-enriched exosomes from sensitized mothers compared with nonsensitized. Furthermore, women with an anthroposophic lifestyle had significantly lower MUC1 expression on their HLA-DR-enriched milk exosomes and up-regulated levels of CD63 on CD63-enriched exosomes compared with nonanthroposophic mothers. Notably, mothers whose children developed sensitization had an increased amount of HLA-ABC on their milk exosomes enriched for CD63. Conclusions: The phenotype of exosomes in breast milk varies with maternal sensitization and lifestyle, which might influence allergy development in the child.
MeSH term(s)	Adult ; Child, Preschool ; Exosomes/immunology ; Exosomes/metabolism ; Female ; Humans ; Hypersensitivity/etiology ; Life Style ; Milk, Human/immunology ; Milk, Human/metabolism ; Mucin-1/metabolism ; Phenotype ; Prospective Studies ; Tetraspanin 30/metabolism ; Time Factors
Chemical Substances	Mucin-1 ; Tetraspanin 30
Language	English
Publishing date	2014-04
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.12357
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Article ; Online: The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis.

Journal of Crohn's & colitis

2019 Volume 14, Issue 4, Page(s) 508–524

Abstract: Background and aims: The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here ... ...

Abstract	Background and aims: The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC. Methods: Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry. Results: Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells. Conclusion: Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance. Podcast: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/pharmacokinetics ; Cell Culture Techniques ; Colitis, Ulcerative/drug therapy ; Colitis, Ulcerative/immunology ; Colitis, Ulcerative/pathology ; Disease Models, Animal ; Female ; Gastrointestinal Agents/administration & dosage ; Gastrointestinal Agents/pharmacokinetics ; Gene Expression Regulation ; Humans ; Immunomodulation ; Interleukin-10/analysis ; Interleukin-17/analysis ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/immunology ; Intestinal Mucosa/pathology ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/pathology ; Male ; Mice ; Middle Aged ; Oligodeoxyribonucleotides/administration & dosage ; Oligodeoxyribonucleotides/pharmacokinetics ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Th17 Cells/drug effects ; Th17 Cells/immunology ; Tissue Array Analysis/methods ; Toll-Like Receptor 9/agonists
Chemical Substances	Anti-Inflammatory Agents ; Gastrointestinal Agents ; Interleukin-17 ; Oligodeoxyribonucleotides ; TLR9 protein, human ; Toll-Like Receptor 9 ; Interleukin-10 (130068-27-8) ; cobitolimod (328101264R)
Language	English
Publishing date	2019-08-24
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjz170
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Article ; Online: Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery.

Lundin, Anders / Porritt, Michelle J / Jaiswal, Himjyot / Seeliger, Frank / Johansson, Camilla / Bidar, Abdel Wahad / Badertscher, Lukas / Wimberger, Sandra / Davies, Emma J / Hardaker, Elizabeth / Martins, Carla P / James, Emily / Admyre, Therese / Taheri-Ghahfarokhi, Amir / Bradley, Jenna / Schantz, Anna / Alaeimahabadi, Babak / Clausen, Maryam / Xu, Xiufeng /

Mayr, Lorenz M / Nitsch, Roberto / Bohlooly-Y, Mohammad / Barry, Simon T / Maresca, Marcello

Nature communications

2020 Volume 11, Issue 1, Page(s) 4903

Abstract: The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with ...

Abstract	The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Line, Tumor ; Doxycycline/pharmacology ; Drug Discovery/methods ; Drug Screening Assays, Antitumor/methods ; Female ; Gene Editing/methods ; Gene Expression/drug effects ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Genetic Vectors/genetics ; HEK293 Cells ; High-Throughput Screening Assays/methods ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Male ; Mice ; Mice, Transgenic ; RNA, Guide, CRISPR-Cas Systems/genetics ; Recombination, Genetic/drug effects ; Reproducibility of Results ; Transcriptional Activation/drug effects ; Transfection/methods ; Transgenes/genetics
Chemical Substances	Antineoplastic Agents ; RNA, Guide, CRISPR-Cas Systems ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Cas9 endonuclease Streptococcus pyogenes (EC 3.1.-) ; Doxycycline (N12000U13O)
Language	English
Publishing date	2020-09-29
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18548-9
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Article ; Online: Cardiac-Specific Overexpression of Oxytocin Receptor Leads to Cardiomyopathy in Mice.

Jung, Christian / Wernly, Bernhard / Bjursell, Mikael / Wiseman, John / Admyre, Therese / Wikström, Johannes / Palmér, Malin / Seeliger, Frank / Lichtenauer, Michael / Franz, Marcus / Frick, Charlotte / Andersson, Ann-Katrin / Elg, Margareta / Pernow, John / Sjöquist, Per-Ove / Bohlooly-Y, Mohammad / Wang, Qing-Dong

Journal of cardiac failure

2018 Volume 24, Issue 7, Page(s) 470–478

Abstract: Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that ... ...

Abstract	Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that overexpress Oxtr specifically in the heart. Methods and results: Cardiac-specific overexpression of Oxtr was obtained by having the α-major histocompatibility complex promoter drive the mouse Oxtr gene (α-Mhc-Oxtr). Left ventricular (LV) function and remodeling were assessed by magnetic resonance imaging and echocardiography. In α-Mhc-Oxtr TG mice, LV ejection fraction was severely compromised at 14 weeks of age compared with wild-type (WT) littermates (25 ± 6% vs 63 ± 3%; P < .001). LV end-diastolic volume was larger in the TG mice (103 ± 6 µL vs 67 ± 5 µL; P < .001). α-Mhc-Oxtr TG animals displayed cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes. Mortality of α-Mhc-Oxtr TG animals was 45% compared with 0% (P < .0001) of WT littermates by 20 weeks of age. Most cardiomyocytes of α-Mhc-Oxtr TG animals but not WT littermates (68.0 ± 12.1% vs 5.6 ± 2.4%; P = .008) were positive in staining for nuclear factor of activated T cells (NFAT). To study if thrombin inhibitor prevents thrombus formation, a cohort of 7-week-old α-Mhc-Oxtr TG mice were treated for 12 weeks with AZD0837, a potent thrombin inhibitor. Treatment with AZD0837 reduced thrombus formation (P < .05) and tended to attenuate fibrosis and increase survival. Conclusions: Cardiac-specific overexpression of Oxtr had negative consequences on LV function and survival in mice. The present findings necessitate further studies to investigate potential adverse effects of chronic Oxt administration. We provide a possible mechanism of Oxtr overexpression leading to heart failure by nuclear factor of activated T cell signaling. The recapitulation of human heart failure and the beneficial effects of the antithrombin inhibitor render the α-Mhc-Oxtr TG mice a promising tool in drug discovery for heart failure.
MeSH term(s)	Animals ; Cardiomyopathies/diagnosis ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Disease Models, Animal ; Echocardiography ; Gene Expression Regulation ; Magnetic Resonance Imaging, Cine ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardium/metabolism ; Myocardium/pathology ; RNA/genetics ; Real-Time Polymerase Chain Reaction ; Receptors, Oxytocin/biosynthesis ; Receptors, Oxytocin/genetics
Chemical Substances	OXTR protein, mouse ; Receptors, Oxytocin ; RNA (63231-63-0)
Language	English
Publishing date	2018-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	1281194-4
ISSN	1532-8414 ; 1071-9164
ISSN (online)	1532-8414
ISSN	1071-9164
DOI	10.1016/j.cardfail.2018.05.004
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Zs.A 4340: Show issues

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Article ; Online: Different types of in vitro generated human monocyte-derived dendritic cells release exosomes with distinct phenotypes.

Johansson, Sara M / Admyre, Charlotte / Scheynius, Annika / Gabrielsson, Susanne

Immunology

2007 Volume 123, Issue 4, Page(s) 491–499

Abstract: Human in vitro generated dendritic cells and the exosomes they release are potential tools for the modulation of immune responses. Here, we characterized differently generated monocyte-derived dendritic cells (MDDCs) and their exosomes. Culturing of ... ...

Abstract	Human in vitro generated dendritic cells and the exosomes they release are potential tools for the modulation of immune responses. Here, we characterized differently generated monocyte-derived dendritic cells (MDDCs) and their exosomes. Culturing of peripheral CD14+ cells from the same individuals with either interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (conventional MDDCs) or alternatively with IL-4 and IL-3 generated immature MDDCs in 7 days. Fluorescence-activated cell sorting (FACS) analysis showed that the IL-4/IL-3-generated MDDCs had significantly lower percentages of CD1a+, CD40+ and CD80+ cells and a higher percentage of CD86+ cells as compared with conventional MDDCs. In addition, IL-4/IL-3-generated MDDCs had significantly higher densities of major histocompatibility complex (MHC) class I [human leucocyte antigen (HLA)-ABC], MHC class II (HLA-DR), CD11c and the tetraspanin CD81 as compared with conventional MDDCs. In a comparison of their ability to stimulate CD8+ T cells, we found that the IL-4/IL-3 MDDCs were slightly more efficient than the conventional MDDCs at inducing interferon (IFN)-gamma release in response to viral peptides. Exosome morphology was confirmed by electron microscopy and exosome phenotypes were analysed by flow cytometry and western blot. In comparison to exosomes from conventional MDDCs, exosomes from IL-4/IL-3-generated MDDCs showed significantly stronger signals for HLA-ABC, HLA-DR, CD11c, CD63 and CD81. Thus, phenotypically the exosomes largely reflected their MDDCs of origin. When exosomes were loaded with viral peptides, both types of exosomes induced IFN-gamma release from CD8+ T cells. Our findings might have significance for the development of DC- and exosome-based therapies.
MeSH term(s)	Antigen Presentation ; Antigens, Viral/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Cytoplasmic Vesicles/immunology ; Cytoplasmic Vesicles/ultrastructure ; Dendritic Cells/immunology ; Dendritic Cells/ultrastructure ; Enzyme-Linked Immunosorbent Assay/methods ; HLA-DR Antigens/metabolism ; Humans ; Interferon-gamma/biosynthesis ; Interleukin-3/immunology ; Interleukin-4/immunology ; Lymphocyte Activation/immunology ; Monocytes/immunology
Chemical Substances	Antigens, Viral ; HLA-DR Antigens ; Interleukin-3 ; Interleukin-4 (207137-56-2) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2007-10-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2007.02714.x
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Article: Exosomes - nanovesicles with possible roles in allergic inflammation

Admyre, C / Telemo, E / Almqvist, N / Lötvall, J / Lahesmaa, R / Scheynius, A / Gabrielsson, S

Allergy. 2008 Apr., v. 63, no. 4

2008

Abstract: Exosomes are nano-sized membrane vesicles which are released extracellularly after fusion of multivesicular endosomes with the cell membrane. Despite their characteristic composition of proteins compared to the cell membrane, no exosome-specific molecule ...

Abstract	Exosomes are nano-sized membrane vesicles which are released extracellularly after fusion of multivesicular endosomes with the cell membrane. Despite their characteristic composition of proteins compared to the cell membrane, no exosome-specific molecule has so far been characterized. Exosomes are found in bronchoalveolar lavage (BAL), urine, serum and breast milk, and are released from several cells implicated in allergy including mast cells, dendritic cells (DC), T cells and epithelial cells. Antigen-loaded exosomes have been shown to be highly immunogenic and we propose that exosomes could be a modulating factor in allergic responses. Allergen-presenting exosomes could transport allergen and stimulate allergen-specific T cells, and possibly also biasing T cell responses depending on the molecules present on the exosome surface. Furthermore, exosomes from mast cells, highly active in allergic reactions, have been found to induce DC maturation and also to be able to transport functional RNA to recipient cells, suggesting a new pathway for cell communication. Reversely, tolerizing exosomes e.g. tolerosomes, from gut or breast milk, could block an allergic response or prevent allergy development. A better understanding of the role of exosomes in allergies could make us understand how allergy can be prevented or lead to the development of more efficient treatments.
Keywords	hypersensitivity ; antigen presentation ; inflammation
Language	English
Dates of publication	2008-04
Size	p. 404-408.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/j.1398-9995.2007.01600.x
Database	NAL-Catalogue (AGRICOLA)

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Zs.MO 125: Show issues

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Article: Direct exosome stimulation of peripheral human T cells detected by ELISPOT.

Admyre, Charlotte / Johansson, Sara M / Paulie, Staffan / Gabrielsson, Susanne

European journal of immunology

2006 Volume 36, Issue 7, Page(s) 1772–1781

Abstract: Exosomes from APC are nano-vesicles that can induce antigen-specific T cell responses and are presently explored as therapeutic tools in different clinical settings. Investigations of the capacity of exosomes to stimulate T cells in vitro have mostly ... ...

Abstract	Exosomes from APC are nano-vesicles that can induce antigen-specific T cell responses and are presently explored as therapeutic tools in different clinical settings. Investigations of the capacity of exosomes to stimulate T cells in vitro have mostly been performed on T cell hybridomas, clones or lines. Whether exosomes can stimulate T cells directly or need the presence of dendritic cells (DC) is debated. We could detect exosome-induced antigen-specific CD8(+) T cell responses in peripheral blood from humans. Exosomes from monocyte-derived DC (MDDC) were loaded with a mix of 23 immunogenic peptides from EBV, CMV and influenza virus, and added to autologous peripheral CD8(+) T cells. IFN-gamma-producing cells were detected by enzyme-linked immunospot assay (ELISPOT). MDDC-exosomes induced IFN-gamma production in CD8(+) T cells without addition of DC. The response was exosome dose dependent, and dependent on exosomal MHC class I. Furthermore, we detected an enhanced T cell stimulatory capacity by exosomes from lipopolysaccharide-matured MDDC compared to exosomes from immature MDDC. Exosomes could also induce TNF-alpha production. These results show, for the first time, that exosomes can directly stimulate human peripheral CD8(+) T cells in an antigen-specific manner and that ELISPOT is a suitable method for detecting exosome-induced peripheral T cell responses. This system may provide a useful tool when developing exosomes as therapeutic agents.
MeSH term(s)	Cells, Cultured ; Cytoplasmic Vesicles/immunology ; Cytoplasmic Vesicles/ultrastructure ; Dendritic Cells/immunology ; Dendritic Cells/ultrastructure ; Enzyme-Linked Immunosorbent Assay/methods ; Humans ; Lymphocyte Activation/immunology ; Microscopy, Immunoelectron ; T-Lymphocytes/immunology
Language	English
Publishing date	2006-07
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.200535615
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Article ; Online: Exosomes - nanovesicles with possible roles in allergic inflammation.

Admyre, C / Telemo, E / Almqvist, N / Lötvall, J / Lahesmaa, R / Scheynius, A / Gabrielsson, S

Allergy

2008 Volume 63, Issue 4, Page(s) 404–408

Abstract	Exosomes are nano-sized membrane vesicles which are released extracellularly after fusion of multivesicular endosomes with the cell membrane. Despite their characteristic composition of proteins compared to the cell membrane, no exosome-specific molecule has so far been characterized. Exosomes are found in bronchoalveolar lavage (BAL), urine, serum and breast milk, and are released from several cells implicated in allergy including mast cells, dendritic cells (DC), T cells and epithelial cells. Antigen-loaded exosomes have been shown to be highly immunogenic and we propose that exosomes could be a modulating factor in allergic responses. Allergen-presenting exosomes could transport allergen and stimulate allergen-specific T cells, and possibly also biasing T cell responses depending on the molecules present on the exosome surface. Furthermore, exosomes from mast cells, highly active in allergic reactions, have been found to induce DC maturation and also to be able to transport functional RNA to recipient cells, suggesting a new pathway for cell communication. Reversely, tolerizing exosomes e.g. tolerosomes, from gut or breast milk, could block an allergic response or prevent allergy development. A better understanding of the role of exosomes in allergies could make us understand how allergy can be prevented or lead to the development of more efficient treatments.
MeSH term(s)	Animals ; Cytoplasmic Vesicles/immunology ; Humans ; Hypersensitivity/immunology ; Immune Tolerance ; Inflammation/immunology
Language	English
Publishing date	2008-04
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/j.1398-9995.2007.01600.x
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