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Baranov, Vladimir
Publications (10 of 30) Show all publications
Mincheva-Nilsson, L. & Baranov, V. (2014). Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success. American Journal of Reproductive Immunology, 72(5), 440-457
Open this publication in new window or tab >>Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success
2014 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 72, no 5, p. 440-457Article, review/survey (Refereed) Published
Abstract [en]

The syncytiotrophoblast (STB) of human placenta constitutively produces and secretes extracellular vesicles of different size, morphology and function that enter the maternal circulation, and participate in the maternal-fetal cross-talk during pregnancy. Syncytiotrophoblast-derived microvesicles/microparticles (STBM) are larger microvesicles (0.2-2m) shed by the apical plasma membrane of the STB as a result of cell activation and turnover. Simultaneously with the STBM shedding, the STB produces and secretes exosomes - nanosized (30-100/150nm) membrane-bound microvesicles that originate from the endosomal compartment. They convey cell-cell contact by proxy' transporting signals/packages of information between donor and recipient cells locally or/and at a distance. STBM and exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, have contrasting biological functions. While the exosomes are immunosuppressive down regulating maternal immunity in pluripotent ways, the main effects of STBM on the maternal immune system are pro-inflammatory, immune activating, and pro-coagulant. Since both STBM and exosomes are present in the maternal circulation throughout normal pregnancy logical questions are what is the net effect of these vesicles on the maternal immune system and is this effect beneficial or detrimental to pregnancy. In this review, the current knowledge about placenta-derived extracellular vesicles with a main focus on exosomes is summarized and discussed. In a concluding remark, a hypothetical proposal on how STBM and exosomes might interact in pregnancy is discussed and a way to evaluate this interaction is suggested.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
exosomes, immunomodulation, microparticles, microvesicles, placenta, pregnancy, STBM
National Category
Immunology in the medical area Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-96493 (URN)10.1111/aji.12311 (DOI)000343731800002 ()
Available from: 2014-12-01 Created: 2014-11-21 Last updated: 2018-06-07Bibliographically approved
Lundholm, M., Schröder, M., Nagaeva, O., Baranov, V., Widmark, A., Mincheva-Nilsson, L. & Wikström, P. (2014). Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8(+) T Cells: Mechanism of Immune Evasion. PLoS ONE, 9(9), e108925
Open this publication in new window or tab >>Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8(+) T Cells: Mechanism of Immune Evasion
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108925-Article in journal (Refereed) Published
Abstract [en]

Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8(+) T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8(+) T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8(+) T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

National Category
Cancer and Oncology Immunology
Identifiers
urn:nbn:se:umu:diva-96829 (URN)10.1371/journal.pone.0108925 (DOI)000343671700191 ()
Available from: 2014-12-05 Created: 2014-12-03 Last updated: 2018-06-07Bibliographically approved
Skogberg, G., Gudmundsdottir, J., van der Post, S., Sandström, K., Bruhn, S., Benson, M., . . . Ekwall, O. (2013). Characterization of human thymic exosomes. PLoS ONE, 8(7), e67554
Open this publication in new window or tab >>Characterization of human thymic exosomes
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e67554-Article in journal (Refereed) Published
Abstract [en]

Exosomes are nanosized membrane-bound vesicles that are released by various cell types and are capable of carrying proteins, lipids and RNAs which can be delivered to recipient cells. Exosomes play a role in intercellular communication and have been described to mediate immunologic information. In this article we report the first isolation and characterization of exosomes from human thymic tissue. Using electron microscopy, particle size determination, density gradient measurement, flow cytometry, proteomic analysis and microRNA profiling we describe the morphology, size, density, protein composition and microRNA content of human thymic exosomes. The thymic exosomes share characteristics with previously described exosomes such as antigen presentation molecules, but they also exhibit thymus specific features regarding surface markers, protein content and microRNA profile. Interestingly, thymic exosomes carry proteins that have a tissue restricted expression in the periphery which may suggest a role in T cell selection and the induction of central tolerance. We speculate that thymic exosomes may provide the means for intercellular information exchange necessary for negative selection and regulatory T cell formation of the developing thymocytes within the human thymic medulla.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-79252 (URN)10.1371/journal.pone.0067554 (DOI)000321341000055 ()
Available from: 2013-09-05 Created: 2013-08-13 Last updated: 2018-06-08Bibliographically approved
Stenqvist, A.-C., Nagaeva, O., Baranov, V. & Mincheva-Nilsson, L. (2013). Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. Journal of Immunology, 191(11), 5515-5523
Open this publication in new window or tab >>Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus
2013 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 11, p. 5515-5523Article in journal (Refereed) Published
Abstract [en]

Apoptosis is crucially important in mediating immune privilege of the fetus during pregnancy. We investigated the expression and in vitro apoptotic activity of two physiologically relevant death messengers, the TNF family members Fas ligand (FasL) and TRAIL in human early and term placentas. Both molecules were intracellularly expressed, confined to the late endosomal compartment of the syncytiotrophoblast, and tightly associated to the generation and secretion of placental exosomes. Using immunoelectron microscopy, we show that FasL and TRAIL are expressed on the limiting membrane of multivesicular bodies where, by membrane invagination, intraluminal microvesicles carrying membranal bioactive FasL and TRAIL are formed and released in the extracellular space as exosomes. Analyzing exosomes secreted from placental explant cultures, to our knowledge, we demonstrate for the first time that FasL and TRAIL are clustered on the exosomal membrane as oligomerized aggregates ready to form death-inducing signaling complex. Consistently, placental FasL-and TRAIL-carrying exosomes triggered apoptosis in Jurkat T cells and activated PBMC in a dose-dependent manner. Limiting the expression of functional FasL and TRAIL to exosomes comprise a dual benefit: 1) storage of exosomal FasL and TRAIL in multivesicular bodies is protected from proteolytic cleavage and 2) upon secretion, delivery of preformed membranal death molecules by exosomes rapidly triggers apoptosis. Our results suggest that bioactive FasL-and TRAIL-carrying exosomes, able to convey apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its exosome-secreting ability.

Place, publisher, year, edition, pages
The American Association of Immunologists, 2013
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-84107 (URN)10.4049/jimmunol.1301885 (DOI)000327180600019 ()
Available from: 2013-12-18 Created: 2013-12-16 Last updated: 2018-06-08Bibliographically approved
Hedberg, M. E., Moore, E. R., Svensson-Stadler, L., Hörstedt, P., Baranov, V., Hernell, O., . . . Hammarström, M.-L. (2012). Lachnoanaerobaculum a new genus in Lachnospiraceae; characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from human small intestine, Lachnoanaerobaculum orale gen. nov., sp. nov., isolated from saliva and reclassification of Eubacterium saburreum (Prevot) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov.. International Journal of Systematic and Evolutionary Microbiology, 62(11), 2685-2690
Open this publication in new window or tab >>Lachnoanaerobaculum a new genus in Lachnospiraceae; characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from human small intestine, Lachnoanaerobaculum orale gen. nov., sp. nov., isolated from saliva and reclassification of Eubacterium saburreum (Prevot) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov.
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2012 (English)In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 62, no 11, p. 2685-2690Article in journal (Refereed) Published
Abstract [en]

Two new obligately anaerobic Gram-positive, saccharolytic and non-proteolytic spore-forming bacilli (strain CD3:22 and N1) are described. Strain CD3:22 was isolated from a biopsy of the small intestine of a child with celiac disease and strain N1 from the saliva of a healthy young man. The cells of both strains were observed to be filamentous with lengths of approximately 5 to >20 µm, some of them curving and with swellings. The novel organisms produced H2S, NH3, butyric acid and acetic acid as major metabolic end products. Phylogenetic analyses, based on comparative 16S rRNA gene sequencing, revealed close relationships (98 % sequence similarity) between the two isolates, as well as the type strain of Eubacterium saburreum CCUG 28089T and four other Lachnospiraceae bacterium/E. saburreum-like organisms. This group of bacteria were clearly different from any of the 19 known genera in the family Lachnospiraceae. While Eubacterium spp. are reported to be non-spore-forming, reanalysis of E. saburreum CCUG 28089T confirmed that the bacterium, indeed, is able to form spores. Based on 16S rRNA gene sequencing, phenotypic and biochemical properties, CD3:22 (CCUG 58757T) and N1 (CCUG 60305T) represent new species of a new and distinct genus, named Lachnoanaerobaculum, in the family Lachnospiraceae [within the order Clostridiales, class Clostridia, phylum Firmicutes]. Strain CD3:22 is the type strain of the type species, Lachnoanaerobaculum umeaense gen. nov., sp. nov., of the proposed new genus. Strain N1 is the type strain of the species, Lachnoanaerobaculum orale gen. nov., sp. nov. Moreover, E. saburreum CCUG 28089T is reclassified as Lachnoanaerobaculum saburreum comb. nov.

National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-51168 (URN)10.1099/ijs.0.033613-0 (DOI)22228654 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 222720Swedish Research Council
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2018-06-08Bibliographically approved
Maguire, C. A., Balaj, L., Sivaraman, S., Crommentuijn, M. H. W., Ericsson, M., Mincheva-Nilsson, L., . . . Skog, J. (2012). Microvesicle-associated AAV Vector as a Novel Gene Delivery System. Molecular Therapy, 20(5), 960-971
Open this publication in new window or tab >>Microvesicle-associated AAV Vector as a Novel Gene Delivery System
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2012 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 20, no 5, p. 960-971Article in journal (Refereed) Published
Abstract [en]

Adeno-associated virus (AAV) vectors have shown remarkable efficiency for gene delivery to cultured cells and in animal models of human disease. However, limitations to AAV vectored gene transfer exist after intravenous transfer, including off-target gene delivery (e.g., liver) and low transduction of target tissue. Here, we show that during production, a fraction of AAV vectors are associated with microvesicles/exosomes, termed vexosomes (vector-exosomes). AAV capsids associated with the surface and in the interior of microvesicles were visualized using electron microscopy. In cultured cells, vexosomes outperformed conventionally purified AAV vectors in transduction efficiency. We found that purified vexosomes were more resistant to a neutralizing anti-AAV antibody compared to conventionally purified AAV. Finally, we show that vexosomes bound to magnetic beads can be attracted to a magnetized area in cultured cells. Vexosomes represent a unique entity which offers a promising strategy to improve gene delivery.

Place, publisher, year, edition, pages
New York: Nature Publishing Group, 2012
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Microbiology
Identifiers
urn:nbn:se:umu:diva-55673 (URN)10.1038/mt.2011.303 (DOI)000303484300012 ()
Available from: 2012-05-29 Created: 2012-05-28 Last updated: 2018-06-08Bibliographically approved
Hedlund, M., Nagaeva, O., Kargl, D., Baranov, V. & Mincheva-Nilsson, L. (2011). Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS ONE, 6(2), e16899
Open this publication in new window or tab >>Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16899-Article in journal (Refereed) Published
Abstract [en]

Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.

Identifiers
urn:nbn:se:umu:diva-42832 (URN)10.1371/journal.pone.0016899 (DOI)21364924 (PubMedID)
Available from: 2011-04-13 Created: 2011-04-13 Last updated: 2018-06-08Bibliographically approved
Hedberg, M., Hammarström, M.-L., Hernell, O., Baranov, V., Wai, S. N., Moore, E. & Hammarström, S. (2010). Clostridiales bacterium CD3:22-an anaerobic spore-forming bacterium isolated from small intestine in a celiac disease patient.
Open this publication in new window or tab >>Clostridiales bacterium CD3:22-an anaerobic spore-forming bacterium isolated from small intestine in a celiac disease patient
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2010 (English)Report (Other academic)
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-35386 (URN)
Note
Kompletteras 2012-09Available from: 2010-08-16 Created: 2010-08-16 Last updated: 2018-06-08Bibliographically approved
Mincheva-Nilsson, L. & Baranov, V. (2010). The role of placental exosomes in reproduction. American Journal of Reproductive Immunology and Microbiology, 63(6), 520-533
Open this publication in new window or tab >>The role of placental exosomes in reproduction
2010 (English)In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 63, no 6, p. 520-533Article in journal (Refereed) Published
Abstract [en]

Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. There is, however, another cell-cell communication by released membrane-bound microvesicles that convey cell-cell contact 'by proxy' transporting signals/packages of information from donor to recipient cells locally and/or at a distance. The nanosized exosomes comprise a specialized type of microvesicles generated within multivesicular bodies (MVB) and released upon MVB fusion with the plasma membrane. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram their recipient cells. Recently, it was discovered that the syncytiotrophoblast constitutively and throughout the pregnancy secretes exosomes. The placenta-derived exosomes are immunosuppressive and carry proteins and RNA molecules that in a redundant way influence a number of mechanisms and promote the fetal allograft survival. In this review, we summarize the current knowledge on the nature of placenta-derived exosomes and discuss their role in pregnancy.

Keywords
Exosomes; FasL; MICA/B; microvesicles; placenta; ULBP
Identifiers
urn:nbn:se:umu:diva-42831 (URN)10.1111/j.1600-0897.2010.00822.x (DOI)000277521800011 ()20331583 (PubMedID)
Available from: 2011-04-13 Created: 2011-04-13 Last updated: 2018-06-08Bibliographically approved
Ou, G., Baranov, V., Lundmark, E., Hammarström, S. & Hammarström, M.-L. (2009). Contribution of intestinal epithelial cells to innate immunity of the human gut: studies on polarized monolayers of colon carcinoma cells. Scandinavian Journal of Immunology, 69(2), 150-161
Open this publication in new window or tab >>Contribution of intestinal epithelial cells to innate immunity of the human gut: studies on polarized monolayers of colon carcinoma cells
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2009 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 2, p. 150-161Article in journal (Refereed) Published
Abstract [en]

The aim was to establish an in vitro model for studies of innate defence mechanisms of human intestinal epithelium. Ultrastructural characterization and determination of mRNA expression levels for apical glycocalyx and mucous components showed that polarized, tight monolayers of the colon carcinoma cell lines T84 and Caco2 acquire the features of mature- and immature columnar epithelial cells, respectively. Polarized monolayers were challenged with non-pathogenic Gram+ and Gram- bacteria from the apical side and the proinflammatory cytokines interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from the basolateral side. Immune responses were estimated as changes in mRNA expression levels for the mucous component mucin-2 (MUC2), the glycocalyx components carcinoembryonic antigen (CEA), CEA-related cell adhesion molecule-1 (CEACAM1), CEACAM6, CEACAM7 and MUC3, the antimicrobial factors human beta-defensin-1 (hBD1), hBD2, hBD3 and lysozyme, the chemokine IL-8 and the cytokines IL-6 and TNF-alpha. Tight monolayer cells were generally unresponsive to bacterial challenge, but increased their hBD2 levels when challenged with Bacillus megaterium. T84 cells also increased their TNF-alpha levels upon bacterial challenge. Tight monolayer cells responded to cytokine challenge suggesting awareness of basolateral attack. TNF-alpha induced significantly increased levels of IL-8 and TNF-alpha itself in both cell lines suggesting recruitment and activation of immune cells in the underlying mucosa in vivo. Cytokine challenge also increased levels of CEACAM1, which includes two functionally different forms, CEACAM1-L and CEACAM1-S. In T84 cells, IFN-gamma was selective for CEACAM1-L while TNF-alpha upregulated both forms. Increased CEACAM1 expression may influence epithelial function and communication between epithelial cells and intraepithelial lymphocytes.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-21077 (URN)10.1111/j.1365-3083.2008.02208.x (DOI)19170965 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2018-06-09Bibliographically approved
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