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Li, X., Singh, K., Luo, Z., Mejia Cordova, M., Jamalpour, M., Lindahl, B., . . . Welsh, M. (2018). Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas. OncoTarget, 9(27), 18720-18733
Open this publication in new window or tab >>Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18720-18733Article in journal (Refereed) Published
Abstract [en]

To assess mechanisms responsible for breast carcinoma metastasis, 4T1 breast carcinomas were grown orthotopically in wild type or Shb knockout mice. Tumor growth, metastasis, vascular characteristics and immune cell properties were analyzed. Absence of Shb did not affect tumor growth although it increased lung metastasis. Shb knockout mouse tumors showed decreased redness and less developed vascular plexa located at the periphery of the tumors. No difference in overall tumor vascular density, leakage or pericyte coverage was noted between the genotypes although the average vessel size was smaller in the knockout. Tumors induced an increase of CD11b+ cells in spleen, lymph node, thymus, bone marrow and blood. Numbers of Shb knockout CD11b/CD8+ cells were decreased in lymph nodes and bone marrow of tumor bearing mice. Mice with tumors had reduced numbers of CD4+ lymphocytes in blood/lymphoid organs, whereas in most of these locations the proportion of CD4+ cells co-expressing FoxP3 was increased, suggesting a relative increase in Treg cells. This finding was reinforced by increased blood interleukin-35 (IL-35) in wild type tumor bearing mice. Shb knockout blood showed in addition an increased proportion of IL-35 expressing Treg cells, supporting the notion that absence of Shb further promotes tumor evasion from immune cell recognition. This could explain the increased number of lung metastases observed under these conditions. In conclusion, 4T1 tumors alter immune cell responses that promote tumor expansion, metastasis and escape from T cell recognition in an Shb dependent manner. 

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-347019 (URN)10.18632/oncotarget.24643 (DOI)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-04-12Bibliographically approved
Espes, D., Singh, K., Sandler, S. & Carlsson, P.-O. (2017). Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide. Diabetes Care, 40(8), 1090-1095
Open this publication in new window or tab >>Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide
2017 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 40, no 8, p. 1090-1095Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease.

RESEARCH DESIGN AND METHODS Patients (n = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide–positive patients and 12 of the C-peptide–negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells.

RESULTS The blood concentration of the cytokine IL-35 was markedly lower in C-peptide–negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35+ regulatory T cells (Tregs), IL-35+ regulatory B cells, and IL-35–producing CD8+Foxp3+ cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to β-cells. We found that the proportions of IL-17a+ cells among the Tregs, CD4+ T cells, and CD8+ T cells were lower in the C-peptide–positive patients.

CONCLUSIONS Patients with remaining endogenous β-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.

National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-329523 (URN)10.2337/dc16-2121 (DOI)000406014200026 ()28620093 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Research Council, 921-2014-7054EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationTorsten Söderbergs stiftelseNovo NordiskSwedish Child Diabetes Foundation
Available from: 2017-09-18 Created: 2017-09-18 Last updated: 2017-11-02Bibliographically approved
Luo, Z., Varli, S., Enström, E., Thorvaldson, L., Blixt, M., Hansell, P., . . . Singh, K. (2017). Kinetics of innate immune and regulatory T cells responses in experimental diabetic nephropathy. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 304-304
Open this publication in new window or tab >>Kinetics of innate immune and regulatory T cells responses in experimental diabetic nephropathy
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 304-304Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346962 (URN)000411865200135 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-03-23Bibliographically approved
Mejia Cordova, M., Soläng, C., Luo, Z., Blixt, M., Thorvaldson, L., Sandler, S. & Singh, K. (2017). Kinetics of the innate immune cell responses in experimental Type 1 Diabetes. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 303-304
Open this publication in new window or tab >>Kinetics of the innate immune cell responses in experimental Type 1 Diabetes
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 303-304Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346961 (URN)000411865200134 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-03-23Bibliographically approved
Digre, A., Singh, K., Åbrink, M., Reijmers, R. M., Sandler, S., Vlodavsky, I. & Li, J.-P. (2017). Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis. Scientific Reports, 7, Article ID 46229.
Open this publication in new window or tab >>Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46229Article in journal (Refereed) Published
Abstract [en]

Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50 % of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+ and CD8+ T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.

Keywords
Collagen-induced arthritis, Heparanase, Heparan Sulfate, Flow cytometry, T cells
National Category
Immunology in the medical area
Research subject
Immunology; Medical Science
Identifiers
urn:nbn:se:uu:diva-315694 (URN)10.1038/srep46229 (DOI)000398988100001 ()28401953 (PubMedID)
Funder
Swedish Research Council, 2015-02595; K2012-56X-15046-09-4Swedish Research Council, 521-2011-3533Swedish Heart Lung Foundation, 20140131Swedish Cancer Society, 150815Swedish Diabetes AssociationSwedish Child Diabetes Foundation
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-01-13Bibliographically approved
Lundin, S., Espes, D., Luo, Z., Blixt, M., Mejia Cordova, M., Carlsson, P.-O., . . . Singh, K. (2017). Role of regulatory B cells in clinical and experimental type 1 diabetes. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 349-349
Open this publication in new window or tab >>Role of regulatory B cells in clinical and experimental type 1 diabetes
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 349-349Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346972 (URN)000411865200233 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28Bibliographically approved
Singh, K., Sandler, S. & Espes, D. (2017). The Increased Circulating Plasma Levels of Vascular Endothelial Growth Factor in Patients with Type 1 Diabetes Do Not Correlate to Metabolic Control. Journal of Diabetes Research, Article ID 6192896.
Open this publication in new window or tab >>The Increased Circulating Plasma Levels of Vascular Endothelial Growth Factor in Patients with Type 1 Diabetes Do Not Correlate to Metabolic Control
2017 (English)In: Journal of Diabetes Research, ISSN 2314-6745, E-ISSN 2314-6753, article id 6192896Article in journal (Refereed) Published
Abstract [en]

Aim. To characterize the plasma levels of vascular endothelial growth factor ( VEGF) in type 1 diabetes mellitus (T1D) and its relation to both present and historical metabolic control and microvascular complications.

Methods. Plasma levels of VEGF and routine clinical parameters were analyzed in 115 patients with long-standing T1D and 45 healthy controls (HC). All patients were under clinical routine diabetes treatment at Uppsala University Hospital.

Results. The plasma levels of VEGF were increased by 37% in patients with T1D when compared to HC (18.2 +/- 0.8 versus 13.2 +/- 1.0 pg/ml, p < 0.001). The levels of VEGF correlated to insulin needs and BMI but not to present or historical metabolic control. The levels of VEGF were similar in patients with T1D and microvascular complications (microalbuminuria and retinopathy) when compared with patients without microvascular complications. Historical HbA1c levels were found to be the best predictor for present metabolic control.

Conclusion. Circulating plasma levels of VEGF do not correlate to present or historical metabolic control in long-standing T1D and the levels are not affected by the presence of microvascular complications.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-359305 (URN)10.1155/2017/6192896 (DOI)000398400100001 ()28421206 (PubMedID)
Funder
Magnus Bergvall FoundationSwedish Child Diabetes Foundation
Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-03Bibliographically approved
Varli, S., Thorvaldson, L., Sandler, S. & Singh, K. (2016). Kinetics of the Foxp3(+) cell response in kidney tissue of both autoimmune and non-autoimmune induced hyperglycemia in mice. Paper presented at International Congress of Immunology (ICI), AUG 21-26, 2016, Melbourne, AUSTRALIA. European Journal of Immunology, 46, 1065-1065
Open this publication in new window or tab >>Kinetics of the Foxp3(+) cell response in kidney tissue of both autoimmune and non-autoimmune induced hyperglycemia in mice
2016 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 1065-1065Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-308497 (URN)000383610402537 ()
Conference
International Congress of Immunology (ICI), AUG 21-26, 2016, Melbourne, AUSTRALIA
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2018-01-13Bibliographically approved
Singh, K., Hjort, M., Thorvaldson, L. & Sandler, S. (2015). Concomitant analysis of Helios and Neuropilin-1 as a marker to detect thymic derived regulatory T cells in naive mice. Scientific Reports, 5, 7767
Open this publication in new window or tab >>Concomitant analysis of Helios and Neuropilin-1 as a marker to detect thymic derived regulatory T cells in naive mice
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 7767-Article in journal (Refereed) Published
Abstract [en]

Regulatory T (Treg) cells are characterized by the expression of CD4, CD25 and the intracellular Foxp3. However, these markers do not indicate whether Treg cells are thymic derived Treg (tTreg) cells or peripherally induced Treg (pTreg) cells. Recently, Helios and Neuropilin-1 (Nrp1) has been reported as potential markers for tTreg cells. Herein, we used flow cytometry to examine the proportion of CD4(+)CD8(-)CD25(+) Treg cells expressing Helios, Nrp1 and Foxp3 in thymus, pancreatic draining lymph nodes (PDLNs) and spleen of CD-1 mice, and thymus of NOD and C57BL/6 mice. The frequency of Helios(+) cells was higher than that of Nrp1(+) cells in CD4(+)CD8(-)CD25(+) and CD4(+)CD8(-)CD25(+)Foxp3(+) Treg cells in thymus. Interestingly, the proportion of IL-10(+), Ebi3(+) and CTLA-4(+) cells was higher in Helios(+) than Nrp1(+) tTreg cells. The anti-apoptotic activity of Helios(+) tTreg cells was higher in thymus compared to Nrp1(+) tTreg cells. Nrp1 seems to be expressed at a later developmental stage compared to Helios and Foxp3. Furthermore, the expression of Nrp1 in CD4(+)CD25(+) T cells of younger mice did not increase after stimulating them in vitro with anti-CD3 and -CD28. Thus, under these conditions, Helios could be considered a more reliable marker for distinguishing tTreg cells from pTreg cells than Nrp1.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-244481 (URN)10.1038/srep07767 (DOI)000347838500002 ()
Available from: 2015-02-25 Created: 2015-02-17 Last updated: 2017-12-04Bibliographically approved
Singh, K., Kadesjö, E., Lindroos, J., Hjort, M., Lundberg, M., Espes, D., . . . Thorvaldson, L. (2015). Interleukin-35 administration counteracts established murine type 1 diabetes - possible involvement of regulatory T cells. Scientific Reports, 5, Article ID 12633.
Open this publication in new window or tab >>Interleukin-35 administration counteracts established murine type 1 diabetes - possible involvement of regulatory T cells
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12633Article in journal (Refereed) Published
Abstract [en]

The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-beta) and increased pro-inflammatory (IFN-gamma, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-261297 (URN)10.1038/srep12633 (DOI)000358867000001 ()26224624 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskSwedish Child Diabetes Foundation
Available from: 2015-09-03 Created: 2015-09-01 Last updated: 2017-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0420-2860

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