| 1. |
|
|
| 2. |
- Digre, Andreas, 1987-, et al.
(author)
-
Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
- 2017
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Journal article (peer-reviewed)abstract
- 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.
|
|
| 3. |
|
|
| 4. |
- Espes, Daniel, 1985-, et al.
(author)
-
Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide
- 2017
-
In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:8, s. 1090-1095
-
Journal article (peer-reviewed)abstract
- 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.
|
|
| 5. |
- Li, Xiujuan, et al.
(author)
-
Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas
- 2018
-
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:27, s. 18720-18733
-
Journal article (peer-reviewed)abstract
- 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.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Luo, Zhengkang, 1994-
(author)
-
Immunological strategies for counteracting type 1 diabetes focusing on IL-35 producing regulatory immune cells
- 2023
-
Doctoral thesis (other academic/artistic)abstract
- Type 1 diabetes (T1D) is an autoimmune disease where pancreatic β-cells are attacked by immune cells. Regulatory T (Treg) cells play critical roles in suppressing immune responses and their involvement have been intensively studied in T1D. Low dose IL-2 has been proposed to selectively boost Treg cells in T1D, with only limited success. We thus further decreased the IL-2 dosage and treated multiple low dose streptozotocin (MLDSTZ) mice with an ultra-low dose IL-2, but it did not protect STZ mice from hyperglycemia. Similarly, low dose IL-2 only partially prevented diabetes. Treg cells’ phenotype was not protected by either dose. These data suggest that alternative IL-2 therapies might be considered. Regulatory B (Breg) cells suppress pro-inflammatory immune responses by producing anti-inflammatory cytokines IL-10 and IL-35. Decreased IL-35+ and increased IFN-γ+ Breg cell proportions were found in T1D patients, and in diabetic mice. IL-35 treatment prevented increased IFN-γ+ Breg cell proportions in STZ mice. These data illustrate Breg cells’ involvement in T1D, and IL-35 treatment prevents hyperglycemia by maintaining Breg cells’ phenotype.Treg cells’ involvement in diabetic nephropathy (DN) has not been studied. Lower plasma IL-35 was found in DN patients than in T1D patients without DN and healthy controls, and was strongly correlated with kidney function. Decreased IL-35+ and increased IL-17+ Treg cells were found in DN patients. Moreover, Foxp3+ cell infiltration was found in the kidneys of diabetic mice, but it failed to counteract mononuclear cell infiltration. IL-35 treatment prevented DN and Treg cells’ phenotypic shift in STZ mice by maintaining the transcription factor Eos. These results demonstrate that IL-35 may be used to prevent DN. Given the instability of IL-35, we explored the effect of IL-6 signaling blockade. Anti-IL-6R completely protected STZ mice from diabetes. Proteomics indicated enhanced metabolism and down-regulated pro-inflammatory pathways. It maintained Treg cells’ phenotype by increasing IL-35 and decreasing IFN-γ production. It also reduced the number of macrophages and conventional dendritic cells type 2 and their CD80 expression. STZ mice remained normoglycemic despite the discontinuation of anti-IL-6R treatment. Therefore, our results illustrate the outcomes of several potential T1D immunotherapies and highlight the involvement of IL-35 producing immune cells in controlling the disease.
|
|
| 10. |
- Luo, Zhengkang, et al.
(author)
-
Interleukin-35 Prevents Development of Autoimmune Diabetes Possibly by Maintaining the Phenotype of Regulatory B Cells
- 2021
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:23
-
Journal article (peer-reviewed)abstract
- The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35(+) Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35(+) Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35(+) Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35(+) Breg cells. A higher proportion of IFN-gamma(+) cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-gamma(+) cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.
|
|
