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Immunological strat...
Immunological strategies for counteracting type 1 diabetes focusing on IL-35 producing regulatory immune cells
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- Luo, Zhengkang, 1994- (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Singh, Kailash, Researcher (preses)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Sandler, Stellan, Professor (preses)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Carlsson, Per-Ola, Professor (preses)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Institutionen för medicinska vetenskaper
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- Blixt, Martin, Lecturer (preses)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Thorvaldson, Lina, Lecturer (preses)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Zaldumbide, Arnaud, Associate Professor (opponent)
- Department of Cell and Chemical Biology, Leiden University Medical Center
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(creator_code:org_t)
- ISBN 9789151319797
- Uppsala : Acta Universitatis Upsaliensis, 2023
- Engelska 41 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1998
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- Type 1 diabetes
- Regulatory T cell
- Regulatory B cell
- Interleukin-35
- Immunologi
- Immunology
- Endocrinology and Diabetology
- Endokrinologi och Diabetologi
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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