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Regulatory B cells in an experimental model of type 1 diabetes

Camargo Da Rosa, Larissa 2017. Regulatory B cells in an experimental model of type 1 diabetes. PhD Thesis, Cardiff University.
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Abstract

Regulatory B cells, producing IL-10, have been studied in many autoimmune diseases. However, less is known about these cells in Type 1 diabetes (T1D), a disease characterized by the destruction of beta-cells by the immune system, leading to deficient production of insulin. Although B cells play a role in development of T1D, most previous investigations have focused on their pathogenic involvement. B cell depletion has been shown to be protective against diabetes development. To examine regulatory B cells in T1D, we used Non-Obese Diabetic (NOD) mice and non-diabetes-prone B6g7 mice as controls. We compared both strains for the production of cytokines and expression of putative regulatory phenotypes in spleen B cells cultured with various stimulants, at different ages. We observed that NOD mice that were > 35 weeks old and naturally protected against T1D had more IL-10-producing B cells than B6g7 and diabetic NOD mice, and this number increased even more on stimulation with lipopolysaccharide (LPS) stimulation. When LPS-stimulated B cells from protected mice were cultured in vitro with CD8 T cells and DCs, their potential for suppression of T cell cytotoxic activity was higher than unstimulated B cells and B cells from diabetic mice. This inhibitory effect was associated with higher levels of IL-10. Lastly, we carried out an investigation where B cells were transiently depleted in transgenic NOD mice expressing human CD20, to enable depletion using a human anti-CD20 monoclonal antibody. We evaluated the effect of depletion and repopulation on regulatory B cells, testing whether the protection afforded by B cell depletion was due to a change in regulatory B cell number or function. B cells with putative regulatory phenotypes were susceptible to depletion and, although the treatment with anti-CD20 reduced the incidence and delayed the onset of diabetes, there was no difference in the IL-10 producing B cell population by the time of full repopulation of B cells. Thus, this protective effect of B cell depletion was unlikely to be due to IL-10-producing B cells. In conclusion, for the first time, regulatory B cells were extensively studied in NOD mice and we demonstrated that protected NOD mice had higher frequencies of spleen B cells producing IL-10 than diabetic NOD mice. Further investigation is warranted to understand how these IL-10-producing B cells contribute to protection against type 1 diabetes.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 11 May 2017
Last Modified: 04 Jun 2017 09:49
URI: http://orca-mwe.cf.ac.uk/id/eprint/100517

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