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This dissertation, The Role of Regulatory B Cells in the Development of Autoimmune Diabetes in NOD Mice by Yang, Liu, 劉洋, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Interleukin (IL)-10-secreting regulatory Bcells(B10) are acknowledged to play important roles in balancing cellular immunity and fighting against autoimmune diseases. Since the early discovery of the potential of B cells in suppressing autoimmunity by secreting IL-10 in a murine model of experimental autoimmune encephalomyelitis(EAE), accumulating evidences have revealed the existence and regulatory function of B10 cells in the progression of several autoimmune diseases including multiple sclerosis (MS), lupus and autoimmune arthritis, suggesting potential values of therapeutic intervention. Autoimmune diabetes is an autoimmune disease in animal models characterized by progressive insulitis and mass destruction of βcells in pancreatic islets. However, the role of Bregsin the development of this disease remains largely unclear. To explore whether Bregs possess a regulatory function in suppressing diabetes, B10 cells were generated from B-cell activation factor (BAFF)-stimulated B cells of Non-obese diabetic (NOD)mice. Notably, NOD mice receiving B10 transfer exhibited delayed diabetes onset and substantially reduced incidence, suggesting some therapeutic effect against autoimmune diabetes. As an important contributor to inflammation and autoimmune disorders, the pathogenic function of IL-17 producing CD4+cells (Th17) in autoimmune diabetes has been increasingly identified, which attracts me to investigate whether B10 cells can contribute to amelioration of autoimmune diabetes via suppressing Th17 cells. During the development of autoimmune diabetes in NOD mice, both B10 and Th17 significantly increased at prediabetic stage and rapidly declined after disease onset. Upon adoptive transfer of B10 cells into prediabetic NOD mice, Th17 cells in pancreatic lymph nodes and pancreas were profoundly reduced. To verify whether B10 cells can directly inhibit Th17 generation in vitro, CFSE-dilution assay combined to Th17 polarization assay was performed. Results indicated that B10 cells suppress Th17 polarization in an IL-10 independent manner, but inhibit Th17 proliferation in an partially IL-10 dependent way. Finally I transferred B10 together with naive CD4+T cells reactive to islets into lymphopenic NOD-SCID mice and detected substantially reduced Th17 frequencies in pancreatic lymph nodes and pancreas, suggesting a potential way of developing new therapeutic strategies in treating Type 1 diabetes in humans. DOI: 10.5353/th_b5194749 Subjects: Diabetes - Molecular aspectsB cells

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