2131-P: Dextran Sulfate and HGF Ameliorate Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) results from loss of immune tolerance and β-cells. Currently, research on T1D treatments focus on regeneration and preservation of β-cells and restoration of immune tolerance. The sulfated synthetic polysaccharide dextran sulfate (DS), a mild anticoagulant and blood volume expander used in clinic, inhibits dendritic cell maturation and activation. DS administration increases circulating hepatocyte growth factor (HGF) in rodents and humans. In this study, we tested the effects of DS on: T1D development in NOD mice; β-cell survival, function and mitochondrial activity in cytokine-treated islets; and, the profile of immune activation and tolerance markers. DS treatment reduced spontaneous T1D onset in female NOD mice from 70% to 20%. T1D prevention in the wake of DS treatment was associated with preserved plasma insulin and β-cell mass, and reduced β-cell death. DS synergized with HGF in protecting mitochondrial function of cytokine-treated islets in vitro, maintaining maximal respiration, ATP production and glucose-stimulated insulin secretion. Pancreas histology showed decreased immune cell infiltration in islets of DS-treated mice. Splenocytes and pancreatic lymph nodes of DS-treated mice displayed decreased IFNγ+ CD8+ and CD4+, and increased IL4+ CD4+ and FoxP3+ CD4+ cells. In vitro, DS+HGF increased both the inhibitory phenotype of bone marrow derived macrophages (BMDM) downregulating IL1β, TNFα, and iNOS and increasing IL10, and the number of FoxP3+ CD4+ treated with αCD3 and αCD28 in the absence of TGF β. DS+HGF enhanced mitochondrial mass, potential, oxidative phosphorylation and expression of OXPHOS complexes, metabolic features of inhibitory BMDMs and regulatory T cells. Collectively, these results indicate that DS and HGF ameliorate T1D in NOD mice by alleviating the metabolic impairment induced by inflammation in islets and by boosting mitochondrial function to preserve β-cell function and upregulate M2 macrophages and regulatory T cells. DS and HGF can be of great value for treating T1D. Disclosure G. Lu: None. T. Zhang: None. D. Homann: None. A. Garcia-Ocaña: None. Funding National Institutes of Health (DK113079, DK020541, W81XWH-17-1-0363)