Type 1 diabetes (T1D), with a prevalence of ~200/100,000 and an incidence that has been increasing by 2-5% worldwide over the past few years, poses a considerable challenge to afflicted individuals, to the development of effective prevention and treatment regimens, and to public health initiatives at large. Therapies focused on preserving functional beta cells; gaining immune tolerance; and inducing beta cell regeneration are a priority for the treatment of the disease. The sulfated polysaccharide Dextran Sulfate (DS) is a polyanionic derivative of the bacterial polysaccharide dextran. Preliminary studies from our lab suggest that low molecular weight DS (5-8kDa) is a prosurvival agent for the beta cell in vitro against cytokines and ER stress. However, the molecular mechanisms involved in these effects are unknown. In addition, whether DS protects beta cell function in a proinflammatory environment is also unknown. Upregulation of the inhibitory co-stimulatory signal PD-1/PD-L1 provides negative stimuli influencing T lymphocyte activation and promoting the maintenance of peripheral tolerance. Preliminary studies indicate that DS treatment of splenocytes in vitro leads to a significant increase in the number of DCs, B cells and macrophages expressing PD-L1. DS also increases the number of activated CD4+ and CD8+ T cells expressing PD-1. This suggests that DS could help to maintain peripheral tolerance in a setting predisposed to autoimmunity. To test the efficacy of DS for T1D treatment, we have analyzed the effect of DS in the prevention and reversal of diabetes in the NOD mouse, the spontaneous mouse model of T1D. DS treatment impairs beta cell death, preserves beta cell mass and prevents the development of T1D in pre-diabetic NOD mice. More importantly, DS treatment of early onset diabetic NOD mice reverses diabetes in ~70% of the mice. DS treatment preserves beta cell mass with intact islets surrounded by massive number of immune cells, suggesting islet infiltration impairment, decreased cytokine production and/or enhanced beta cell survival. Interestingly, treatment of NOD mice with a blocking mAb against PD-L1 completely abrogated the preventive effects of DS in diabetes development. Collectively, these studies suggest a promising therapeutic effect of DS for T1D by potentially preserving functional beta cells, gaining immune tolerance and enhancing beta cell regeneration. Our hypothesis is that DS reverses T1D by favoring the survival and maintaining the function of the beta cell in an islet inflammation environment, and by modulating the immune system to enhance tolerance. To determine whether our hypothesis is correct, we will develop the following Specific Aims:
Specific Aim 1. To determine the effect and molecular mechanisms mediated by DS on beta cell survival and function in the context of T1D.
Specific Aim 2. To analyze the efficacy of dextran sulfate (DS) treatment alone or in combination with hepatocyte growth factor (HGF) for reversing diabetes in NOD mice.
Specific Aim 3. To dissect and stratify DS-induced immunomodulatory effects on human T cell responses. The proposed studies will provide significant information regarding the therapeutic potential of DS for T1D and the cellular and molecular mechanisms involved in the beneficial effects of this sulfated polysaccharide.
In this application, we will fully define the therapeutic potential of the sulfated polysaccharide dextran sulfate and HGF for the treatment of type 1 diabetes. These studies are directly relevant to the 3 million people in the US and the many more millions worldwide with type 1 diabetes whom will benefit from the knowledge generated with these studies that could lead to the development of a therapeutic strategy to treat this disease.
