Clinically, markers of inflammation remain after intensive glycemic control, suggesting a vascular pathology initiated prior to, or concurrent with, the development of diabetes. Our preliminary observations suggest that vascular inflammation and oxidative stress are present prior to hyperglycemia in T1D;these defects result in impaired endothelial-dependent vasodilation and appear to be mechanistically linked to T cell-mediated autoimmunity. Herein, we propose a new paradigm where the homeostatic mechanisms that facilitate expansion of diabetogenic T cells also allow for activation of T-cell-dependent oxidant burden, epigenetic changes in pro-inflammatory genes and subsequent vascular dysfunction/injury. Thus, we are linking adaptive immune changes in diabetes to early triggers in the vasculature that become symptomatic later in life. While cardiovascular disease is clearly an inflammatory disorder initiated via endothelial injury, the role of adaptive immunity in the initiation and progression of atherosclerotic plaque remained notably unexplored until recently. Similar to rampant 2-cell destruction in T1D, the link between altered regulatory T cell function and atherogenesis is now recognized. The prevailing hypothesis is that plaque formation is the result of an imbalance, either in function and/or in number, between pathogenic T cells and Tregs in response to altered self antigens. That is, T regs cells may serve as natural immunologic inhibitors of this autoreactive, T cell- driven vascular inflammatory response. The NOD mouse is a well-established model of T1D and has been used extensively by investigators to study the immune changes associated with disease pathogenesis. Not surprisingly, immunodeficient NOD mice, or mice that have mutations in co-stimulatory pathways, fail to develop diabetes. Conversely, failure to limit the expansion of autoreactive T cells results in the onset of disease. While there has been little application of this model to the investigation of diabetic vascular complications, our laboratory recently identified a distinct vasculopathy in these mice during the pre-diabetic phase. In this project we propose a series of experiments to characterize the T-cell-endothelial cell interactions that initiate vascular dysfunction prior to the onset of hyperglycemia but accelerate vascular injury later in the disease. We will identify specific immune cells implicated in promoting endothelial cell dysfunction. We will employ an arterial shear-stress injury model in the presence of specific diabetogenic T cells both in vitro and in vivo. Overall, we wish to define the temporal association between vascular injury and T cell trafficking, as well as the distinct inflammatory mechanisms involved in this process. Significance of the work to T1D: Herein we propose that the immune dysregulation that results from an imbalance between regulatory T cells and the effector arm of the immune system leads to targeted inflammation, promoting early endothelial dysfunction/injury independent of glycemic status. Within this paradigm, the homeostatic mechanisms that allow for expansion of diabetogenic T cells may also promote accelerated vascular injury. Thus, autoimmunity may lead to both diabetes and early cardiovascular disease.
Heart attacks, strokes and atherosclerosis remain significant late vascular complications in patients with type 1 diabetes in spite of tight glycemic control. Our studies suggest that the underlying auto-immunity plays an early role by damaging the endothelial cells that line the blood vessels in a subset of diabetic patients. This initiative attempts to characterize which leukocytes are involved in this process. Additionally, we wish to identify biologic therapies which may be initiated early in the disease process to ultimately enhance the quality of life and improve long-term survival for patients with type I diabetes.
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|Zimmerman, Michael A; Grenz, Almut; Tak, Eunyoung et al. (2013) Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver. Proc Natl Acad Sci U S A 110:12012-7|
|Zimmerman, Michael A; Haskins, Kathryn; Bradley, Brenda et al. (2011) Autoimmune-mediated vascular injury occurs prior to sustained hyperglycemia in a murine model of type I diabetes mellitus. J Surg Res 168:e195-202|