ANALYSIS OF CD1D/NKT CELL IMMUNOREGULATORY CIRCUIT IN TYPE 1 DIABETES

Type 1 diabetes (T1D) is an autoimmune disease caused by cells of the bodys own immune system that attack pancreatic beta islets. Those self-reactive immune cells are present in healthy people and they should be tightly controlled by regulatory mechanisms to avoid autoimmune disease. A specific cell population of the immune system, named NKT cells, plays a key role in control of immune responses including autoreactive ones. They have the ability to decide whether to start an immune response or turn it off. Recent findings demonstrated that peripheral activation of NKT cells by administration of their specific antigen prevent autoimmune disease in pre-clinical models of type 1 diabetes and multiple sclerosis. We want to analyze mechanisms responsible for NKT cell activation and modulation of autoimmunity and specifically address whether they are defective in autoimmune-prone individuals. The study is centered on analysis of pre-clinical model of T1D (NOD mice) as well as of a transgenic NOD model. Based on our findings in mice we will develop a future plan for analysis of defective NKT cell activation and function in diabetic patients. Moreover, we planned a pre-clinical experiment (aim 1c) to establish whether NKT cells that received efficient activation and showed regulatory properties in vitro could avert diabetes in NOD mice. The same protocol could be used to derive regulatory NKT cells from blood of diabetic patients and trigger their regulatory ability in vitro. A cure for T1DM should aim to counterregulate the defective mechanisms that are responsible for immune attack to insulin-secreting cells of the pancreas. We believe our study will provide further insights into mechanisms that prevent this attack. Furthermore, it will ultimately provide a practical tool to restore defective function of regulatory cells and preserve beta cell mass in early-diagnosed patients or improve survival of islet grafts.