Steady-State Cell Apoptosis and Immune Tolerance - Induction of Tolerance Using Apoptotic Cells in Type 1 Diabetes and Other Immune-Mediated Disorders

Type 1 diabetes (T1D) is also named insulin-dependent diabetes mellitus. Because T1D is more frequently seen in children, it is also called juvenile diabetes. Currently the standard treatment for T1D is the daily use of exogenous insulin. Because of the poor compliance with insulin use, T1D patients often suffer from hyperglycemia or hypoglycemia (1; 2). In addition, T1D patients are at high risk for experiencing ketoacidosis due to a variety of different reasons (3-5). Many T1D patients will inevitably develop serious, chronic complications in organs such as heart and kidney (6-9). Therefore, T1D is a devastating disease for young individuals. Thus far, there has been no cure for T1D, and the search for its cure is a long-term goal in T1D research. Regarding the pathogenesis of T1D, it is clear that T1D is an autoimmune disease that is mediated by pathogenic T cell responses to pancreatic islet cells (10-12). The fundamental problem in T1D is the breakdown of immune tolerance to self antigens. More specifically, cell antigen-specific T cells, which are usually well controlled in healthy individuals through various self tolerance mechanisms, attack insulin-producing cells. Thus, to cure T1D, restoration of immune tolerance against cell antigens is necessary. Numerous investigators have expended tremendous energy and efforts in finding ways to prevent or cure T1D; however, much work still remains. During fetal development, the majority of self-reactive T cell clones are deleted in the thymus. This process is referred to as central tolerance. Some self-reactive T cell clones do escape T cell deletion mechanisms and are exported to the periphery, leading to a potential risk for development of autoimmune diseases. In healthy individuals, self-reactive T cell clones are not pathogenic, because of well-functioning peripheral regulatory mechanisms (13; 14). One of the major mechanisms by which self tolerance is maintained is through the steady-state processing of apoptotic cells during normal tissue turnover (14). Evidence has