Kim Campbell

Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells.

Purpose of reviewThis review is intended to introduce recent advances in the research surrounding extracorporeal photopheresis (ECP) with a focus on how apoptotic cells modulate antigen-presenting cells and induce regulatory T cells, given that ECP therapy induces apoptosis of leukocytes collected through leukapheresis. Recent findingsIt has been suggested that ECP therapy, unlike other immunosuppressive regimens, does not cause global immunosuppression, but induces immune tolerance. Recent clinical and animal studies demonstrate that ECP therapy induces antigen-specific regulatory T cells, including CD4+CD25+FoxP3+ T cells and IL-10-producing Tr1 cells, that may arise secondarily to the induction of tolerogenic antigen-presenting cells (APCs) by infusion of apoptotic cells. It has also been suggested that ECP therapy may induce IL-10-producing regulatory B cells and regulatory CD8+ T cells. Finally, several recent studies, which examined the cellular elements involved in the uptake of apoptotic cells, demonstrated that apoptotic cells modulate APCs through binding to specific receptors, particularly TAM receptors that provide inhibitory signals that block APC activation. SummaryECP therapy induces immune tolerance through modulation of antigen-presenting cells as well as induction of regulatory T cells. ECP therapy has great potential in the management of allogeneic transplantation and autoimmune diseases.

Experimental extracorporeal photopheresis therapy significantly delays the development of diabetes in non-obese diabetic mice.

In our previous studies, we demonstrated that infusion of apoptotic cells significantly prevented type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Extracorporeal photopheresis (ECP) is an apoptotic cell-based therapy used clinically for immune-mediated disorders. In this study, we examined the effect that intravenous delivery of apoptotic cells (ECP-treated) has in the prevention of T1D in NOD mice. We discovered that five weekly injections of ECP-treated NOD spleen cells, beginning at 8 weeks of age, significantly delayed diabetes onset. Furthermore, cell dose studies demonstrated that low dose ECP-treated spleen cells (2x10(5) cells/injection/mouse) had similar protective effects as compared to high dose (5x10(6) cells/injection). In contrast to ECP-treated cells alone, ECP-treated cells combined with beta cell antigens appeared to improve the protective effect as shown by the marked reduction in insulitis in the islets. Delivery of ECP-treated spleen cells or ECP-treated spleen cells plus beta cell antigen increased Foxp3(+) Tregs, and beta cell antigen-specific T cell proliferation was significantly suppressed in vivo in these two groups. In addition, we found that ECP-treated cells did not induce global immunosuppression or autoimmunity against nuclear antigens. In conclusion, ECP-treated cells provide a safe and effective approach in T1D prevention, suggesting that clinical ECP has great potential for managing human T1D.

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