Abstract
Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re-establish tolerance to beta cells.
Highlights
Pancreatic beta cells are destroyed by T cells of the immune system, precipitating type 1 diabetes (T1D)
We describe the process by which insulin-producing beta cells are destroyed and contrast the roles of CD4+ and CD8 T cells during autoimmune pathogenesis
A full account of the physiology behind this discordance is outside the scope of this review, but may include (a) more synchronous T cell infiltration into pancreatic islets in non-obese diabetic (NOD) mice than in at-risk human subjects, (b) the potential for a greater dependence on CD8 T cells in diabetes pathogenesis in human disease [10], and (c) confounding effects of multiple concurrent T cell responses in human patients exposed to the “universe” of viral and bacterial pathogens as opposed to inbred specific pathogen-free NOD mouse colonies
Summary
Pancreatic beta cells are destroyed by T cells of the immune system, precipitating type 1 diabetes (T1D). To develop a successful approach to protect beta cells, we must understand how and why T cells are directed to destroy insulin-producing cells in the pancreas while sparing adjacent hormone-producing cells including alpha, delta, and epsilon cells. The first section of this review outlines our current understanding of the pathogenesis of autoimmune diabetes. The second section of this review briefly describes the necessity for pancreas or islet transplantation to treat severe diabetic complications. The third section of this review focuses on islet replacement strategies and briefly outlines beta cell regeneration. While there has been considerable progress in both strategies, a cure for established T1D must involve targeted immunotherapy This approach must inhibit memory autoreactive T cells and naive allograft-reactive immune responses. Recent evidence suggests that the presence of autoimmunity acts as an “adjuvant,” accelerating and strengthening the conventional alloimmune response
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