The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes: An Immune Cell Perspective

Type 1 diabetes (T1DM) is an autoimmune disorder resulting in destruction of the insulin producing pancreatic β-cells that reside in the Islets of Langerhans. Despite significant progress in the understanding of T1DM pathogenesis, some fundamental contributing mechanisms remain to be fully elucidated. The receptor for advanced glycation end products (RAGE) and its ligands are increasingly believed to play a role in the development of T1DM, but this is not well understood. The location of RAGE gene is shared with major T1DM genetic susceptibility loci on chromosome 6 and polymorphism of this region confers risk for T1DM. Furthermore, changes in RAGE expression on and ligand binding by immune cells, in particular T cells, are associated with pro-inflammatory and autoimmune profiles key for T1DM development. Indeed, in murine models for T1DM, targeting of RAGE or its ligands decreased onset and severity of disease including favorable immune cell profiles and infiltration and improved beta cell insulin secretory function. Further understanding of RAGE expression and signaling in immune cells in T1DM will provide valuable insights into disease pathogenesis and therapy development. This chapter will discuss what is currently known about RAGE in the immune cells integral for the pathogenesis of T1DM

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention

A Question of Tolerance—Antigen-Specific Immunotherapy for Type 1 Diabetes

Purpose of Review: Antigen-specific immunotherapy (ASI) is a long sought-after goal for type 1 diabetes (T1D), with the potential of greater long-term safety than non-specific immunotherapy. We review the most recent advances in identification of target islet epitopes, delivery platforms and the ongoing challenges. Recent Findings: It is now recognised that human proinsulin contains a hotspot of epitopes targeted in people with T1D. Beta-cell neoantigens are also under investigation as ASI target epitopes. Consideration of the predicted HLA-specificity of the target antigen for subject selection is now being incorporated into trial design. Cell-free ASI approaches delivering antigen with or without additional immunomodulatory agents can induce antigen-specific regulatory T cell responses, including in patients and many novel nanoparticle-based platforms are under development. Summary: ASI for T1D is rapidly advancing with a number of modalities currently being trialled in patients and many more under development in preclinical models

Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development

Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host’s immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host–pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention

Regulatory T cells induced by single-peptide liposome immunotherapy suppress islet-Specific T cell responses to multiple antigens and protect from autoimmune diabetes

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4 mimotope (BDC2.5) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3 and Foxp3 PD1 CD73 ICOS IL-10 peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5/calcitriol liposome administration, adoptive transfer of CD4 T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5/calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8 T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4 peptide, BDC2.5, and calcitriol induce ChgA-specific CD4 T cells that regulate CD4 and CD8 self-antigen specificities and autoimmune diabetes in NOD mice

Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice

Enhancement of regulatory T cell (T-reg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of T-reg cell homeostasis and function. We investigated how IL-2 pathway defects impact T-reg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD T-reg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, T-reg cell frequency was preserved through expansion of CD25(low), effector phenotype T-reg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD T-reg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD T-reg cells in the spleen and blood, but had reduced efficacy on lymph node T-reg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD T-reg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2