Immune Checkpoint Molecules, Personalized Immunotherapy, and Autoimmune Diabetes

T1D is a heterogeneous autoimmune disease for which an effective cure by immunotherapy has not yet been identified. Immune checkpoint molecules are regulators of the immune system that maintain self-tolerance and prevent autoimmunity. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immune checkpoint enzyme that is defective in patients affected by T1D and is characterized by genetic polymorphism. Restoration of full IDO1 activity can be obtained in vitro by using a blocker of the interleukin-6 receptor (tocilizumab) in peripheral blood mononuclear cells from patients with T1D characterized by a specific IDO1 genotype (rs7820268 C>T) . Personalized drug targeting of IDO1 may lead to an effective cure by immunotherapy in patients with T1D. Although significant progress has been made in understanding autoimmunity, no immunotherapy to effectively halt immune-mediated destruction of β cells in type 1 diabetes (T1D) is currently available. For successful immunotherapy it will be necessary to identify novel drug targets as well as robust immunologic biomarkers to predict disease heterogeneity and patient responsiveness. Inhibition of immune checkpoint mechanisms represents a novel and effective strategy in tumor immunotherapy. Because they are fundamental to rewiring immune circuits, the underlying mechanisms could be therapeutically enhanced and used as biomarkers in T1D. We examine here current knowledge of immune checkpoint molecules in T1D. One specific immune checkpoint mechanism, namely tryptophan metabolism, may meet the need for a valid drug target and robust biomarker in the quest for effective and personalized immunotherapy in T1D. Although significant progress has been made in understanding autoimmunity, no immunotherapy to effectively halt immune-mediated destruction of β cells in type 1 diabetes (T1D) is currently available. For successful immunotherapy it will be necessary to identify novel drug targets as well as robust immunologic biomarkers to predict disease heterogeneity and patient responsiveness. Inhibition of immune checkpoint mechanisms represents a novel and effective strategy in tumor immunotherapy. Because they are fundamental to rewiring immune circuits, the underlying mechanisms could be therapeutically enhanced and used as biomarkers in T1D. We examine here current knowledge of immune checkpoint molecules in T1D. One specific immune checkpoint mechanism, namely tryptophan metabolism, may meet the need for a valid drug target and robust biomarker in the quest for effective and personalized immunotherapy in T1D. a ligand-operated transcription factor originally recognized as a mediator of the toxicity of dioxins. When activated by physiological ligands, AhR contributes to immune homeostasis by promoting immunoregulatory and host-protective effects. antibodies produced by an organism to constituents of its own tissues (self-antigens). The presence of autoantibodies with specificity for islet cell self-antigens is strongly associated with the development of type 1 diabetes (T1D). bone marrow-derived cells known for their ability to present antigens to naïve T cells and orchestrate adaptive immunity. DCs can also trigger inhibitory circuits that ensure immunological tolerance and tissue homeostasis. a broad term that refers to an abnormality of blood glucose levels, including hypoglycemia and hyperglycemia. a member of the tumor necrosis factor receptor superfamily that modulates acquired and natural immune response. It is expressed in several cells and tissues, including T cells, natural killer cells, and, at lower levels, in cells of innate immunity. GITR is activated by its ligand, GITR-L, which is mainly expressed on antigen-presenting cells and endothelial cells. bone marrow-derived, pluripotent cells being investigated for hematological recovery after cytoreductive therapy and transplantation, as well as for cell-based therapies for non-hematopoietic disorders. a gene complex encoding the major histocompatibility complex in humans. They are highly polymorphic, exist in different alleles, and fine-tune adaptive immune responses. acute or chronic inflammation of the pituitary gland resulting in varying degrees of pituitary gland failure. an immunoregulatory enzyme that degrades the essential amino acid tryptophan into kynurenines. an immune checkpoint protein expressed on activated T cells and which is triggered by ICOS ligand, ICOS-L. an enzymatic cascade, whose rate-limiting step is catalyzed by IDO1, that produces several tryptophan metabolites collectively known as kynurenines that have several biological effects, including mediating immune tolerance. small noncoding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. an animal model for human T1D; spontaneous disease occurs in 60–80% of female and 20–30% male mice, and is preceded by asymptomatic insulitis, as in diabetic patients. formerly known as suppressor T cells, Tregs are a subpopulation of T lymphocytes that modulate the immune system, maintaining tolerance to self-antigens and preventing autoimmune diseases. because in some cases primary ligands have evolved into ancillary receptors, a mechanism of intercellular communication has emerged during evolution that enables a ligand-bearing cell to receive immediate feedback upon activation of the cognate receptor on an adjacent cell. the most common type of genetic variation in humans; when SNPs occur within a gene or in a regulatory region near a gene, they may play a direct role in disease by affecting the function of that gene. immune regulatory circuits are functional pathways whereby lymphocytes, accessory cells, and cytokines impact on each other’s expression and function through feedback or feedforward mechanisms in a local tissue microenvironment.