Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes

Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β cell reactive effector T cells and a deficiency of β cell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases

Programing of the autoimmune diabetogenic response in the thymus during fetal and perinatal life

The presentation of self-peptides in the thymus is responsible both for negative selection of self-reactive T cells emerging during stochastic TCR recombination in fetal life, as well as positive selection of self-specific regulatory thymic T (tTreg) cells during and after perinatal life. The combination of these two sequential processes programs central self-tolerance, a fundamental property of the adaptive immune system. A defect in intrathymic self-presentation, either genetic or acquired, is the earliest event in the pathogenesis of autoimmunity already during fetal development. This defect is necessary but not sufficient for the appearance of a classical autoimmune disease like type 1 diabetes (T1D). Environmental factors are required for activation of the diabetogenic autoimmune response that targets insulin-secreting β cells in pancreatic Langerhans’ islets. Based on epidemiological studies, viral infections have been suspected for a long time to be one of those environmental factors. In this Debate article, we present a series of experimental data that support the hypothesis that, following vertical transplacental transfer, viruses might infect the fetal thymus and disturb already in utero central self-tolerance orchestrated by this organ

Type 1 Diabetes Immunological Tolerance and Immunotherapy

Type 1 diabetes (T1D) is a chronic autoimmune disorder associated, in genetically susceptible individuals, with the generation and activation of autoreactive CD4+ and CD8+ T cells that infiltrate the pancreas and selectively destroy the insulin-producing β-cells in the islets. The impairment of T-cell tolerance in T1D has been reported at many levels including abnormal self-antigen presentation in the thymus and periphery, autoreactive T-cell resistance to apoptosis, unbalanced immunoregulatory T-cell function, and deregulation of Th1/Th2/Th17 axes. Despite the identification of type1 diabetes-associated autoantigens and their derived CD4+ and CD8+ T-cell epitopes, numerous antigen-specific immunoregulatory therapies have failed when evaluated for their utility in the prevention and treatment of T1D. In this special issue, we invite authors to submit original research and review articles highlighting the recent advances that have broadened our understanding of immunological tolerance and T1D vaccine strategies. Also, we welcome papers that seek to define immunoregulatory properties of T cells to provide new insights as to their potential for clinical use. We are interested in articles that explore salient aspects of T1D-associated tolerance and immunotherapy. Potential topics include, but are not limited to: * T1D-associated central and peripheral tolerance mechanisms * Elucidating the functional impairment in immunoregulatory T-cell function in T1D * New animal models to test and understand dysfunctional immunity in T1D * Identification of new beta islet-specific autoantigens * Development of antigen-based immunotherapeutic strategies to prevent or treat T1D * Clinical trials with novel antigen-specific immunoregulatory therapie

Presentation of neuroendocrine self in the thymus: toward a novel type of vaccine/immunotherapy

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune toxicity. Amongst those tolerogenic pathways, the thymus occupies a central place both by deleting self-reactive T cells that are produced in the thymus during random recombination of gene segments encoding the variable parts of the T-cell receptor for antigen (TCR) (negative selection), and by generating self-antigen specific regulatory T cells (Tr). A repertoire of neuroendocrine-related genes are transcribed by thymic stromal cells — epithelial and ‘nurse’ cells (TEC/TNC), dendritic cells (DC) and macrophages (MF) — in such a way that a dominant protein precursor is expressed in the thymus environment. Oxytocin (OT) and neurokinin A (NKA) are the dominant thymic precursors for the neurohypophysial hormone and tachykinin families, respectively. With regard to the insulin gene family, all members are transcribed following a precise cell topography and hierarchy in the profile of gene expression: IGF2 (TEC/TNC) > IGF1 (MF) >> INS (medullary TEC and/or DC). This hierarchy implies that IGF-2 is more tolerated than IGF-1, and much more than Insulin (Ins). The low level of INS transcription in the thymus also explains why Ins displays immunogenic properties, as well as the significant prevalence (±40%) of anti-Ins autoantibodies in the general population. Ins administration failed in providing tolerance or protection toward islet ß cells in type 1 diabetes (T1D). In contrast, the presentation of IGF-2 B11-25, the homologous sequence of Ins B9-23, to peripheral blood mononuclear cells (PBMC) isolated from DQ8+ T1D adolescents significantly increases IL-10 secretion and IL10 expression. Given the potent regulatory/suppressive properties of IL-10 on the autoimmune response toward islet ß cells, these data support that IGF-2 derived sequences constitute a strong basis for the development of an antigen-specific driven tolerogenic approach for T1D prevention and/or cure.Peer reviewe

Importance of a Thymus Dysfunction in the Pathophysiology of Type 1 Diabetes

peer reviewedThe autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related autoantigens (insulin, GAD65 and phosphatase IA-2), the origin of this immune dysregulation still remains unknown. More and more evidence supports a thymic dysfunction in the establishment of central self-tolerance to the insulin family as a crucial factor in the development of the autoimmune response selective of pancreatic insulin-secreting islet beta cells. All the genes of the insulin family (INS, IGF1 and IGF2) are expressed in the thymus network. However, IGF-2 is the dominant member of this family first encountered by T cells in the thymus, and only IGFs control early T-cell differentiation. IGF2 transcription is defective in the thymus in one animal model of type 1 diabetes, the Bio-Breeding (BB) rat. The sequence B9-23, one dominant autoantigen of insulin, and the homologous sequence B11-25 derived from IGF-2 exibit the same affinity and fully compete for binding to DQ8, one class-II major histocompatibility complex (MHC-II) conferring major genetic susceptibility to type 1 diabetes. Compared to insulin B9-23, the presentation of IGF-2 B11-25 to peripheral mononuclear cells (PBMCs) isolated from type 1 diabetic DQ8+ adolescents elicits a regulatory/tolerogenic cytokine profile (*IL-10, *IL-10/IFN-g, *IL-4). Thus, administration of IGF-2 derived self-antigen(s) might constitute a novel form of vaccine/immunotherapy combining both an antagonism for the site of presentation of a susceptible MHC allele, as well as a downstream tolerogenic/regulatory immune response