Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigenspecific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans. IntroductionType 1 diabetes (T1D) is an autoimmune disease characterized by breach in tolerance toward pancreatic insulin-producing β cells (1, 2). Interventions aimed at arresting β cell destruction once the autoimmune attack has set in, as is the case in antibody-positive or newly diagnosed patients, have not been successful, with the exception of trials using frank immunosuppression such as cyclosporine or high doses of nonspecific immune modulators such as anti-CD3 mAbs. High doses of these Abs reverted disease in mouse models of T1D (3, 4) and preserved C-peptide production in recently diagnosed patients for more than 1 year in two phase II studies (5-7). However, the high doses of anti-CD3 required for efficacy were accompanied by moderate cytokine release-related symptoms at the time of administration and transient Epstein-Barr virus reactivation (8), whereas recent studies such as DEFEND-1 (9) and Protégé (10) demonstrate that low doses of anti-CD3 by themselves do not robustly influence the course of β cell destruction in T1D in humans. Post hoc analysis in the recent Protégé trial of patient subgroups treated

Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional b-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4+ regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D.Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing b-cells in the islets of Langerhans in the pancreas (1). Past and current attempts to cure this immune-mediated disease included antigen-specific therapies and systemic immunomodulatory and immunosuppressive agents (1-4), but many of these trials suffered from a lack of efficacy, as reflected by only transient b-cell preservation, or adverse effects due to immune suppression. Autoantigenspecific therapies remain appealing to restore tolerance in T1D patients because they hold promise in targeting only b-cell-reactive T cells without impairing normal immune responses to diabetes-unrelated antigens. Studies in man and NOD mice, the most widely used preclinical model of T1D, have identified glutamic acid decarboxylase (GAD65) as one of the major autoantigens in this disease (5,6). GAD65 is expressed not only in the central nervous system but also in the b-cell (7), and peptide sequences within GAD65 behave as autoantigens in T1D both in man and in NOD mice (5,8). The majority of prediabetic and newly diagnosed T1D patients test positive for anti-GAD65 autoantibodies (6,9) or GAD65-reactive T cells (10). In NOD mice, GAD65-specific T-cell responses can be detected as early as 4 weeks of age (5). Although its role in initiating human T1D remains controversial, preclinical studies in NOD mice have shown that vaccines based on GAD65

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Summary It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have shown that dendritic cells (DCs) in the pancreas required IL-21R, not for antigen uptake, but to acquire the chemokine receptor CCR7 and migrate into the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) Class II and CD86 was provided to autoreactive effector cells in Il21r-/- mice, impairing CD4+ T cell activation, CD40:CD40L interactions and pancreatic infiltration by autoreactive T cells. CD40 cross-linking restored defective CD4+ cell expansion and CD4-independently expanded autoreactive CD8+ cells, but CD8+ cells still required CD4+ cells to reach the pancreas and induce diabetes. Diabetes induction by transferred T cells required IL-21R-sufficient host antigen presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r-/- mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4+ cells for autoreactive CD8+ cells to reach the islets.