diabetes: translating mechanistic observations into effective clinical

diagnosis the proportion of subjects who maintain this level is small.Studies in preclinical models have added to our understanding of the antigens, cells and mechanisms that are involved in T1D development and progression. Furthermore, recent clinical investigations have refined, and in some cases changed, these concepts. In this Review, we discuss the concepts that led to clinical studies in patients with T1D and the results of testing those hypotheses in clinical trials. Similarly to the clinical observations that led to the original hypothesis that T1D is an autoimmune disease, translational research efforts in humans and animal models continue to be a source of new discoveries that shape the T1D field. Abstract | Type 1 diabetes (T1D) remains an important health problem, particularly in western countries, where the incidence has been increasing in younger children. In 1986, Eisenbarth described T1D as a chronic autoimmune disease. Work over the past three-and-a-half decades has identified many of the genetic, immunological and environmental factors that are involved in the disease and have led to hypotheses concerning its pathogenesis. Clinical trials have been conducted to test these hypotheses but have had mixed results. Here, we discuss the findings that have led to our current at least one autoantibody, and the presence of autoantibodies identifies relatives of patients who are at a high risk for the disease (typical targets of these autoantibodies include glutamic acid decarboxylase (GAD65), IA2 (also known as ICA512 and PTPRN), insulin, IGRP (also known as G6PC2), zinc transporter 8 (ZNT8) and islet cell autoantigen (ICA)) 77,158,159 . The peak incidence of disease onset is between 6 and 15 years of age, and a second peak occurs later in adolescence. At the time of presentation, most patients have signs and symptoms of hyperglycaemia and insulin deficiency (such as polyuria, polydipsia, visual change, weight loss and elevated glycosylated haemoglobin A1c levels) or even more severe metabolic decompensation with ketoacidosis. However, some patients are identified on routine urine or blood tests, before β -cell destruction and insulin deficiency have resulted in symptoms. After presentation and metabolic stabilization, many patients enter a clinical ‘honeymoon’, in which time insulin secretion improves, and some patients can even discontinue the use of exogenous insulin. This period is invariably followed by a loss of insulin production and an increasing dependence on exogenous insulin 7,160 . Owing to the absolute deficiency in insulin production, replacement with exogenous insulin and dietary regulation are the mainstays of treatment. Retention of some endogenous insulin production, which is reflected by the level of C peptide (the by-product of processing of proinsulin that is synthesized by β -cells) of at least 0.2 nmol L –1 , has been associated with improved metabolic control and reduced risk of long-term complications, such as eye and renal disease, as well as the acute complication of insulin-induced hypoglycaemia 7,8 . Metabolic control is monitored by measurement of glycosylated haemoglobin A1c levels, which indicate blood glucose levels and reflect the glucose control over the previous months. respectively. This can occur by inducing apoptosis of T or B cells or, in the case of B cells, by altering the specificity of the B cell receptor (BCR) in a process termed receptor editing 162,163 . These mechanisms are restricted to antigens that are presented or expressed in those compartments, and as a result potentially autoreactive T and B cells may escape into the periphery. Both cell-intrinsic and cell-extrinsic mechanisms are involved in controlling the activation of those cells. Cell-intrinsic mechanisms include modulators of BCR and T cell receptor (TCR) signalling, such as induction of inhibitory receptors (for example, cytotoxic T lymphocyte protein 4 (CTLA4), programmed cell death 1 (PD1) and lymphocyte activation gene 3 protein (LAG3)) or ubiquitin ligases (for example, CBL). Extrinsic factors involve restriction of the required co-stimulatory ligands on antigen-presenting cells (for example, the B7 molecules CD80 and CD86, which are required for CD28-mediated co-stimulation of T cells), limiting the availability of survival factors (such as BAFF (also known as TNFSF13B) and interleukin-17 (IL-7)), or exposure to inhibitory cytokines (such as IL-10) or regulatory populations (for example, regulatory T (T Reg ) cells). T Reg cells may develop in the thymus or in the periphery 164 . T Reg cells are characterized by the expression of the X-linked forkhead transcription factor FOXP3, which is a master regulator required for their maximal development and function. A genetic mutation of FOXP3 abolishes T Reg cell function, leading in humans to the immuno dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, which is a severe multi-organ autoimmune syndrome caused by uncontrolled immune activation. protein 60 (HSP60), which is thought to enhance regulatory T (T Reg ) cell functions by signalling via Toll-like receptor 2 (TLR2), has shown a beneficial effect on C peptide responses 107 . A pilot trial of a soluble tumour necrosis factor (TNF) receptor (etanercept) resulted in lower blood glucose levels and increased insulin production in patients 180 . In a trial of avoidance of cows’ milk, a reduced rate of new autoantibody formation was seen, but the mechanisms of this effect are not clear. very effective in elucidating mechanisms of action that are relevant to human disease. The challenge is how to apply the data from preclinical models to human patients. End points of clinical trials should be carefully chosen to identify biological proof of efficacy and mechanism of action, giving outcomes that are important for the design of a combinatorial approach that will successfully achieve clinical end points. Considering the heterogeneity of human subjects, efforts to identify individuals that are most likely to respond to a particular intervention on the basis of clinical parameters or immunologic markers may be very valuable. and, compared with conventional mature T cells, express TCRs that show increased affinity for self antigens. Owing to their demethylation of the FOXP3 locus and expression of FOXP3 protein, T Reg cells have anti-inflammatory functions. However, in patients with type 1 diabetes (T1D) and other autoimmune diseases, T Reg cells may not maintain complete demethylation of FOXP3 owing to defects in interleukin-2 signalling or other mechanisms (right-hand panel). These ‘ex-T Reg ’ cells remain autoreactive and, in the absence of FOXP3 expression, can produce potentially pathogenic pro-inflammatory cytokines. It has been suggested that such cells will participate in pathological immune responses to self antigens. In addition, failure to eliminate highly autoreactive T cells during thymic development may lead to the escape of potentially pathologic T cells into the periphery.