Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: A randomised double-blind trial

Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
The Lancet (Impact Factor: 45.22). 06/2011; 378(9788):319-27. DOI: 10.1016/S0140-6736(11)60895-7
Source: PubMed


Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes.
Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with, number NCT00529399.
145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups.
Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge.
US National Institutes of Health.

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    • "Another example is Diamyd®, GAD65 formulated in alum adjuvant, a classic T1D-associated autoantigen. Whereas Phase 2 trials suggested that the drug had regulatory capacities and could preserve C-peptide, two recent Phase 3 trials failed to achieve their endpoints [36,37]. Finally, the parenteral arm of the DPT-1 trial, referenced above, treated at-risk subjects with insulin injections with the aim of correcting metabolic and immunological imbalances prior to diagnosis [38]. "
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    ABSTRACT: Up to 25 per cent of the world׳s adult population may have the metabolic syndrome, a condition closely associated with central obesity. The metabolic syndrome is a major risk factor for cardiovascular disease and type 2 diabetes and therefore represents an important worldwide health problem. In addition to metabolic abnormalities such as raised fasting plasma glucose, high cholesterol and high blood pressure, there is consensus that obese subjects develop a state of low-grade chronic immune activation. This sustained pro-inflammatory response in fat tissue is thought to worsen insulin resistance and dyslipidemia. Likewise, the immune system contributes to the detrimental cascade of events leading to plaque formation in atherosclerosis. It has long been assumed that the innate arm of the immune system was the only key player, but emerging evidence suggests that there is in fact a sizeable adaptive immune component to obesity and cardiovascular disease. From a therapeutic perspective, it could be envisioned that immune modulation drugs such as cytokine inhibitors, co-stimulation blockers or anti-T cell agents could offer benefit. It is questionable, however, whether chronic treatment with for instance biologicals will have a favorable risk/benefit profile in a silent condition such as the metabolic syndrome. An attractive alternative could be the development of antigen-specific T cell therapies, not unlike those currently in various phases of development for type 1 diabetes. In this article, we will give an overview of antigen-specific treatment modalities in type 1 diabetes, followed by a review of the evidence for T cell involvement in obesity and atherosclerosis.
    Full-text · Article · Jun 2014 · Molecular Metabolism
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    • "insulin or s.c. GAD65/alum failed to show a protective effect [10], [36]–[38]. Also in other autoimmune diseases, human trials with oral autoantigens have not led to satisfactory outcomes - (reviewed in [39]. "
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    ABSTRACT: Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4+Foxp3+ T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4+Foxp3+ T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "The most studied of these are proinsulin and GAD65, both of which are very effective in reversing and preventing diabetes in non-obese diabetic (NOD) mouse model of T1D, though somewhat disappointing when translated to clinical trials [13] [14]. A recent example was vaccination with GAD-alum which induced regulatory T cells [15] and delayed the loss of glucose-stimulated C-peptide levels in patients treated soon after diagnosis, but did not prevent the disease [16] [17]. While disheartening, these results indicate that autoantigen-based therapies in humans can restore immune balance when administered in the right context and with an optimal regimen. "
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    ABSTRACT: Type 1 diabetes (T1D) is a metabolic disease that is initiated by the autoimmune destruction of pancreatic insulin-producing beta cells that is accompanied by the development of antigen-specific antibodies and cytotoxic T lymphocytes (CTLs). Several studies have shown that vaccination with diabetic autoantigens provides some protection against this process. In this report we describe a new oral vaccine that utilizes live attenuated Salmonella for simultaneous delivery of autoantigens in conjunction with immunomodulatory cytokine genes to immune cells in the gut mucosa. Recent data showed that live attenuated Salmonella is a safe, simple and effective vector for expression of antigens and cytokines by antigen-presenting cells (APCs) of gut-associated lymphatic tissue (GALT). This novel strategy was tested by fusion of the diabetic autoantigen preproinsulin with Salmonella secretory effector protein (SseF) of pathogenicity island-2 (SPI2). In this way the autoantigen is only expressed inside the host immune cells and translocated to the host cell cytosol. In addition Salmonella was used to deliver the gene for the immunomodulatory cytokine transforming growth factor beta (TGFβ) for host cell expression. Oral co-vaccination of 8 week-old non-obese diabetic (NOD) mice with three weekly doses of both the autoantigen and cytokine significantly reduced the development of diabetes, improved the response to glucose challenge, preserved beta cell mass, and reduced the severity of insulitis compared with controls and autoantigen alone. Combination therapy also resulted in increased circulating levels of IL10 four weeks post-vaccination and IL2 for 12 weeks post-vaccination, but without effect on proinflammatory cytokines IL6, IL12(p70), IL17 and IFNγ. However, in non-responders there was a significant rise in IL12 compared with responders. Future studies will examine the mechanism of this vaccination strategy in more detail. In conclusion, Salmonella-based oral vaccines expressing autoantigens combined with imunomodulatory cytokines appears to be a promising therapy for prevention of T1D.
    Full-text · Article · Mar 2014 · Vaccine
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