Safety and efficacy of autoantigen‐specific therapy with 2 doses of alum‐formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial

Larsson, Helena Elding; Lundgren, Markus; Jonsdottir, Berglind; Cuthbertson, David; Krischer, Jeffrey P.

doi:10.1111/pedi.12611

Cited by 47 publications

(30 citation statements)

References 27 publications

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“…The same vaccine was administered in children at risk to develop T1D, who were followed up for 5 years (DIAPREV-IT). The study failed to show any effect on the progression to T1D [25]. Lower doses of GAD-alum administered into lymphonodes induced higher GADA levels than subcutaneous injections with reduced IgG1 GADA and increased IgG2, IgG3, and IgG4 subclasses.…”

Section: Studies In the Symptomatic Phase Of T1dmentioning

confidence: 77%

“…insulin reduced T cell responses; increased antibodies [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] GAD-Alum increased Treg [25] Abatacept (CTLA4-Ig) reduced T cell costimulation [29] Teplizumab (anti-CD3) increased CD8 T cells with markers of T cell exhaustion [26] Otelixizumab (anti-CD3) increased Treg; downregulation of pathogenic T cells [38] Rituximab (anti-CD20) B lymphocytes depletion [27] Etanercept blocking TNF-α [30] Anakinra (IL-1ra) antagonism on IL-1 receptor [31,39] ATG + G-CSF reduced CD4:CD8 T cell ratio; increased Treg/conventional CD4 T cell ratio; increased CD45RO+…”

Section: Treatment Immune Cell Effect Refmentioning

confidence: 99%

“…Another autoantigen used to interact with antigen-specific β cell autoimmunity is the Alhydrogen (aluminium hydroxide, Alum) formulate Glutamate Decarboxylase (GAD-Alum). In a recent paper [25], Elding Larsson H. et al aimed, for the first time, to evaluate safety and efficacy of autoantigen-specific therapy with GAD-Alum (two doses of 20 mcg subcutaneously administered in nondiabetic children with multiple islet autoantibodies). The study (named DiAPREV-IT) was a randomized clinical trial versus placebo and did not demonstrate the efficacy of GAD-Alum autoantigen therapy in preventing progression to T1D.…”

Section: Immunotherapeutic Approaches In the Presymptomatic Stage Of T1dmentioning

confidence: 99%

“…The study (named DiAPREV-IT) was a randomized clinical trial versus placebo and did not demonstrate the efficacy of GAD-Alum autoantigen therapy in preventing progression to T1D. Treatment produced an increase in Treg cells, which are supposed to down-regulate GAD65-specific autoreactive T cells (reviewed (rev) in [25]) (Tables 1 and 3) .…”

Section: Immunotherapeutic Approaches In the Presymptomatic Stage Of T1dmentioning

confidence: 99%

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Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview

Rapini

Schiaffini

Fierabracci

2020

IJMS

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Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to prevent hyperglycaemia (which is associated with long-term microvascular and macrovascular complications) and to avoid recurrent episodes of hypoglycaemia (which may have adverse effects on cognitive function). However, despite continuing optimization of insulin therapy regimes, the actual hormonal substitutive administration acts only to treat the symptoms without an effect on disease pathology and etiopathogenesis. In recent decades, a great deal of interest has been focused on prevention approaches in high-risk individuals, based on the hypothesis that a therapeutic intervention, if applied at the early stage of disease, might contribute to maintaining endogenous β cell function by preserving the residual β cell reservoir from autoimmune attack. This manuscript provides an overview of the most important immunotherapeutic interventions established so far for Type 1 diabetes treatment at different stages of disease that have reached an advanced stage of assessment.

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Section: Studies In the Symptomatic Phase Of T1dmentioning

confidence: 77%

Section: Treatment Immune Cell Effect Refmentioning

confidence: 99%

Section: Immunotherapeutic Approaches In the Presymptomatic Stage Of T1dmentioning

confidence: 99%

Section: Immunotherapeutic Approaches In the Presymptomatic Stage Of T1dmentioning

confidence: 99%

See 2 more Smart Citations

Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview

Rapini

Schiaffini

Fierabracci

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…GAD-alum has also been used in a small prevention trial. The treatment was safe and gave no adverse events, but no efficacy was found [74]. Peptide immunotherapy has been tried to restore immune homeostasis via the expansion of Tregs and the deletion and/or anergy of the pathogenic T-cell population [75].…”

Section: Peptides In Autoantigen Treatmentmentioning

confidence: 99%

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

Ludvigsson¹

2020

IJMS

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Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

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Early Diagnosis of Type 1 Diabetes – Useful or a Pyrrhic Victory?

Pozzilli

Pieralice

2021

Clinical Dilemmas in Diabetes

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Safety and efficacy of autoantigen‐specific therapy with 2 doses of alum‐formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial

Abstract: GAD-Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD-Alum should prove useful in future prevention studies.

Cited by 47 publications

References 27 publications

Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview

Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

Early Diagnosis of Type 1 Diabetes – Useful or a Pyrrhic Victory?

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