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

Ludvigsson, Johnny

doi:10.3390/ijms21051598

Cited by 28 publications

(23 citation statements)

References 142 publications

(157 reference statements)

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“…Autoantigen treatment has been tried in many autoimmune diseases, with poor results. There are several problems to be solved, such as selection of autoantigen, dose, timing, and route of administration ( 32 ). This study confirmed the positive effects of intralymphatic autoantigen treatment, suggested in our previous first-in-human pilot trial ( 19 ), and this route of administration may therefore be of interest for trials in other autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial

et al. 2021

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OBJECTIVE To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

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Section: Discussionmentioning

confidence: 99%

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial

et al. 2021

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“…In a more recent trial, GAD‐alum was administered subcutaneously in a prime‐boost regimen to children with existing islet autoimmunity in order to prevent disease development but, although well‐tolerated, the primary endpoint was not reached 53 . Interestingly, subsequent analysis of these trials has revealed that GAD‐alum treatment is more efficacious in preserving C‐peptide secretion in patients positive for HLA‐DR3/DQ2—a haplotype associated with GAD65 autoimmunity—than in patients with a DR4/DQ8 genotype 54 …”

Section: Fighting Fire With Fire: Antigen‐specific Interventionsmentioning

confidence: 99%

“…53 Interestingly, subsequent analysis of these trials has revealed that GADalum treatment is more efficacious in preserving Cpeptide secretion in patients positive for HLA-DR3/DQ2 -a haplotype associated with GAD65 autoimmunitythan in patients with a DR4/DQ8 genotype. 54 Recent studies have combined GAD-alum with other immunomodulatory agents. In the DIAGNODE-1 study, patients with newly diagnosed T1D received three lowdose GAD-alum injections directly into an inguinal lymph node and an oral vitD supplement.…”

Section: Fighting Fire With Fire: Antigen-specific Interventionsmentioning

confidence: 99%

A century later, still fighting back: antigen‐specific immunotherapies for type 1 diabetes

Rodríguez-Fernández

Almenara-Fuentes

Perna-Barrull

et al. 2021

Immunol. Cell Biol.

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Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin‐producing β‐cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen‐specific immunotherapies with potential to restore selectively the breach of tolerance to β‐cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen‐specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell‐based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen‐specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.

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“…In some cases, immune suppression may be efficaceous, but it will be difficult to avoid unacceptable adverse events and risks. Auto-antigen treatment may become a safe way forward but we need to know more about the route of administration, doses, what autoantigens to use in different patients [ 49 ]. Furthermore, we will probably need to combine different regimens and agents, in a similar way as been used with great success in, for example, pediatric oncology [ 34 ].…”

Section: Future Perspectivementioning

confidence: 99%

Combined Vitamin D, Ibuprofen and Glutamic Acid decarboxylase-alum Treatment in Recent Onset Type I Diabetes: Lessons from the DIABGAD Randomized Pilot Trial

et al. 2020

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Aim: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). Methods: 64 patients (T1D since <4 months, age 10–17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1–90 400 mg/day Ibuprofen, D1–450 vitamin D 2000 IU/day, D15, 45 sc. 20 μg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 μg GAD-alum D15, 45; placebo. Results: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). Conclusion: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 ( ClinicalTrials.gov ).

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

Cited by 28 publications

References 142 publications

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial

A century later, still fighting back: antigen‐specific immunotherapies for type 1 diabetes

Combined Vitamin D, Ibuprofen and Glutamic Acid decarboxylase-alum Treatment in Recent Onset Type I Diabetes: Lessons from the DIABGAD Randomized Pilot Trial

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