Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes
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SHORT COMMUNICATION
Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes Ulf Hannelius 1
&
Craig A. Beam 2
&
Johnny Ludvigsson 3,4
Received: 28 April 2020 / Accepted: 11 June 2020 # The Author(s) 2020
Abstract Aims/hypothesis The aim of this study was to determine if retention of C-peptide following immunotherapy using recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum) is influenced by HLA risk haplotypes DR3-DQ2 and DR4-DQ8. Methods HLA-dependent treatment effect of GAD-alum therapy on C-peptide retention in individuals with recent-onset type 1 diabetes was evaluated using individual-level patient data from three placebo-controlled, randomised clinical trials using a mixed repeated measures model. Results A significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3DQ2 but not HLA-DR4-DQ8 and in the broader subgroup of individuals positive for all genotypes that include HLA-DR3-DQ2 (i.e. including those also positive for HLA-DR4-DQ8). Higher doses (three or four injections) showed a treatment effect ratio of 1.596 (95% CI 1.132, 2.249; adjusted p = 0.0035) and 1.441 (95% CI 1.188, 1.749; adjusted p = 0.0007) vs placebo for the two respective HLA subgroups. Conclusions/interpretation GAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype. Keywords Antigen-specific . Autoimmune diabetes . C-peptide . GAD . Glutamic acid decarboxylase . HLA . Immunotherapy . Type 1 diabetes . Vaccine
Abbreviation GAD-alum Recombinant human GAD65 conjugated to aluminium hydroxide rhGAD65 Recombinant human GAD65
* Ulf Hannelius [email protected] * Johnny Ludvigsson [email protected]; [email protected] 1
Diamyd Medical AB, Kungsgatan 29, 111 56 Stockholm, Sweden
2
Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
3
Crown Princess Victoria Children’s Hospital, Linköping, Sweden
4
Division of Pediatrics, Department of Biomedical and Clinical Sciences (BKV), Medical Faculty, Linköping University, SE 58185 Linköping, Sweden
Introduction Recombinant human GAD65 conjugated to aluminium hydroxide (GAD-alum) is an antigen-specific immunotherapy intended to induce specific immunological tolerance to preserve the pancreatic beta cells that are targeted in type 1 diabetes by autoreactive cytotoxic T cells. The active ingredient, recombinant human GAD65, is a pancreatic beta cell protein, GAD65 being one of the most frequent autoantigens associated with type 1 diabetes. The effect of GAD-alum on preserving endogenous insulin production has been evaluated in several placebo-controlled, randomised trials in individuals recently diagnosed with type 1 diabetes, albeit with inconclusive results [1–4]. It is becoming increasingly clear that factors such as genetic background in the form of HLA genotype affect both the ri
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