Diamyd Medical AB, Kungsgatan 29, 111 56, Stockholm, Sweden.
Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
Diabetologia. 2020 Oct;63(10):2177-2181. doi: 10.1007/s00125-020-05227-z. Epub 2020 Aug 5.
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.
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.
A significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3-DQ2 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. Graphical abstract.
目的/假设：本研究旨在确定使用与氢氧化铝偶联的重组 GAD65（GAD-alum）进行免疫治疗后 C 肽的保留是否受 HLA 风险单倍型 DR3-DQ2 和 DR4-DQ8 的影响。
使用来自三项安慰剂对照、随机临床试验的个体水平患者数据，使用混合重复测量模型，评估 GAD-alum 治疗对近期发生 1 型糖尿病个体中 C 肽保留的 HLA 依赖性治疗效果。
在 HLA-DR3-DQ2 阳性但 HLA-DR4-DQ8 阴性的个体以及包括 HLA-DR3-DQ2 的更广泛的个体阳性所有基因型（即也包括 HLA-DR4-DQ8 阳性的个体）中，观察到与剂量相关的显著治疗效果。较高剂量（三或四针）的治疗效果比值分别为 1.596（95%CI 1.132, 2.249；调整后 p=0.0035）和 1.441（95%CI 1.188, 1.749；调整后 p=0.0007），与安慰剂相比，分别在两个各自的 HLA 亚组中。
结论/解释：在具有 DR3-DQ2 单倍型的近期发生 1 型糖尿病个体中，GAD65 特异性免疫疗法对 C 肽保留有显著影响。
