Uibo Raivo, Lernmark Ake
Department of Immunology, IGMP, Centre of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia.
Adv Immunol. 2008;100:39-78. doi: 10.1016/S0065-2776(08)00803-1.
Type 1 diabetes (T1D) in children and particularly in teenagers and adults is strongly associated with autoreactivity to the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65). Autoantibodies to GAD65 are common at the time of clinical diagnosis and may be present for years prior to the onset of hyperglycemia. GAD65 autoantibodies predict conversion to insulin dependence when present in patients classified with type 2 diabetes nowadays more often referred to as patients with latent autoimmune diabetes in the adult (LADA) or type 1,5 diabetes. Analyses of T cells with HLA DRB1 0401-tetramers with GAD65-specific peptides as well as of anti-idiotypic GAD65 autoantibodies suggest that GAD65 autoreactivity is common. The immunological balance is disturbed and the appearance of GAD65 autoantibodies represents markers of autoreactive loss of pancreatic beta cells. Extensive experimental animal research, in particular of the Non-obese diabetic (NOD) mouse, showed that GAD65 therapies reduce insulitis and prevent spontaneous diabetes. Recombinant human GAD65 produced by current Good Manufacturing Practice (cGMP) and formulated with alum was found to be safe in Phase I and II placebo-controlled, double-blind, randomized clinical trials. The approach to modulate GAD65 autoreactivity with subcutaneous immunotherapy (SCIT) showed promise as alum-formulated GAD65 induced a dose-dependent reduction in the disappearance rate of endogenous residual C-peptide production. Additional controlled clinical trials are needed to uncover the mechanisms by which subcutaneous injections of recombinant human GAD65 may alter GAD65 autoreactivity.
儿童尤其是青少年和成人的1型糖尿病（T1D）与针对分子量65,000的谷氨酸脱羧酶（GAD65）同工型的自身反应性密切相关。GAD65自身抗体在临床诊断时很常见，并且可能在高血糖发作前数年就已存在。如今，在被归类为2型糖尿病（现在更常称为成人隐匿性自身免疫性糖尿病（LADA）或1.5型糖尿病）的患者中，GAD65自身抗体可预测其向胰岛素依赖的转变。用GAD65特异性肽的HLA DRB1 0401四聚体分析T细胞以及抗独特型GAD65自身抗体表明，GAD65自身反应性很常见。免疫平衡受到干扰，GAD65自身抗体的出现代表胰腺β细胞自身反应性丧失的标志物。广泛的实验动物研究，特别是对非肥胖糖尿病（NOD）小鼠的研究表明，GAD65疗法可减轻胰岛炎并预防自发性糖尿病。在I期和II期安慰剂对照、双盲、随机临床试验中发现，按照现行药品生产质量管理规范（cGMP）生产并用明矾配制的重组人GAD65是安全的。皮下免疫疗法（SCIT）调节GAD65自身反应性的方法显示出前景，因为明矾配制的GAD65可使内源性残余C肽产生的消失率呈剂量依赖性降低。需要更多对照临床试验来揭示皮下注射重组人GAD65可能改变GAD65自身反应性的机制。
