Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.
Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.
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DOI：
10.1016/s0140-6736(11)60895-7
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发表时间：
2011-07-23
期刊：
影响因子：
168.9
通讯作者：
Skyler, Jay S.
中科院分区：
文献类型：
--
作者：
Wherrett, Diane K.;Bundy, Brian;Becker, Dorothy J.;DiMeglio, Linda A.;Gitelman, Stephen E.;Goland, Robin;Gottlieb, Peter A.;Greenbaum, Carla J.;Herold, Kevan C.;Marks, Jennifer B.;Monzavi, Roshanak;Moran, Antoinette;Orban, Tihamer;Palmer, Jerry P.;Raskin, Philip;Rodriguez, Henry;Schatz, Desmond;Wilson, Darrell M.;Krischer, Jeffrey P.;Skyler, Jay S.
1型糖尿病(T1 DM)是一种自身免疫性疾病，导致产生胰岛素的β细胞破坏，终生需要胰岛素治疗。谷氨酸脱羧酶(GAD)是这种免疫反应的主要靶点。对自身免疫动物模型的研究表明，用靶抗原治疗可以调节侵袭性自身免疫。我们评估了用氢氧化铝(明胶)配制的GAD作为新近发病的T1 DM的佐剂的免疫效果。在这项多中心、双盲、随机对照试验中，145名年龄在3个月以下的T1 DM患者在基线、4周和8周后分别接受3次20μg GAD-明矾注射(48例)、2次GAD-明矾注射和1次明矾皮下注射(49例)或3次明矾注射(48例)。主要结果是基线调整后的几何平均2小时曲线下面积(AUC)，在一年的混合膳食耐量试验后测定血清C肽。次要结果包括糖化血红蛋白和胰岛素剂量的变化以及安全性。这项试验已在ClinicalTrials.gov(NCT00529399)上注册。GAD-明矾×3组和GAD-明矾×2/明矾×1组的调整群体C肽均值之比分别为0.998(95%CI：[0.779，1.22]，p=0.98)和0.926(95%CI：[0.720，1.13]，p=0.50)。糖化血红蛋白和胰岛素的使用在不同组之间没有差异。两组之间的不良事件发生率或严重程度没有差异。以抗原为基础的免疫疗法使用GAD-明矾，在4到12周内分两次或三次皮下注射，并不能改变新近诊断的T1 DM患者一年内胰岛素分泌丧失的过程。虽然基于抗原的治疗是一种非常可取的治疗方法，在动物模型中也是有效的，但将其转化为人类自身免疫性疾病仍然是一个挑战。美国国立卫生研究院。
Type 1 diabetes (T1DM) is an autoimmune disease leading to destruction of insulin producing beta cells and life-long requirement for insulin therapy. Glutamic acid decarboxylase (GAD) is a major target of this immune response. Studies in animal models of autoimmunity have shown that treatment with a target antigen can modulate aggressive autoimmunity. We evaluated immunization with GAD formulated in aluminum hydroxide (alum) as an adjuvant in recent onset T1DM. In this multicentre, double-masked, randomised controlled trial, 145 subjects (ages 3-45) with T1DM for less than 3 months received 3 injections of 20 μg GAD-alum (48 subjects), 2 injections of GAD-alum and one of alum alone (49 subjects) or 3 injections of alum (48 subjects) subcutaneously at baseline, 4 weeks later and 8 weeks after the second injection. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at one year. Secondary outcomes included changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00529399). The ratio (experimental to control) of the adjusted population mean of C-peptide for the GAD-alum ×3 and GAD-alum ×2/alum ×1 groups is 0.998 (95% CI: [0.779, 1.22], p = 0.98) and 0.926 (95% CI: [0.720, 1.13], p = 0.50), respectively. HbA1c and insulin use did not differ between groups. There was no difference in rate or severity of adverse events between groups. Antigen-based immunotherapy therapy using GAD-alum given subcutaneously in two or three doses over 4 to 12 weeks does not alter the course of loss of insulin secretion over one year in subjects with recently diagnosed T1DM. While antigen-based therapy is a highly desireable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. National Institutes of Health.