Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes The Pre-POINT Randomized Clinical Trial
Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes The Pre-POINT Randomized Clinical Trial
复制标题
DOI：
10.1001/jama.2015.2928
复制
发表时间：
2015-04-21
影响因子：
120.7
通讯作者：
Achenbach, Peter
中科院分区：
文献类型：
--
作者：
Bonifacio, Ezio;Ziegler, Anette-G.;Achenbach, Peter
将口腔粘膜暴露于抗原可刺激免疫耐受。目前尚不清楚口服胰岛素治疗是否可以在遗传易感1型糖尿病的儿童中诱导耐受性免疫反应。目的评估自身抗体阴性、遗传高危儿童口服胰岛素相关的免疫反应和不良事件。设计、设置和参与者于2009年至2013年在德国、奥地利、美国和英国进行了一项双盲、安慰剂对照、剂量递增、1/2期临床先导研究，招募了25名2至7岁具有1型糖尿病家族史和人类白细胞抗原II类易感基因的胰岛自身抗体阴性儿童。随访于2013年8月完成。干预儿童随机接受口服胰岛素(n=15)或安慰剂(n=10)，每天一次，持续3至18个月。9例6个月后胰岛素剂量由2.5 mg增至7.5 mg(n=3)，2.5 mg增至22.5 mg(n=3)，7.5 mg增至67.5 mg(n=3)；6名儿童仅接受22.5 mg(n=3)或67.5 mg(n=3)的剂量。主要结果和测量胰岛素的免疫应答，测量血清免疫球蛋白G和唾液IgA与胰岛素的结合，以及CD4(+)T细胞对胰岛素的增殖反应。结果观察到2/10(20%[95%CI，0.1%-45%])的安慰剂治疗的儿童和1/6(16.7%[95%CI，16.7%[95%CI，胰岛素2.5 mg组1例(16.7%[95%CI，0.1%-46%])，22.5 mg组2例(33.3%[95%CI，0.1%-71%])，67.5 mg组5例(83.3%[95%CI，53%-99.9%])(P=0.02)。口服胰岛素治疗后，胰岛素反应性T细胞表现出调节性T细胞特征。没有观察到低血糖，对胰岛素的IgE反应，谷氨酸脱羧酶或胰岛素瘤相关抗原2的自身抗体，或糖尿病。在12名接受胰岛素治疗的儿童(67个事件)和10名接受安慰剂治疗的儿童(35个事件)中，报告了不良事件。结论和相关性在这项针对1型糖尿病高危儿童的先导性研究中，与安慰剂相比，每天口服67.5 mg的胰岛素导致了没有低血糖的免疫反应。这些发现支持3期试验的必要性，以确定口服胰岛素是否可以预防此类儿童的胰岛自身免疫和糖尿病。
IMPORTANCE Exposing the oral mucosa to antigen may stimulate immune tolerance. It is unknown whether treatment with oral insulin can induce a tolerogenic immune response in children genetically susceptible to type 1 diabetes.OBJECTIVE To assess the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children.DESIGN, SETTING, AND PARTICIPANTS The Pre-POINT study, a double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical pilot study performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolling 25 islet autoantibody-negative children aged 2 to 7 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Follow-up was completed in August 2013.INTERVENTIONS Children were randomized to receive oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Nine children received insulin with dose escalations from 2.5 to 7.5 mg (n = 3), 2.5 to 22.5mg (n = 3), or 7.5 to 67.5 mg (n = 3) after 6 months; 6 children only received doses of 22.5 mg (n = 3) or 67.5 mg (n = 3).MAIN OUTCOMES AND MEASURES An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4(+) T-cell proliferative responses to insulin.RESULTS Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4(+) T-cell proliferative responses to insulin were observed in 2 of 10 (20%[95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7%[95% CI, 0.1%-46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[95% CI, 0.1%-46%]) treated with 7.5mg, 2 of 6 (33.3%[95% CI, 0.1%-71%]) treated with 22.5mg, and 5 of 6 (83.3%[95% CI, 53%-99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events).CONCLUSIONS AND RELEVANCE In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.