DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany2Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Technische Universität Dresden, Dresden, Germany3Forschergru.
Forschergruppe Diabetes e.V., Neuherberg, Germany4Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
JAMA. 2015 Apr 21;313(15):1541-9. doi: 10.1001/jama.2015.2928.
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.
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.
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 22.5 mg (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).
An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin.
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 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%-71%]) treated with 22.5 mg, 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).
In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg 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.
isrctn.org Identifier: ISRCTN76104595.
目的：评估口服胰岛素在自身抗体阴性、遗传易感 1 型糖尿病儿童中的免疫应答和不良事件。
背景：将口腔黏膜暴露于抗原可能会刺激免疫耐受。目前尚不清楚口服胰岛素是否能在遗传易感 1 型糖尿病的儿童中诱导出耐受原性免疫应答。
设计、地点和参与者：Pre-POINT 研究是 2009 年至 2013 年在德国、奥地利、美国和英国进行的一项双盲、安慰剂对照、剂量递增、1/2 期临床先导研究，共纳入 25 名胰岛自身抗体阴性、有 1 型糖尿病家族史且携带易感人类白细胞抗原 II 基因型的 2 至 7 岁儿童。随访于 2013 年 8 月完成。
干预措施：儿童随机接受口服胰岛素（n = 15）或安慰剂（n = 10）治疗，持续 3 至 18 个月。9 名儿童在 6 个月后接受了从 2.5 至 7.5 mg（n = 3）、2.5 至 22.5 mg（n = 3）或 7.5 至 67.5 mg（n = 3）的递增剂量；6 名儿童仅接受 22.5 mg（n = 3）或 67.5 mg（n = 3）的剂量。
主要结局和测量指标：胰岛素的免疫应答，测量指标为血清 IgG 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：在 10 名安慰剂治疗的儿童中有 2 名（20%[95%CI，0.1%-45%]）和 6 名接受 2.5 mg 胰岛素治疗的儿童中有 1 名（16.7%[95%CI，0.1%-46%]）、6 名接受 7.5 mg 胰岛素治疗的儿童中有 1 名（16.7%[95%CI，0.1%-46%]）、6 名接受 22.5 mg 胰岛素治疗的儿童中有 2 名（33.3%[95%CI，0.1%-71%]）和 6 名接受 67.5 mg 胰岛素治疗的儿童中有 5 名（83.3%[95%CI，53%-99.9%]）出现了胰岛素应答 T 细胞的免疫应答（P = .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。未观察到低血糖、胰岛素 IgE 应答、谷氨酸脱羧酶或胰岛相关抗原 2 自身抗体或糖尿病。在 12 名接受胰岛素治疗的儿童（67 例事件）和 10 名接受安慰剂治疗的儿童（35 例事件）中报告了不良事件。
结论：在这项针对 1 型糖尿病高危儿童的初步研究中，与安慰剂相比，每日口服 67.5 mg 胰岛素可引起免疫应答而无低血糖。这些发现支持进行 3 期临床试验，以确定口服胰岛素是否能预防此类儿童的胰岛自身免疫和糖尿病。
