Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes
Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes
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DOI：
10.1371/journal.pone.0041756
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发表时间：
2012-08-08
期刊：
影响因子：
3.7
通讯作者：
Nathan, David M.
中科院分区：
文献类型：
--
作者：
Faustman, Denise L.;Wang, Limei;Nathan, David M.
背景：没有靶向免疫疗法逆转人类1型糖尿病。然而，在1型糖尿病的啮齿动物模型中，卡介苗（BCG）通过恢复胰岛素分泌来逆转疾病。具体而言，它通过诱导宿主产生肿瘤坏死因子（TNF）来刺激先天免疫，进而杀死致病的自身免疫细胞并通过再生恢复胰腺β细胞功能。方法学/主要发现：将这些发现转化为人类，我们以原理验证的双盲方式给予BCG，一种通用疫苗，在北美的一个临床中心进行的一项长期1型糖尿病成人（平均年龄：15.3年）安慰剂对照试验。6名受试者被随机分配到BCG或安慰剂组，并与自身、健康配对对照组（n = 6）或有（n = 57）或无（n = 16）1型糖尿病的参考受试者进行比较，这取决于结果测量。我们每周监测20周的血液样本，以检测胰岛素自身反应性T细胞、调节性T细胞（Tcells）、谷氨酸脱羧酶（GAD）和其他自身抗体以及C肽（胰岛素分泌的标志物）。BCG治疗的患者和1例安慰剂治疗的患者在入组后意外发生急性EB病毒感染（一种已知的TNF诱导剂），仅显示死亡的胰岛素自身反应性T细胞增加和TcB诱导。两名BCG治疗受试者（平均值：3.49 pmol/L [95% CI 2.95-3.8]，2.57 [95% CI 1.65-3.49]）和EBV感染受试者（3.16 [95% CI 2.54-3.69]）的C肽水平（pmol/L）显著一过性升高，而对照糖尿病受试者为1.65 [95% CI 1.55-3.2]。接受BCG治疗的受试者中，有50%以上的C肽值高于参考受试者的第95百分位数。EBV感染的受试者有18%的C-肽值高于此level.Conclusions/Significance：我们得出结论，BCG治疗或EBV感染瞬时修改的自身免疫，基础1型糖尿病刺激宿主先天免疫反应。这表明BCG或其他宿主先天免疫刺激物可能在治疗长期糖尿病中具有价值。
Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.Methodology/Principal Findings: Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs. 1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.