Abstract

Background

Cows’ milk allergy (CMA) is a hypersensitivity immune reaction brought on by specific immunologic mechanisms to cow’s milk proteins. As one of the most common food allergies in infants, the incidence of CMA during the first year of life is estimated to be nearly 7.5%. Due to the limitation in the knowledge of the pathological mechanism underlying CMA, however, the clinical interventions and therapies remain very unsatisfactory.

Aim of the study

The transcriptional factor FOXP3 possesses crucial roles in CMA, and increased FOXP3 mRNA expression has a predictive function in faster acquisition of tolerance in infants with CMA. But the exact mechanism remains not fully elucidated.

Methods

For PAG treatment, PAG (dissolved in saline 30 mg/mL, 0, 5, 10, 20 mg/kg BW) was administered daily intraperitoneally (ip) for one week at the time that 6 weeks after the CMP sensitisation.

Results

In the present study, we revealed that the expression of FOXP3 is significantly up-regulated in PBMCs from CMA patients and CMA mice on mRNA and protein level. Furthermore, a dramatic reduction in the FOXP3 TSDR methylation and a significant increase in the expression of TET2 are observed in CMA patients and CMA mice. More importantly, we found that propargylglycine (PAG) significantly alleviates symptoms of CMA in mice by suppressing the expression of FOXP3 through restoring TET2 expression.

Conclusions

Our work revealed a novel function of PAG on CMA, which may provide a deeper insight into the pathomechanism of CMA and a novel therapy target for CMA clinical interventions.

中文翻译：

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DL-炔丙基甘氨酸给药抑制 TET2 和 FOXP3 表达并减轻小鼠模型中新生儿牛奶过敏的症状

摘要

背景

牛奶过敏 (CMA) 是由对牛奶蛋白质的特定免疫机制引起的超敏免疫反应。作为婴儿最常见的食物过敏之一，CMA 在出生后第一年的发生率估计接近 7.5%。然而，由于对 CMA 病理机制的认识有限，临床干预和治疗仍然很不令人满意。

研究目的

转录因子 FOXP3 在 CMA 中具有关键作用，增加的 FOXP3 mRNA 表达在 CMA 婴儿更快获得耐受性方面具有预测功能。但确切的机制仍未完全阐明。

方法

对于 PAG 治疗，在 CMP 致敏后 6 周时，每天腹膜内 (ip) 施用 PAG（溶于 30 mg/mL 盐水，0、5、10、20 mg/kg BW）一周。

结果

在本研究中，我们发现 FOXP3 的表达在来自 CMA 患者和 CMA 小鼠的 PBMC 中在 mRNA 和蛋白质水平上显着上调。此外，在 CMA 患者和 CMA 小鼠中观察到 FOXP3 TSDR 甲基化的显着减少和 TET2 表达的显着增加。更重要的是，我们发现炔丙基甘氨酸（PAG）通过恢复 TET2 表达来抑制 FOXP3 的表达，从而显着减轻小鼠的 CMA 症状。

结论

我们的工作揭示了 PAG 对 CMA 的新功能，这可能有助于更深入地了解 CMA 的发病机制和 CMA 临床干预的新治疗靶点。