Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome.
Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome.
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DOI：
10.1172/jci125607
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发表时间：
2019-11
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通讯作者：
A. Sosa;B. Kariuki;Q. Gan;A. Knutsen;C. Bellone;Miguel A. Guzmán;L. Barrera;S. Tomatsu;A. Chauhan;E. Armbrecht;A. Montaño
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作者：
A. Sosa;B. Kariuki;Q. Gan;A. Knutsen;C. Bellone;Miguel A. Guzmán;L. Barrera;S. Tomatsu;A. Chauhan;E. Armbrecht;A. Montaño
对治疗性酶的免疫应答对患者安全性和治疗结果造成损害。酶替代疗法（ERT）是某些类型的粘多糖沉积症（包括由GALNS缺乏引起的Morquio A综合征）的标准治疗选择。目前的方案耐受使用细胞毒性免疫抑制剂的患者，这可能导致不良反应。在此，我们显示了在ERT之前的10天期间通过口服递送肽或GALNS在Morquio A小鼠中的耐受性的发展。我们的研究结果表明，在ERT之前使用免疫显性肽（I10）或完全酶（GALNS）口服诱导对GALNS的耐受，导致小鼠中ERT的几种改善：i）体外GALNS刺激后脾细胞增殖减少; ii）细胞因子分泌谱的调节; iii）GALNS特异性IgG或IgE血浆的减少; iv）肝脏中GAG储存减少;和v）血浆中较少的循环免疫复合物。该模型可外推至免疫反应阻碍ERT的其他溶酶体贮积症。
Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of Mucopolysaccharidoses including Morquio A syndrome caused by GALNS deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives which can cause adverse effects. Here we show development of tolerance in Morquio A mice via oral delivery of peptide or GALNS during ten days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete enzyme (GALNS) to orally induce tolerance to GALNS prior to ERT, resulted in several improvements to ERT in mice: i) decreased splenocyte proliferation after in-vitro GALNS stimulation; ii) modulation of cytokine secretion profile; iii) decline in GALNS-specific IgG or IgE plasma; iv) decreased GAG storage in liver; and v) fewer circulating immune-complexes in plasma. This model could be extrapolated to other lysosomal storage disorders where immune response hinders ERT.