Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome
Angela C. Sosa, … , Eric Armbrecht, Adriana M. Montaño
Angela C. Sosa, … , Eric Armbrecht, Adriana M. Montaño
Published November 19, 2019
Citation Information: J Clin Invest. 2020;130(3):1288-1300. https://doi.org/10.1172/JCI125607.
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Research Article Genetics Immunology

Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome

Abstract

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 N-acetylgalactosamine-6-sulfate sulfatase (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 for 10 days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete GALNS enzyme to orally induce tolerance to GALNS prior to ERT resulted in several improvements to ERT in mice: (a) decreased splenocyte proliferation after in vitro GALNS stimulation, (b) modulation of the cytokine secretion profile, (c) decrease in GALNS-specific IgG or IgE in plasma, (d) decreased GAG storage in liver, and (e) fewer circulating immune complexes in plasma. This model could be extrapolated to other lysosomal storage disorders in which immune response hinders ERT.

Authors

Angela C. Sosa, Barbara Kariuki, Qi Gan, Alan P. Knutsen, Clifford J. Bellone, Miguel A. Guzmán, Luis A. Barrera, Shunji Tomatsu, Anil K. Chauhan, Eric Armbrecht, Adriana M. Montaño

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Figure 4

Mesenteric lymph nodes play a role in oral tolerance to GALNS.

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Mesenteric lymph nodes play a role in oral tolerance to GALNS. RNA from ...
RNA from MLNs and PPs of tolerized and nontolerized mice were used to perform quantitative RT-PCR analysis. Expression levels of Foxp3 were measured in (A) MLNs and (B) PPs. Expression levels of Tgfb1 were measured in (C) MLNs and (D) PPs. Fold change indicates the change in RNA transcripts of tolerized mice and nontolerized mice normalized by untreated (PBS-PBS) mice. Quantitative data are represented as a box-and-whisker plot, with bounds from 25th to 75th percentile, median line, and whiskers ranging from 5th and 95th percentile values of 9 measurements from 3 mice. *P < 0.025, Benjamini and Hochberg adjusted, for differences between tolerized and nontolerized (PBS-ERT) mice. The dotted horizontal line indicates 1-fold change.