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 5

Circulating immune complexes in plasma.

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Circulating immune complexes in plasma. Quantities of M complement prote...
Quantities of M complement proteins C1q, C3, C4, and C5 bound to circulating immune complexes (CICs) were measured using a Preceptor CIC ELISA kit. Oral tolerance was induced by feeding MKC mice with 50, 100, or 500 μg of peptide I10 (red) or GALNS enzyme (blue). Control groups were fed with PBS (gray and purple). One week after the last oral dose, mice received 16 weekly intravenous infusions of human GALNS (red, blue, and gray) or PBS (purple). Blood samples were obtained 10 days after the last infusion. Control naive MKC mice did not undergo any treatment (orange). Data are shown as scatter plots with mean ± 95% CI. Each scatter plot represents the average of 10 measurements from 5 mice. *P < 0.05, Benjamini and Hochberg adjusted, for differences between tolerized and nontolerized (PBS-ERT) mice. §P < 0.007, Benjamini and Hochberg adjusted, for differences between ERT-treated mice and untreated (PBS-PBS) mice.