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.
View: Text | PDF
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

×

Figure 1

Selection of immunodominant peptides within the GALNS enzyme.

Options: View larger image (or click on image) Download as PowerPoint
Selection of immunodominant peptides within the GALNS enzyme. (A) Locati...
(A) Location of the synthetic peptides in the 3D structure of GALNS enzyme. Peptides A2 (blue), B3 (green), C4 (magenta), D9 (yellow), E8 (violet), F5 (orange), G6 (cyan), H7 (light blue), I10 (purple), and J1 (light green) are highlighted. The active site of the protein (C79) is shown in red. (B–F) Selection of immunodominant peptides after in vitro stimulation of splenocytes. MKC mice were treated with 16 intravenous weekly infusions of human GALNS (E, black dots) or PBS (P, red dots). Ten days after the last infusion, mice were euthanized and splenocytes were in vitro stimulated with GALNS or a single peptide. The background levels from unstimulated cells were subtracted. (B) Levels of splenocyte proliferation (n = 6 measurements from 2 different mice) and secretion levels of cytokines (C) IFN-γ, (D) IL-4, (E) IL-5, and (F) IL-13 (n = 9 measurements from 3 different mice). Data are shown as scatter plots with mean ± 95% CI. *P < 0.05; **P < 0.01; ***P < 0.001 represent statistically significant differences between treated and untreated mice as determined by 2-tailed paired t test.