Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in Infantile- vs. late-onset Pompe disease patients.

Authors

Parisa Amirifar, Ankit K Desai, Seung-Hye Jung, Sarah P Young, P Brian Smith, Cheng Lu, Bijan Abar, Priya S Kishnani, Trevor D Burt

Published in

Frontiers in immunology. Volume 17. Pages 1843379. Epub Sep 04, 2026.

Abstract

Transient low-dose methotrexate (MTX) induces long-term immune tolerance to enzyme replacement therapy (ERT) in Pompe disease; however, the underlying immunological mechanisms remain unclear. We hypothesized that TLD-MTX would reduce immune activation and induce a regulatory phenotype in patients with Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD) treated with ERT.
We evaluated immune cell profile changes in patients treated with ERT+MTX using multiparameter flow cytometry on peripheral blood mononuclear cells collected at baseline and six months post-treatment. We analyzed 40 immune parameters in (1) thirteen unpaired samples from ERT+MTX-untreated (n=10) and -treated (n=3) IOPD patients and (2) six paired pre- and post-treatment samples from LOPD (n=6) patients. Linear regression analyses were used to assess correlations between immune parameters and disease activity measured by urinary glucose tetrasaccharide (Glc₄; a breakdown product of glycogen).
In IOPD, ERT+MTX-treated samples (median age: 12.3 months) showed reduced % CD16⁺ monocytes and increased classical CD14⁺CD16^- monocytes, suggesting a shift toward a less activated immune profile. Untreated samples had higher % mature memory B cells and lower % plasmablasts, central memory CD4⁺ and CD8⁺ T cells, and TIGIT⁺ CD8⁺ T cells. In contrast, LOPD patients (median age: 51.5 years) exhibited decreased % B cells and increased % TIGIT⁺ CD4⁺ T cells after treatment. Baseline Glc₄ levels were higher in IOPD than LOPD (42.5 vs. 7) and decreased in both groups following ERT+MTX. In untreated IOPD patients, Glc₄ levels positively correlated with CD16⁺ monocytes, mature memory B cells, and terminally differentiated CD8⁺ T cells; these associations were not observed after treatment. In LOPD, T follicular regulatory cells correlated with Glc₄ prior to treatment but not after, and no additional significant correlations were identified.
These findings demonstrate distinct immune profiles before and after ERT+MTX treatment in IOPD and LOPD patients. In IOPD, reduced pro-inflammatory monocytes and memory T cells provide evidence to suggest decreased immune activation. In LOPD, increased TIGIT⁺ CD4⁺ T cells may reflect a regulatory mechanism contributing to immune tolerance.

PMID:
42760993
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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