Mapping the T helper cell response to acid alpha-glucosidase in Pompe mice

    Authors

    S. Nayak; R. Sivakumar; O. Cao; H. Daniell; B. J. Byrne;R. W. Herzog

    Comments

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    Abbreviated Journal Title

    Mol. Genet. Metab.

    Keywords

    alpha-Glucosidase; Pompe; Immune response; T cell; Antibody; DISEASE TYPE-II; INHIBITOR FORMATION; IMMUNE TOLERANCE; FACTOR-IX; EPITOPE; GENE; ANAPHYLAXIS; THERAPY; ELISPOT; MODEL; Biochemistry & Molecular Biology; Genetics & Heredity; Medicine, ; Research & Experimental

    Abstract

    Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The resulting accumulation of glycogen causes muscle weakness with the severe form of the disease resulting in death by cardiorespiratory failure in the first year of life. The only available treatment, enzyme replacement therapy (ERT) with recombinant GAA (rhGAA), is severely hampered by antibody responses that reduce efficacy and cause immunotoxicities. Currently, Pompe mice represent the only pre-clinical model for development of new treatments and for immunological studies. While antibody formation following ERT in this model has been described, the underlying T cell response has not been studied. In order to define the T helper response to rhGAA in Pompe mice, immunodominant CD4(+) T cell epitopes were mapped in GAA(-/-) 129SVE mice using ELISpot. Additionally, cytokine responses and antibody formation against rhGAA during ERT were measured. Among the three CD4(+) T cell epitopes identified, only epitope IFLGPEPKSVVQ predicted to be the strongest MHC II binder, consistently contributed to IL-4 production. Frequencies of IL-4 producing T cells were considerably higher than those of IL-17 or IFN-gamma producing cells, suggesting a predominantly Th2 cell mediated response. This is further supported by IgG1 being the prevalent antibody subclass against rhGAA during ERT and consistent with prior reports on IgE formation and anaphylaxis in this model. These results will facilitate mechanistic studies of the immune response to rhGAA in Pompe mice during development of new therapies and tolerance protocols. (C) 2012 Elsevier Inc. All rights reserved.

    Journal Title

    Molecular Genetics and Metabolism

    Volume

    106

    Issue/Number

    2

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    189

    Last Page

    195

    WOS Identifier

    WOS:000304581000007

    ISSN

    1096-7192

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