Title

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

Authors

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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