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

Abstract

Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid α-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-γ 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.

• Authors: Sushrusha Nayak, Ramya Sivakumar, Ou Cao, Henry Daniell, Barry J Byrne, Roland W Herzog
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 106 Issue 2 Pg. 189-95 (Jun 2012) ISSN: 1096-7206 [Electronic] United States
• PMID: 22494547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Epitopes, T-Lymphocyte
• Immunoglobulin G
• Peptide Library
• alpha-Glucosidases

Topics

• Amino Acid Sequence
• Animals
• Cytokines (immunology)
• Disease Models, Animal
• Enzyme Replacement Therapy (adverse effects)
• Epitope Mapping
• Epitopes, T-Lymphocyte (chemistry, immunology)
• Glycogen Storage Disease Type II (immunology, therapy)
• Humans
• Immunoglobulin G (blood, immunology)
• Mice
• Mice, 129 Strain
• Mice, Knockout
• Molecular Sequence Data
• Peptide Library
• T-Lymphocytes, Helper-Inducer (immunology)
• Th2 Cells (immunology)
• alpha-Glucosidases (immunology, therapeutic use)