Mannose 6-phosphate conjugation is not sufficient to allow induction of immune tolerance to phenylalanine ammonia-lyase in dogs

Moin Vera, Thomas Lester, Bin Zhao, Pascale Tiger, Scott Clarke, Brigette L. Tippin, Merry B. Passage, Steven Q. Le, Javier Femenia, Jeffrey F. Lemontt, Emil D. Kakkis, Patricia I. Dickson

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

1 Scopus citations

Abstract

The immune response to exogenous protein has been shown to reduce therapeutic efficacy in animal models of enzyme replacement therapy. A previously published study demonstrated an immunosuppressive regimen which successfully induced immune tolerance to α-l-iduronidase in canines with mucopolysaccharidosis I. The two key requirements for success were high-affinity receptor-mediated enzyme uptake, conferred by mannose 6-phosphate conjugation, and immunosuppression with low-dose antigen exposure. In this study, we attempted to induce immune tolerance to phenylalanine ammonia-lyase by producing a recombinant mannose 6-phosphate conjugated form and administering it to normal dogs according to the previously published tolerance induction regimen. We found that the recombinant conjugated enzyme was stable, could bind to the mannose 6-phosphate receptor with high affinity, and its uptake into fibroblast cells was mediated by this receptor. However, at the end of a tolerance induction period, all dogs demonstrated an antigen-specific immune response when challenged with increasing doses of unconjugated phenylalanine ammonia-lyase. The average time to seroconvert was not significantly different among three separate groups of test animals (n = 3 per group) and was not significantly different from one group of control animals (n = 3). None of the nine test group animals developed immune tolerance to the enzyme using this method. This suggests that high-affinity cellular uptake mediated by the mannose 6-phosphate receptor combined with a previously studied tolerizing regimen is not sufficient to induce immune tolerance to an exogenous protein and that other factors affecting antigen distribution, uptake, and presentation are likely to be important.

Original languageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages63-72
Number of pages10
DOIs
StatePublished - 2013

Publication series

NameJIMD Reports
Volume8
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Keywords

  • Enzyme replacement therapy
  • Fabry disease
  • Human fibroblast cell
  • Immune tolerance
  • Tolerance induction

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