Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model

Clin Exp Immunol. 2008 Apr;152(1):138-46. doi: 10.1111/j.1365-2249.2008.03602.x. Epub 2008 Feb 25.


Clinical investigations of recombinant human acid alpha-glucosidase for the treatment of Pompe disease often reveal the appearance of therapy-specific antibodies. These antibodies could potentially interfere with recombinant human acid alpha-glucosidase efficacy and induce immunological consequences. Several immunosuppressive agents, including methotrexate, mycophenolate mofetil and cyclosporin A with azathioprine, were evaluated for their potential to induce immune tolerance to recombinant human acid alpha-glucosidase. Methotrexate was the only agent that reduced recombinant human acid alpha-glucosidase-specific antibody responses in acid alpha-glucosidase knock-out mice. A 3-week, low-dose methotrexate regimen controlled recombinant human acid alpha-glucosidase-specific antibody levels throughout 8 months of weekly recombinant human acid alpha-glucosidase treatment. The success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid alpha-glucosidase treatment. In an attempt to understand the benefit of methotrexate within the first day of recombinant human acid alpha-glucosidase administration, the immune response 24 h following intravenous recombinant human acid alpha-glucosidase treatment was investigated. A consistent expansion of peritoneal B1 B cells was observed. Control over this B1 B cell response may be part of the complex mechanism of action of methotrexate-induced immune tolerance.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Immunologic
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical / methods
  • Female
  • Glycogen Storage Disease Type II / drug therapy*
  • Glycogen Storage Disease Type II / immunology
  • Immune Tolerance / drug effects*
  • Immunoglobulin G / biosynthesis
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacology*
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacology*
  • Mice
  • Mice, Knockout
  • Recombinant Proteins / immunology
  • Recombinant Proteins / therapeutic use
  • alpha-Glucosidases / administration & dosage
  • alpha-Glucosidases / immunology*
  • alpha-Glucosidases / therapeutic use


  • Immunoglobulin G
  • Immunosuppressive Agents
  • Recombinant Proteins
  • GAA protein, human
  • alpha-Glucosidases
  • Methotrexate