title: Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model.
abstract: 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.
authors.affiliation: Immunology Laboratory, Biologics R&D, Genzyme Corporation, Framingham, MA 01701, USA. alexandra.joseph@genzyme.com
authors.forename: A
authors.initials: A
authors.lastname: Joseph
authors.forename: K
authors.initials: K
authors.lastname: Munroe
authors.forename: M
authors.initials: M
authors.lastname: Housman
authors.forename: R
authors.initials: R
authors.lastname: Garman
authors.forename: S
authors.initials: S
authors.lastname: Richards
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D000520:alpha-Glucosidases / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; C509951:GAA protein, human; D000520:alpha-Glucosidases; D008727:Methotrexate