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

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

Author information

1
Immunology Laboratory, Biologics R&D, Genzyme Corporation, Framingham, MA 01701, USA. alexandra.joseph@genzyme.com

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.

PMID:
18307520
PMCID:
PMC2384062
DOI:
10.1111/j.1365-2249.2008.03602.x
[Indexed for MEDLINE]
Free PMC Article

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