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

• Published in: Clinical and experimental immunology Vol. 152; no. 1; pp. 138 - 146
• Main Authors: Joseph, A, Munroe, K, Housman, M, Garman, R, Richards, S
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.04.2008; Blackwell Publishing Ltd; Blackwell; Blackwell Science Inc
• Subjects: acid-α-glucosidase; alpha-Glucosidases - administration & dosage; alpha-Glucosidases - immunology; alpha-Glucosidases - therapeutic use; Analytical, structural and metabolic biochemistry; Animals; antibodies; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Disease Models, Animal; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Drug Evaluation, Preclinical - methods; Errors of metabolism; Female; Fundamental and applied biological sciences. Psychology; Glycogen Storage Disease Type II - drug therapy; Glycogen Storage Disease Type II - immunology; Immune Tolerance - drug effects; immune tolerance induction; Immunoglobulin G - biosynthesis; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Injections, Intraperitoneal; Injections, Intravenous; Male; Medical sciences; Metabolic diseases; methotrexate; Methotrexate - administration & dosage; Methotrexate - pharmacology; Mice; Mice, Knockout; Pompe; Recombinant Proteins - immunology; Recombinant Proteins - therapeutic use; Translational Studies; Replacement therapy; Glycogenosis II Pompe; Biochemistry; Enzymopathy; Antifolate; acid-α-glucosidase; Carbohydrate; antibodies; Methotrexate; Antibody; Enzyme; Low dose; immune tolerance induction; Rodentia; Metabolic diseases; Genetic disease; Glycosylases; Vertebrata; Mammalia; Antimetabolic; Mouse; α-Glucosidase; Glycosidases; Animal; Immune tolerance; Pompe; Hydrolases; Models
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2008.03602.x

Clinical investigations of recombinant human acid α-glucosidase for the treatment of Pompe disease often reveal the appearance of therapy-specific antibodies. These antibodies could potentially interfere with recombinant human acid α-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 α-glucosidase. Methotrexate was the only agent that reduced recombinant human acid α-glucosidase-specific antibody responses in acid α-glucosidase knock-out mice. A 3-week, low-dose methotrexate regimen controlled recombinant human acid α-glucosidase-specific antibody levels throughout 8 months of weekly recombinant human acid α-glucosidase treatment. The success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid α-glucosidase treatment. In an attempt to understand the benefit of methotrexate within the first day of recombinant human acid α-glucosidase administration, the immune response 24 h following intravenous recombinant human acid α-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.