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

Authors: Joseph, A.; Munroe, K.; Housman, M.; Garman, R.; Richards, S.

Source: Clinical & Experimental Immunology, Volume 152, Number 1, April 2008 , pp. 138-146(9)

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Abstract:

Summary

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.

Keywords: acid-α-glucosidase; antibodies; immune tolerance induction; methotrexate; Pompe

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2249.2008.03602.x

Publication date: 2008-04-01

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

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