Methotrexate reduces antibody responses to recombinant humanα-galactosidase A therapy in a mouse model of Fabry disease
- 23 July 2004
- journal article
- Published by Oxford University Press (OUP) in Clinical and Experimental Immunology
- Vol. 137 (3), 496-502
- https://doi.org/10.1111/j.1365-2249.2004.02567.x
Abstract
SUMMARY: Therapeutic enzymes are often recognized as foreign by the immune system of patients undergoing enzyme replacement therapy. The antibodies that develop may alter pharmacokinetics and biodistribution of the therapeutic protein, may be able to neutralize the activity of the enzyme, or may cause immune reactions in certain patients. We have explored treatment regimens to reduce the antibody response to human α-galactosidase A (r-hαGAL) in Fabry (αGAL knock-out) and normal BALB/c mice. A wide variety of treatment modalities were tested, including high dose tolerance induction, increased frequency of therapeutic doses and immunosuppressive drugs in combination with administration of enzyme. The most substantial effects were observed in mice injected intravenously with r-hαGAL in combination with methotrexate (MTX), which significantly lowered r-hαGAL-specific serum antibody levels. A short course of treatment with MTX was able to reduce antibody and spleen cell proliferative responses to long-term r-hαGAL treatment. MTX was able to suppress the development of r-hαGAL-specific IgG in antigen-primed mice. However, MTX was not effective in dampening robust ongoing antibody responses. These experiments provide a framework for the design of clinical protocols to prevent the drug-specific antibody responses of patients undergoing enzyme replacement therapy.Keywords
This publication has 24 references indexed in Scilit:
- Significance of immune response to enzyme-replacement therapy for patients with a lysosomal storage disorderTrends in Molecular Medicine, 2003
- A survey of British rheumatologists' DMARD preferences for rheumatoid arthritisRheumatology, 2003
- Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic reviewHaemophilia, 2003
- A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry diseaseGlycobiology, 2003
- Immunologic considerations for enzyme replacement therapy in the treatment of lysosomal storage disordersClinical and Applied Immunology Reviews, 2002
- Safety and Efficacy of Recombinant Human α-Galactosidase A Replacement Therapy in Fabry's DiseaseNew England Journal of Medicine, 2001
- Fabry Disease: Preclinical Studies Demonstrate the Effectiveness of α-Galactosidase A Replacement in Enzyme-Deficient MiceAmerican Journal of Human Genetics, 2001
- Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells.JCI Insight, 1998
- Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis.Proceedings of the National Academy of Sciences, 1996
- Drug-Induced Tolerance: Selective Induction with Immunosuppressive Drugs and Their Synergistic InteractionInternational Archives of Allergy and Immunology, 1975