Abstract:
:Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme alpha-l-iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human alpha-l-iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because alpha-l-iduronidase and alpha-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated alpha-l-iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.
journal_name
Proc Natl Acad Sci U S Aauthors
Kakkis E,Lester T,Yang R,Tanaka C,Anand V,Lemontt J,Peinovich M,Passage Mdoi
10.1073/pnas.0305480101keywords:
subject
Has Abstractpub_date
2004-01-20 00:00:00pages
829-34issue
3eissn
0027-8424issn
1091-6490pii
0305480101journal_volume
101pub_type
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