Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain

Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve to...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2006-10, Vol.4 (10), p.2172-2179
Main Authors: RAWLE, F. E., PRATT, K. P., LABELLE, A., WEINER, H. L., HOUGH, C., LILLICRAP, D.
Format: Article
Language:English
Subjects:
Administration, Intranasal
Animals
CD4-Positive T-Lymphocytes - metabolism
Cytokines - metabolism
Enzyme-Linked Immunosorbent Assay
factor VIII
Factor VIII - chemistry
Factor VIII - genetics
Factor VIII - metabolism
Factor VIII - therapeutic use
Female
hemophilia
Hemophilia A - blood
Hemophilia A - genetics
Immune Tolerance
inhibitors
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mucous Membrane - metabolism
Mucous Membrane - pathology
oral tolerance
Protein Structure, Tertiary
Spleen - cytology
Time Factors
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Summary:Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII. Methods: We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII‐C2) to FVIII‐deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII‐C2, followed by a subcutaneous challenge of either FVIII‐C2 or FVIII. The development of anti‐FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed. Results and Conclusions: Mucosal administration of FVIII‐C2 decreases the titer of anti‐FVIII‐C2 inhibitors after FVIII‐C2 challenge, and decreases the percentage of FVIII‐C2 specific antibodies after challenge with full‐length FVIII. Tolerance induction to FVIII‐C2 is associated with increased IL‐10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII‐C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII‐specific mucosal tolerance induction as an immunotherapy treatment for anti‐FVIII inhibitor development warrants further investigation.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2006.02118.x