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Oral Delivery of Factor VIII Reduces the Magnitude of the Anti-FVIII Immune Response and Increases Splenic Treg Numbers

T. Afrin1, C. Hough1, D. Lillicrap1

1Queen's University, Kingston, Canada

Abstract Number: OC 38.2

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic

Background: Antibody (inhibitor) formation to Factor VIII (FVIII) replacement therapy is the most significant complication in patients with severe hemophilia A. Although epidemiological studies have identified risk factors for inhibitor formation, there are currently no therapeutic strategies to reduce the risk or prevent this immune response.

Aims: To evaluate whether orally delivered FVIII can reduce the immune response to intravenous FVIII replacement, via induction of immune tolerance in a hemophilia A mouse model.

Methods: Levels of inhibitors and total anti-FVIII IgG antibody levels were determined using a Bethesda and ELISA assay respectively. Immunophenotyping of Treg in spleen and MLNs tissue samples was also performed.

Figure

Results: While there was no statistically significantly difference between the two cohorts (Control vs Kogenate® ) in levels of total anti-FVIII IgG (15564 vs 10283, P =0.15 ) and inhibitors (175 vs 139,  P =0.46), 42% of mice that received oral delivery of full-length FVIII had inhibitor titers > 40 BU/mL (3/12 and 2/12 mice had inhibitors >15 BU/mL and  >40 BU/ml respectively).In contrast, 91 % of control mice (11/12) had  high titers of >40  BU/mL (109 ~ 275 BU/ml). Importantly, there was a statistically significantly increase (P = 0.045) in LAP+ CD4+CD25+FoxP3+ cells in the spleen (not in MLNs, p=0.23) of the experimental.

Conclusions: This study demonstrates that oral delivery of full-length FVIII reduces the magnitude of the anti-FVIII immune response in hemophilia A mice. Coincident with the oral administration of FVIII and the subsequent reduced anti-FVIII antibody titers, the numbers of splenic LAP+ CD4+CD25+FoxP3+ Tregs were increased. These results indicate that mucosal delivery of FVIII may still hold promise for mitigating anti-FVIII immunogenicity.  

To cite this abstract in AMA style:

Afrin T, Hough C, Lillicrap D. Oral Delivery of Factor VIII Reduces the Magnitude of the Anti-FVIII Immune Response and Increases Splenic Treg Numbers [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/oral-delivery-of-factor-viii-reduces-the-magnitude-of-the-anti-fviii-immune-response-and-increases-splenic-treg-numbers/. Accessed October 1, 2023.

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