Inhibitory antibodies to factor Vlll develop in approximately 30% of patients with severe and moderately severe hemophilia A in response to infusions of factor Vlll. Inhibitor development is associated with a lower quality of life and an increased economic burden. Consequently, inhibitor development cunrently is considered the most significant complication of the management of in hemophilia A. Additionally, factor Vlll inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Recent developments have made it possible to ask increasingly focused questions regarding the pathogenesis of factor Vlll inhibitor development and to test novel diagnostic and therapeutic approaches to the problem. There are four Specific Aims in this project.
In Aim 1, novel immunodominant epitopes recognized by anti-factor Vlll antibodies produced in a murine hemophilia A immunogenicity model will be identified and characterized. This will be accomplished using several methods, including domain-specific antibody mapping, homolog and site-directed mutagenesis of factor Vlll, and functional analysis of anti-factor Vlll antibodies. Additionally, the pathogenicity of anti-factor Vlll antibodies will be evaluated in hemophilia A mice.
In Aim 2, mechanisms of antigen presentation during the immune response to factor Vlll in the murine hemophilia A model will be determined. Factor Vlll is an extremely potent immunogen in hemophilia A mice under conditions in which most proteins are not immunogenic. We will test the hypothesis that antigen presentation by dendritic cells and/or macrophages is more efficient in the case of factor Vlll compared with other proteins. Additionally, we will attempt to identify the underlying mechanism for this phenomenon by identifying receptors that are involved in presentation of factor Vlll. The role von Willebrand factor (VWF) plays in the immune response to factor Vlll is controversial. Our experiments will include determination of whether the immune response to factor Vlll depends on its association with VWF.
In Aim 3, the immunogenicity of factor Vlll will be decreased by antigen-specific deletion of naive and memory factor B-cells.

Public Health Relevance

Patients with hemophilia A have a deficiency in the blood coagulation protein factor Vlll. Some patients with hemophilia A develop antibodies to factor Vlll that worsens their bleeding problems and makes therapy difficult and expensive. In this project, we will develop a better understanding of how the antibodies form, which may lead to better treatment alternatives.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112309-02
Application #
8464232
Study Section
Special Emphasis Panel (ZHL1-CSR-C)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$374,911
Indirect Cost
$132,928
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Brown, Harrison C; Zakas, Philip M; George, Stephan N et al. (2018) Target-Cell-Directed Bioengineering Approaches for Gene Therapy of Hemophilia A. Mol Ther Methods Clin Dev 9:57-69
Zhang, Yun; Qiu, Yongzhi; Blanchard, Aaron T et al. (2018) Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation. Proc Natl Acad Sci U S A 115:325-330
Healey, J F; Parker, E T; Lollar, P (2018) Identification of aggregates in therapeutic formulations of recombinant full-length factor VIII products by sedimentation velocity analytical ultracentrifugation. J Thromb Haemost 16:303-315
Batsuli, G; Ito, J; Mercer, R et al. (2018) Anti-C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model. J Thromb Haemost 16:1779-1788
Qiu, Yongzhi; Ahn, Byungwook; Sakurai, Yumiko et al. (2018) Microvasculature-on-a-chip for the long-term study of endothelial barrier dysfunction and microvascular obstruction in disease. Nat Biomed Eng 2:453-463
Sakurai, Yumiko; Hardy, Elaissa T; Ahn, Byungwook et al. (2018) A microengineered vascularized bleeding model that integrates the principal components of hemostasis. Nat Commun 9:509
Brockman, Joshua M; Blanchard, Aaron T; Pui-Yan Ma, Victor et al. (2018) Mapping the 3D orientation of piconewton integrin traction forces. Nat Methods 15:115-118
Qiu, Yongzhi; Tong, Sheng; Zhang, Linlin et al. (2017) Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions. Nat Commun 8:15594
Deng, W; Wang, Y; Druzak, S A et al. (2017) A discontinuous autoinhibitory module masks the A1 domain of von Willebrand factor. J Thromb Haemost 15:1867-1877
Mannino, Robert G; Santiago-Miranda, Adriana N; Pradhan, Pallab et al. (2017) 3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro. Lab Chip 17:407-414

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