- Molecular determinants of FVIII immunogenicity in hemophilia A
A. ten Brinke
- Award date
- 24 May 2013
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Replacement therapy comprising regular injections with either plasma-derived or recombinant FVIII remains the major treatment used for hemophilia patients. Unfortunately, its high cost hampers its availability for many patients. Moreover, it frequently results in development of inhibitory, anti-FVIII antibodies, rendering the therapy ineffective. Therefore, design of long-lived, less immunogenic FVIII remains the most important goal for future studies in the field of hemophilia. Here we provide insights into different receptors present on antigen-presenting cells (APCs) and their role in uptake of FVIII. Moreover, we show that the C1 domain contains a major determinant for immune recognition of FVIII by APCs. Follow up studies demonstrate that modification of an exposed loop in the C1 domain decreases endocytosis of FVIII by human and murine APCs. Based on these findings, we present novel FVIII molecule characterized by reduced immune recognition, diminished binding to the major clearance receptor - LRP, and unaffected binding to VWF. However, further studies need still to prove its use in clinical set-up. Furthermore, we show how presence of anti-FVIII antibodies modulates FVIII endocytosis and subsequent T cell responses. Collectively, this thesis describes several studies that aim to increase our understanding of the immunological mechanisms related to the development of anti-FVIII antibodies in patients with hemophilia A.
- Research conducted at: Universiteit van Amsterdam
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