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.
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