Immune recognition and processing of blood coagulation factor VIII by antigen-presenting cells

Abstract

Hemophilia A is an X chromosome-linked bleeding disorder caused by a reduction or com­plete absence of coagulation factor VIII (FVIII). The bleeding tendency in patients suffering from hemophilia A can be treated by regular intravenous administrations of FVIII. A severe complication that occurs in approximately 30% of hemophilia A patients is the recognition of administered FVIII as “non-self” by the recipients’ immune system, leading to the formation of FVIII-neutralizing antibodies. The initial steps in the formation of these antibodies are recognition and uptake of the administered FVIII by antigen-presenting cells, which is followed by presentation of FVIII fragments to the immune system on MHC class II complexes. In this thesis the mechanism of FVIII endocytosis and presentation on MHC class II by antigen-presenting cells was investigated. The thesis describes that the uptake of FVIII by antigen-presenting cells can be inhibited by shielding or modifying certain amino acids in the C1 domain of FVIII. A FVIII variant was constructed that is less immunogenic. Administration of this FVIII variant to hemophilic mice led to significantly less antibody formation than administration of normal FVIII. Additionally, it was shown that recognition of FVIII by antigen-presenting cells leads to donor-dependent differences in the presentation of FVIII fragments on MHC class II. The results described in this thesis contribute to the development of alternative treatments for hemophilia A patients resulting in less formation of antibodies against FVIII.