Scientific Publications by FDA Staff

Thromb Res 2005;116(4):335-44

Identification of a novel immunodominant cytotoxic T lymphocyte epitope derived from human factor VIII in a murine model of hemophilia A.

Wang W, Merchlinsky M, Inman J, Golding B

Wang WL, US FDA, Lab Plasma Derivat, Div Hematol, Off Blood Res & Review,Ctr Biol Evaluat & Res, 29 Lincoln Dr, Bethesda, MD 20892 USA US FDA, Lab Plasma Derivat, Div Hematol, Off Blood Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA US FDA, Div Viral Prod, Off Vaccine Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20892 USA NIAID, Bethesda, MD 20892 USA

Gene therapy of hemophilia A could be complicated by the development of immune responses against the vector as well as the Factor VIII (FVIII) transgene. Previous efforts have been focused on identifying FVIII inhibitor antibody epitopes, whereas the cytotoxic T lymphocyte (CTL) epitopes have not been characterized. CTL would kill cells expressing such epitopes and thus limit the efficacy of gene therapy. To investigate CTL responses against human FVIII in a mouse model of hemophilia A, a computer algorithm program (BIMAS) was employed to predict CTL epitopes of human FVIII. The potential binding of these predicted peptides to MHC class I K(b) was evaluated in a TAP-deficient cell line. When recombinant vaccinia virus expressing B domain-deleted human FVIII (vv-FVIII) was used to immunize E16 hemophilia A mice, a specific CTL response against FVIII(152-159) was generated. In contrast, a CTL response to four other FVIII peptides was not detected. Therefore, FVIII(152-159) represents a dominant CTL epitope. Identification of this epitope raises the possibility that CTL response to FVIII gene-transduced cells can be diminished by deliberatively mutating the dominant CTL epitope while retaining the biologic function of FVIII for hemophilia A gene therapy.