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

Article Authors:Weila Wang; Michael Merchlinsky; John Inman; Basil Golding
Article Title:Identification of a novel immunodominant cytotoxic T lymphocyte epitope derived from human factor VIII in a murine model of hemophilia A.
Reference Detail
Reference ID:1017095
Abstract: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 FVIII152-159 was generated. In contrast, a CTL response to four other FVIII peptides was not detected. Therefore, FVIII152-159 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.
Affiliations:Laboratory of Plasma Derivatives, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, MD 20892, USA. wangw@cber.fda.gov
Reference Type:Literature
PubMed ID:16038719
Journal:Thromb Res
Journal Volume:116
Article Pages:335-44
Journal ISSN:0049-3848
Article Chemical List:B-domain-deleted factor VIII;Immunodominant Epitopes;Peptide Fragments;Factor VIII
Article MeSH List:Algorithms; Animals; Disease Models, Animal; Factor VIII(administration & dosage; genetics; immunology); Hemophilia A(immunology); Humans; Immunization; Immunodominant Epitopes(analysis); Mice; Peptide Fragments(administration & dosage; genetics); T-Lymphocytes, Cytotoxic(immunology); Vaccinia virus(genetics)
Curation Last Updated:2013-05-28 21:56:55