title: CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice.
abstract: Today it is generally accepted that B cells require cognate interactions with CD4(+) T cells to develop high-affinity antibodies against proteins. CD4(+) T cells recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4(+) T cells that can bind to the MHC class II-peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4(+) T-cell epitopes presented by HLA-DRB1*1501 to CD4(+) T cells during immune responses against FVIII. CD4(+) T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays.
authors.affiliation: Baxter BioScience, Industriestrasse 72, Vienna, Austria.
authors.forename: Katharina N
authors.initials: KN
authors.lastname: Steinitz
authors.forename: Pauline M
authors.initials: PM
authors.lastname: van Helden
authors.forename: Brigitte
authors.initials: B
authors.lastname: Binder
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
authors.forename: Sabine
authors.initials: S
authors.lastname: Unterthurner
authors.forename: Corinna
authors.initials: C
authors.lastname: Hermann
authors.forename: Maria
authors.initials: M
authors.lastname: Schuster
authors.forename: Rafi U
authors.initials: RU
authors.lastname: Ahmad
authors.forename: Markus
authors.initials: M
authors.lastname: Weiller
authors.forename: Christian
authors.initials: C
authors.lastname: Lubich
authors.forename: Maurus
authors.initials: M
authors.lastname: de la Rosa
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005169:Factor VIII / Q000008:administration & dosage* / Q000276:immunology*; D059811:HLA-DRB1 Chains / Q000276:immunology* / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006467:Hemophilia A / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; D011994:Recombinant Proteins; D005169:Factor VIII