title: Suppression of the immune response to FVIII in hemophilia A mice by transgene modified tolerogenic dendritic cells.
abstract: Current methods for eradicating clinically significant inhibitory antibodies to human factor VIII (hFVIII) in patients with hemophilia A rely on repeated delivery of high doses of factor concentrates for a minimum of many months. We hypothesize that tolerance can be induced more efficiently and reliably through hFVIII antigen presentation by tolerogenic dendritic cells (tDCs). In this study, we generated tDCs from hemophilia A mice and modified them with a foamy virus vector expressing a bioengineered hFVIII transgene. Naive and preimmunized mice infused with hFVIII expressing tDCs showed suppression of the T cell and inhibitor responses to recombinant hFVIII (rhFVIII). Treatment with hFVIII expressing tDCs was also associated with a higher percentage of splenocytes demonstrating a regulatory T cell phenotype in immunized mice. Furthermore, CD4(+) T cells harvested from recipients of hFVIII expression vector-modified tDCs were able to mediate antigen-specific immune suppression in naive secondary recipients. We also demonstrated a trend for improved suppression of inhibitor formation by coexpressing interleukin-10 (IL-10) and hFVIII from a bicistronic vector. These preclinical results demonstrate the potential for employing vector modified ex vivo generated tDCs to treat high titer inhibitors in patients with hemophilia A.
authors.affiliation: Puget Sound Blood Center, Seattle, Washington 98104-1256, USA.
authors.forename: Rui-Jun
authors.initials: RJ
authors.lastname: Su
authors.forename: Angela
authors.initials: A
authors.lastname: Epp
authors.forename: Junli
authors.initials: J
authors.lastname: Feng
authors.forename: Jackie
authors.initials: J
authors.lastname: Roy
authors.forename: Yvette
authors.initials: Y
authors.lastname: Latchman
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.forename: Doug
authors.initials: D
authors.lastname: Bolgiano
authors.forename: Neil C
authors.initials: NC
authors.lastname: Josephson
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology; D006467:Hemophilia A / Q000276:immunology*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019076:Transgenes
chemical_list: D005169:Factor VIII