title: Repression of Factor VIII Inhibitor Development with Apoptotic Factor VIII-expressing Embryonic Stem Cells.
abstract: Development of factor VIII (fVIII)-neutralizing antibodies, called inhibitors, is a challenging problem in the management of hemophilia A patients. We explored the possibility of pretreatment with apoptotic fVIII-expressing embryonic stem (ES) cells to prevent the development of fVIII inhibitors. Murine ES cells integrated with the human F8 gene were differentiated into embryoid bodies, dissociated to a single cell suspension, subjected to hypo-osmotic shock to induce apoptosis, and intraperitoneally injected into hemophilia A mice. Inhibitors were induced by periodic intraperitoneal injections of recombinant human fVIII (rhfVIII). In the groups in which intraperitoneal injections of rhfVIII began at 1-3 weeks after pretreatment, the titers of inhibitors were significantly lower after the third administration of rhfVIII compared with that in the control group in which apoptotic Ainv18 ES cells (without the human F8 gene) were used for pretreatment, and continued to show lower levels until the sixth administration of rhfVIII. These results suggest that pretreatment with apoptotic hfVIII-expressing ES cells might be promising for the prevention of fVIII inhibitor development in hemophilia A patients.
authors.affiliation: Departments of Pediatrics, Nara Medical University School of Medicine , Kashihara ; Department of Pediatrics, Nara Prefectural Mimuro Hospital, Sango.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Shogo
authors.initials: S
authors.lastname: Kasuda
authors.forename: Kohei
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Junko
authors.initials: J
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kubo
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
keywords: apoptosis; embryonic stem cells; fVIII inhibitors; hemophilia; prevention