Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells

  • Yoshihiko Sakurai | ysakurai21@gmail.com Departments of Pediatrics, Nara Medical University School of Medicine, Kashihara; Department of Pediatrics, Nara Prefectural Mimuro Hospital, Sango, Japan.
  • Shogo Kasuda Legal Medicine, Nara Medical University School of Medicine, Kashihara, Japan.
  • Kohei Tatsumi Departments of Pediatrics, Nara Medical University School of Medicine, Kashihara, Japan.
  • Tomohiro Takeda Departments of Pediatrics, Nara Medical University School of Medicine, Kashihara, Japan.
  • Junko Kato Departments of Pediatrics, Nara Medical University School of Medicine, Kashihara, Japan.
  • Atsushi Kubo First Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara, Japan.
  • Midori Shima Departments of Pediatrics, Nara Medical University School of Medicine, Kashihara, Japan.

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.

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Published
2013-07-01
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Original Articles
Keywords:
hemophilia, fVIII inhibitors, prevention, embryonic stem cells, apoptosis
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How to Cite
Sakurai, Y., Kasuda, S., Tatsumi, K., Takeda, T., Kato, J., Kubo, A., & Shima, M. (2013). Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells. Hematology Reports, 5(2), e9. https://doi.org/10.4081/hr.2013.e9