Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice

Lingfei Xu, Manxue Mei, Mark E. Haskins, Timothy C. Nichols, Patricia O'Donnell, Karyn Cullen, Aaron Dillow, Dwight Bellinger, Katherine P. Ponder

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Introduction: Gene therapy could prevent bleeding in hemophilia. However, antibodies could inhibit coagulation, while cytotoxic T lymphocytes could destroy modified cells. The immaturity of the newborn immune system might prevent these immune responses from occurring after neonatal gene therapy. Materials and methods: Newborn dogs, cats, or mice were injected intravenously with a retroviral vector expressing human Factor IX. Plasma was evaluated for antigen and anti-human Factor IX antibodies. Cytotoxic T lymphocyte responses were evaluated indirectly by analysis of retroviral vector RNA in liver. Lymphocytes were evaluated for cytokine secretion and the ability to suppress an immune response to human Factor IX in mice. Results and conclusions: Hemophilia B dogs that achieved 942 ± 500 ng/ml (19% normal) or 5 ± 0.4 ng/ml (0.1% normal) of human Factor IX in plasma only bled 0 or 1.2 times per year, respectively, and were tolerant to infusion of human Factor IX. Normal cats expressed human Factor IX at 118 +/- 29 ng/ml (2% normal) in plasma without antibody formation. However, plasma human Factor IX disappeared at late times in 1 of 4 cats, which was probably due to a cytotoxic T lymphocyte response that destroyed cells with high expression. C3H mice were tolerant to human Factor IX after neonatal gene therapy, which may involve clonal deletion of human Factor IX-responsive cells. These data demonstrate that neonatal gene therapy does not induce antibodies to human Factor IX in dogs, cats, or mice. The putative cytotoxic T lymphocyte response in one cat requires further study.

Original languageEnglish
Pages (from-to)269-280
Number of pages12
JournalThrombosis Research
Volume120
Issue number2
DOIs
StatePublished - 2007

Keywords

  • Cytotoxic T lymphocytes
  • Gene therapy
  • Hemophilia B
  • Inhibitor
  • Newborn
  • Retroviral vector

Fingerprint

Dive into the research topics of 'Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice'. Together they form a unique fingerprint.

Cite this