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


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.


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.
Xu
Lingfei
L
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mei
Manxue
M
Haskins
Mark E
ME
Nichols
Timothy C
TC
O'donnell
Patricia
P
Cullen
Karyn
K
Dillow
Aaron
A
Bellinger
Dwight
D
Ponder
Katherine P
KP
D000818:Animals; D000831:Animals, Newborn; D002415:Cats; D016207:Cytokines / Q000096:biosynthesis; D004283:Dog Diseases / Q000097:blood / Q000235:genetics / Q000628:therapy; D004285:Dogs; D005164:Factor IX / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D002836:Hemophilia B / Q000097:blood / Q000235:genetics / Q000628:therapy / Q000662:veterinary; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D016207:Cytokines; D011994:Recombinant Proteins; D005164:Factor IX