Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice.
A robust humoral immune response against human factor VIII (hFVIII) following naked DNA transfer into immunocompetent hemophilia A mice completely inhibits circulating FVIII activity despite initial high-level hFVIII gene expression. To prevent this undesirable response, we compared transient immunomodulation strategies. Eight groups of mice (n = 4-9 per group) were treated with naked DNA transfer of pBS-HCRHPI-hFVIIIA simultaneously with immunosuppressive reagents that included cyclosporine A (CSA), rapamycin (RAP), mycophenylate mofetil (MMF), a combination of CSA and MMF, a combination of RAP and MMF, a monoclonal antibody against murine CD40 ligand (MR1), recombinant murine Ctla4Ig, and a combination of MR1 and Ctla4Ig. All animals except those receiving only CSA exhibited delayed or absent immune responses against hFVIII. The most effective immunosuppressive regimen, the combination of Ctla4Ig and MR1, prevented inhibitor formation in 8 of 9 animals; the ninth had transient low-titer antibodies. All 9 mice of this group produced persistent, therapeutic levels of hFVIII for more than 6 months. When challenged with the T-dependent antigen bacteriophage Phix174, tolerized mice exhibited normal primary and secondary antibody responses, suggesting that transient immunomodulation to disrupt B/T-cell interaction at the time of plasmid injection effectively promoted long-term immune tolerance specific for hFVIII.
Miao
Carol H
CH
Children's Hospital and Regional Medical Center, Department of Pediatrics, University of Washington, Seattle, WA 98109, USA. miao@u.washington.edu
Ye
Peiqing
P
Thompson
Arthur R
AR
Rawlings
David J
DJ
Ochs
Hans D
HD
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D023201:CD40 Ligand / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004247:DNA / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019076:Transgenes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018796:Immunoconjugates; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D000069594:Abatacept; D005169:Factor VIII; D004247:DNA