Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice.
A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were co-delivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.
Liu
L
L
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Liu
H
H
Mah
C
C
Fletcher
B S
BS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015153:Blotting, Western; D018106:CD28 Antigens / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy; D007165:Immunosuppression Therapy / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000276:immunology; D007275:Injections, Intravenous; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010957:Plasmids; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology*; D019895:Transposases / Q000008:administration & dosage / Q000235:genetics; D014364:Tryptophan / Q000378:metabolism
D001323:Autoantibodies; D018106:CD28 Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D005169:Factor VIII; D019895:Transposases; C494471:sleeping beauty transposase, human