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Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Gene Therapy volume 16, pages 724–733 (2009)Cite this article

Abstract

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.

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Acknowledgements

We gratefully acknowledge funding of this work by the Judith Graham Pool Postdoctoral Research Fellowship from the National Hemophilia Foundation to LL. We also thank Dr Zhongbo Hu for technical support in isolation of PBMC and flow cytometry.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA

    L Liu & B S Fletcher

  2. Division of Pulmonary Medicine, Children's Hospital of Boston, Harvard Medical School, Harvard University, Boston, MA, USA

    H Liu

  3. Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA

    C Mah

  4. Department of Veteran Affairs Medical Center, Medical Research Service, Gainesville, FL, USA

    B S Fletcher

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Correspondence to B S Fletcher.

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Liu, L., Liu, H., Mah, C. et al. Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice. Gene Ther 16, 724–733 (2009). https://doi.org/10.1038/gt.2009.13

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