Blockade of tryptophan catabolism prevents spontaneous tolerogenicity of liver allografts

Miki, Toshio; Sun, Haiguo; Lee, Y. H.; Tandin, A; Kovscek, A. M.; Субботин, Владимир; Fung, John J.; Valdivia, Luis A.

doi:10.1016/s0041-1345(00)02792-5

Cited by 58 publications

(47 citation statements)

References 7 publications

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“…Although only one of several modes of tolerance induction, the immunosuppressive pathway of tryptophan catabolism has been shown to contribute to successful pregnancy [32] and transplantation [33][34][35], as well as to effective control of autoimmunity [14,16,36]. We have proposed a model of transplantation tolerance that might apply to both transplantation and autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

et al. 2005

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DAP12 is an immunoreceptor tyrosine-based activation motif-bearing membrane adapter molecule expressed by different cell types. Although several receptors associate with DAP12 in murine dendritic cells (DC), the function of these receptors is as yet unknown. Here we report that splenic mature DC with DAP12 overexpression are characterized by an impaired tolerogenic potential. In contrast, inhibition of DAP12 function results in enhanced tolerogenesis and constitutive expression of immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO). Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression. Therefore, DAP12-related receptors act as negative regulators of IDO-mediated tolerance in vivo.

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Section: Discussionmentioning

confidence: 99%

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

et al. 2005

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“…In studies with human IDO ϩ DCs and macrophages addition of the IDO inhibitor 1-methyl-tryptophan or excess tryptophan restored T cell proliferation (9, 11) 1-methyl-tryptophan enhanced T cell responses during murine gestation or following adoptive transfer of alloreactive T cells and abrogated regulatory processes that suppressed T cell responses to tumorassociated Ags, autoantigens in EAE, and liver allografts (15,(25)(26)(27)(28). Genetic approaches complement studies using 1-methyl-tryptophan.…”

Section: Prediction 2: Ido؉ Apcs Block T Cell Clonal Expansionmentioning

confidence: 99%

Tryptophan Catabolism and Regulation of Adaptive Immunity

Mellor

Munn

2003

The Journal of Immunology

189

134

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“…26 Cells transfected or transduced to overexpress IDO acquire the ability to inhibit T-cell proliferation in vitro and to suppress T-cell responses to cell and tissue allografts in vivo. [27][28][29] On the basis of these observations, we hypothesized that co-delivery of the FVIII and IDO genes would prevent FVIII inhibitor development and may prevent the destruction of FVIII-expressing cells leading to an enhanced therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Mah

et al. 2009

Gene Ther

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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 codelivered. 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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Blockade of tryptophan catabolism prevents spontaneous tolerogenicity of liver allografts

Cited by 58 publications

References 7 publications

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

Tryptophan Catabolism and Regulation of Adaptive Immunity

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

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