Novel Action of Indoleamine 2,3-Dioxygenase Attenuating Acute Lung Allograft Injury

Liu, Hanzhong; Liu, Li; Fletcher, Bradley S.; Visner, Gary

doi:10.1164/rccm.200509-1413oc

Cited by 85 publications

(114 citation statements)

References 33 publications

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“…3,30 To verify co-gene delivery of FVIII and IDO can effectively express both proteins in vivo, hemophilia mice received a hydrodynamic injection containing equal amounts of the transposons pMSZ-CMV-FVIII and pMSZ-CMV-IDO (100 mg each), and 20 mg of transposase plasmid. Animals were killed 3 days or 4 weeks after gene delivery and transgene expression from liver tissue was analyzed by western blotting.…”

Section: Co-expression Of Fviii and Ido In Vivomentioning

confidence: 99%

“…3,30 The hyperactive transposase expression plasmid (pCMV-HSB16) was used in these studies. 45 The ability of these plasmids to express biologically active protein was confirmed in vitro before the animal studies.…”

Section: Vector Constructionmentioning

confidence: 99%

“…At 3 days and 4 weeks after gene delivery, three mice in each group were euthanized to obtain liver tissue that was analyzed by western blotting to detect IDO and FVIII expression as described previously. 3,30 FVIII activity assay, Bethesda titers and kynurenine concentrations Detection of biologically active human FVIII in tissue culture supernatants and mouse plasma was measured using the chromogenic Coatest from diaPharma (West Chester, OH, USA) according to our previous publications. 3 Anti-human FVIII inhibitory antibodies were measured using the Bethesda assay.…”

Section: In Vivo Gene Delivery and Western Blottingmentioning

confidence: 99%

“…For samples with high Bethesda titers (44 BU), serial dilutions of the plasma in assay buffer were used to better fit the standard curve. Plasma kynurenine concentrations were determined at the indicated time points according to the methods described previously 30 using purified L-kynurenine (0-1000 mM) as a standard.…”

Section: In Vivo Gene Delivery and Western Blottingmentioning

confidence: 99%

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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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Section: Co-expression Of Fviii and Ido In Vivomentioning

confidence: 99%

Section: Vector Constructionmentioning

confidence: 99%

Section: In Vivo Gene Delivery and Western Blottingmentioning

confidence: 99%

Section: In Vivo Gene Delivery and Western Blottingmentioning

confidence: 99%

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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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“…They have also found that tryptophan catabolism prevents T cell-driven complement activation and inflammation during pregnancy (11), suggesting that IDO plays a key role in placenta immune privilege. IDOexpressing dendritic cells suppress allogeneic T cell proliferation in vitro by tryptophan metabolites (7) and IDO action attenuates allograft injury or rejection (12)(13)(14). Tryptophan catabolism also induces regulatory cells and is a means by which CTLA-4 signaling functions in vivo (15)(16)(17) while inhibiting IDO restores antitumor immunity (18).…”

Section: Suppression Of Memory Cd8 T Cell Generation Andmentioning

confidence: 99%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

Dai

et al. 2007

The Journal of Immunology

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Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.

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High expression of IMPACT protein promotes resistance to indoleamine 2,3‐dioxygenase‐induced cell death

Habibi

Jalili

Forouzandeh

et al. 2010

Journal Cellular Physiology

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. IDO expression in fibroblasts selectively induces apoptosis in immune cells but not in primary skin cells. However, the mechanism(s) of this selective effect of IDO-induced low tryptophan environment is not elucidated. The aim of present study was to investigate whether the activity of general control non-derepressible-2(GCN2) kinase stress-responsive pathway and its known inhibitor, protein IMPACT homolog, in immune and skin cells are differentially regulated in response to IDO-induced low tryptophan environment. IDO-expressing human fibroblasts were co-cultured with Jurkat cells, human T cells, fibroblasts, or keratinocytes. Activation of GCN2 pathway was significantly higher in immune cells exposed to IDO-expressing environment relative to that of skin cells. In contrast, IMPACT was highly and constitutively expressed in skin cells while its expression was very low in stimulated T cells and undetectable in Jurkat cells. A significant IDO-induced suppressive as well as apoptotic effect was demonstrated in IMPACT knocked down fibroblasts co-cultured with IDO-expressing fibroblasts. Proliferation of Jurkat cells, stably transduced with IMPACT-expressing vector, was rescued significantly in tryptophan-deficient but not IDO-expressing environment. This may be due to the ability of IMPACT to recover the effects of IDO-mediated tryptophan depletion (GCN2 dependent) but not the effects of IDO-generated cytotoxic metabolites. These findings collectively suggest for the first time that high expression of protein IMPACT homolog in non-immune cells such as skin cells acts as a protective mechanism against IDO-induced GCN2 activation, therefore, makes them resistant to the amino acid-deprived environment caused by IDO.

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Novel Action of Indoleamine 2,3-Dioxygenase Attenuating Acute Lung Allograft Injury

Abstract: These results demonstrate that IDO prevents acute lung allograft injury through augmenting the local antioxidant defense system and inhibiting alloreactive T-cell responses.

Cited by 85 publications

References 33 publications

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

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

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

High expression of IMPACT protein promotes resistance to indoleamine 2,3‐dioxygenase‐induced cell death

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