Expression of Indoleamine 2,3-Dioxygenase (IDO) by Endothelial Cells: Implications for the Control of Alloresponses

Beutelspacher, S.C.; Tan, PH; McClure, Myra O.; Larkin, Frank; Ri, Lechler; George, Andrew J.T.

doi:10.1111/j.1600-6143.2006.01324.x

Cited by 85 publications

(68 citation statements)

References 48 publications

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“…Notably, IDO has been shown to be expressed at the protein level mainly by vascular endothelial cells in term placenta (Ligam et al, 2005) and in renal cell carcinoma (Riesenberg et al, 2007). Furthermore, inhibition of IDO activity is known to improve the ability of HUVEC cells to stimulate allogenic T cell responses, and HUVEC cells transfected with the IDO gene induce anergy in allospecific T cells (Beutelspacher et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

Feder-Mengus¹,

Wyler²,

Hudolin³

et al. 2008

European Journal of Cancer

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Arginase 2, inducible-and endothelial-nitric-oxide synthase (iNOS and eNOS), indoleamine 2,3-dioxygenase (IDO) and TGF-beta, might impair immune functions in prostate cancer (PCA) patients. However, their expression was not comparatively analysed in PCA and benign prostatic hyperplasia (BPH). We evaluated the expression of these genes in PCA and BPH tissues. Seventy-six patients (42 BPH, 34 PCA) were enrolled. Arginase 2, eNOS and iNOS gene expression was similar in BPH and PCA tissues. TGF-beta1 gene expression was higher in BPH than in PCA tissues (p=0.035). IDO gene expression was more frequently detectable (p=0.00007) and quantitatively higher (p=0.00001) in PCA tissues than in BPH. IDO protein, expressed in endothelial cells from both BPH and PCA, was detectable in tumour cells in PCA showing evidence of high specific gene expression. In these patients, IDO gene expression correlated with kynurenine/tryptophan ratio in sera. Thus high expression of IDO gene is specifically detectable in PCA. 1 High expression of indoleamine 2,3-dioxygenase gene in prostate cancerChantal FEDER-MENGUS 1 * and Stephen WYLER 1 * , Tvrtko HUDOLIN 2 , Robin RUSZAT 1 , Lukas BUBENDORF 3 , Alberto CHIARUGI 4 , Maria PITTELLI 4 , Walter P. Seventy-six patients, 42 BPH and 34 PCA, were enrolled. Expression of arginase 2, eNOS and iNOS genes was similar in BPH and PCA tissues. TGF-β1 gene expression was significantly higher in BPH than in PCA tissues (p=0.035). In contrast IDO gene expression was more frequently detectable in PCA as compared to BPH (p=0.00007). Its extent was also significantly higher in PCA than in BPH (p=0.00001).Immunohistochemistry revealed IDO protein in endothelial cells from both BPH and PCA. However, in PCA showing evidence of high specific gene expression, IDO was detectable in tumor cells as well. In patients bearing these tumors, IDO gene expression correlated with kynurenine/tryptophan ratio in sera.These data indicate that while genes encoding Arginase 2, iNOS, eNOS and TGF-β immunosuppressive factors are expressed in PCA and BPH, high expression of IDO gene is only detectable in PCA.

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Section: Discussionmentioning

confidence: 99%

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

Feder-Mengus¹,

Wyler²,

Hudolin³

et al. 2008

European Journal of Cancer

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“…According to this view, tryptophan degradation by IDO inhibits accumulation of specific T lymphocytes at the tumor site, likely because T cells are much more sensitive than tumor cells to tryptophan shortage or to cytotoxic effects caused by tryptophan catabolites (28). Remarkably, endothelial cells have also been reported to express IDO in response to stimulation with IFNg (46). IDO expression in antigen-presenting cells in tumor-draining lymph nodes can also contribute to immune escape (34).…”

Section: Discussionmentioning

confidence: 99%

Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ

Gasparri

Jachetti

Colombo

et al. 2008

Molecular Cancer Therapeutics

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Targeted delivery of IFN; to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFN;-NGR) in animal models is greater than that of IFN;, frequent administrations of IFN;-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFN;-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFN;-NGR. The study was carried out in immunocompetent mice and in nu/nu mice bearing RMA lymphoma, B16F melanoma, or WEHI-164 fibrosarcoma and in vitro using cultured tumor cells. IDO activity was increased in lymphoma homogenates after multiple treatments with IFN;-NGR but not after a single treatment. Coadministration of 1-methyltryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFN;-NGR and 1-methyl-tryptophan was observed in vitro in tumor cell proliferation assays or in nu/nu tumor-bearing mice, suggesting that the antitumor effect was host mediated. We conclude that IDO is critically involved in tumor resistance to repeated treatments with IFN;-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFN;-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity. [Mol Cancer Ther 2008;7(12):3859 -66]

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“…Besides interacting with donor and recipient DC, it is possible that T R cells interact with vascular endothelial cells in the kidney transplant inducing yet another pathway of bystander suppression, for example, via induction of IDO (47). This pathway of efferent suppression would not be relevant for minor Ags such as HA-1, which is generally restricted in its expression to cells of hemopoietic origin (46).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Type Determines the Mechanism of Bystander Suppression by Adaptive T Regulatory Cells Specific for the Minor Antigen HA-1

Derks

Jankowska‐Gan

et al. 2007

The Journal of Immunology

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One hallmark of acquired tolerance is bystander suppression, a process whereby Ag-specific (adaptive) T regulatory cells (TR) inhibit the T effector cell response both to specific Ag and to a colocalized third-party Ag. Using peripheral blood T cells from recipients of HLA-identical kidney transplants as responders in the trans vivo-delayed type hypersensitivity assay, we found that dendritic cells (DC), but not monocyte APCs, could mediate bystander suppression of EBV-specific recall response. When HA-1H peptide was added to mixtures of plasmacytoid DC (pDC) and T cells, bystander suppression of the response to a colocalized recall Ag occurred primarily via indolamine-2,3-dioxygenase (IDO) production. Similarly, addition of HA-1H peptide to cocultures of T cells and pDC, but not myeloid DC (mDC), induced IDO activity in vitro. When mDC presented HA-1H peptide to Ag-specific CD8+ TR, cytokine release (TGF-β, IL-10, or both) was the primary mode of bystander suppression. Bystander suppression via mDC was reversed not only by Ab to TGF-β and its receptor on T cells, but also by Ab to thrombospondin-1. EBV addition did not induce IDO or thrombospondin-1 in T-DC cocultures, suggesting that these DC products are not induced by T effector cells, but only by TR cells. These results shed light upon the mechanism of bystander suppression by donor Ag-specific TR in patients with organ transplant tolerance and underscores the distinct and critical roles of mDC and pDCs in this phenomenon.

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Expression of Indoleamine 2,3-Dioxygenase (IDO) by Endothelial Cells: Implications for the Control of Alloresponses

Cited by 85 publications

References 48 publications

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ

Dendritic Cell Type Determines the Mechanism of Bystander Suppression by Adaptive T Regulatory Cells Specific for the Minor Antigen HA-1

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