Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice

Ball, Helen J.; Sánchez-Pérez, Alicia; Weiser, Silvia; Austin, Christopher; Astelbauer, Florian; Miu, Jenny; McQuillan, James A.; Stocker, Roland; Jermiin, Lars S.; Hunt, Nicholas H.

doi:10.1016/j.gene.2007.04.010

Cited by 391 publications

(386 citation statements)

References 47 publications

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“…Although the data obtained with 1-MT and L-kynurenine clearly demonstrated that tryptophan catabolism is involved in the control of CIA progression, enzymes other than IDO could contribute to that process (22,23). In order to rule out that possibility and to ascertain the role of IDO in CIA, we performed a series of experiments in IDOdeficient (Indo Ϫ/Ϫ ) mice (24).…”

Section: Resultsmentioning

confidence: 99%

“…The recent description of another enzyme of the IDO family (IDO-L, IDO2) and the finding that the dextrorotatory form of 1-MT inhibits preferentially this new protein (22,23) have cast some doubts on results of experiments based on the pharmacologic inhibition of IDO using 1-MT. In our experiments, we used a racemic mixture of 1-MT; therefore, a contribution of IDO2 could still be possible.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

Criado

Šimelyte

Inglis

et al. 2009

Arthritis & Rheumatism

117

104

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

Criado

Šimelyte

Inglis

et al. 2009

Arthritis & Rheumatism

117

104

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“…IDO-like proteins (INDOL, IDO2) have been found in man and mouse, with highest activity in the epididymis after the kidney. 116 Although TGF-a, VEGF, IDO and cathepsin D, which act against anti-tumour immune cells in cancers, are expressed by the epididymis, immune cells persist there (see section on 'Eradication of early tumour cells'). This may reflect the absence of necessary coeffectors for attacking anti-tumour immune cells in the healthy organ.…”

Section: Escape Of Early Tumour Cells From Immunological Surveillancementioning

confidence: 99%

Why are epididymal tumours so rare?

Yeung¹,

Wang²,

Cooper³

2012

Asian J Androl

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Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro-proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general.

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“…Two related enzymes process tryptophan into kynurenine and its downstream catabolites: IDO (IDO1), expressed by cells of the immune system in an inducible manner, and tryptophan 2,3-dioxygenase (TDO), expressed in the liver and responsible for catabolizing dietary tryptophan. The role of an additional tryptophan-catabolizing enzyme, IDO2, is uncertain at this point, as there are functionally inactive polymorphisms found in approximately 50% of examined populations with limited or no correlation to tumorigenesis (11,12). However, based on the well-known role of IDO in fetal immune privilege, it is clear that IDO is important for the function of the immune system.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Koblish

Hansbury

Bowman

et al. 2010

Molecular Cancer Therapeutics

238

191

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Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose-and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489-98.

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Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice

Cited by 391 publications

References 47 publications

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

Why are epididymal tumours so rare?

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

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