Indoleamine 2,3-dioxygenase–dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model

Taher, Yousef A.; Piavaux, Benoit Jaak Alain; Gras, R.; Esch, Betty C.A.M. van; Hofman, Gerard A.; Bloksma, N.; Henricks, Paul A.J.; Oosterhout, Antoon J. M. van

doi:10.1016/j.jaci.2007.11.021

Cited by 69 publications

(81 citation statements)

References 45 publications

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“…Interestingly, we have shown previously that IDO contributes to SIT-induced tolerance induction in our model [23]. Recently, an early induction of IDO has been observed after venom SIT, suggesting a role for IDO in SIT-induced allergen tolerance in human patients [24].…”

Section: Introductionsupporting

confidence: 51%

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Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

Maazi

Shirinbak

Boef³

et al. 2013

Clinical and Experimental Immunology

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SummaryAllergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4-Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4-Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4-Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4-Ig. Co-administration of CTLA-4-Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4-Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4-Ig is independent of IDO expression. We show that CTLA-4-Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4-Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation.

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Section: Introductionsupporting

confidence: 51%

“…Airway reactivity to methacholine was evaluated by direct measurement of airway resistance in response to increasing doses of methacholine, as explained previously [23]. In brief, anaesthetized mice (by i.p.…”

Section: Measurement Of Lung Functionmentioning

confidence: 99%

Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

Maazi

Shirinbak

Boef³

et al. 2013

Clinical and Experimental Immunology

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“…This effect may be linked to active IDO induction and IL-10 production by Treg activation during physiological immunotherapy in these individuals. In contrast to allergic inflammation, specific IgE blood levels seem not to be affected by induction of the trp degradation pathway during SIT in mouse studies (47). This is similar to the situation in AA: These individuals do have considerable specific blood IgE levels against common aeroallergens (51), although the IDO pathway seems to be active during allergen exposure.…”

Section: Ido and The Ido Pathway Control Allergic Inflammationmentioning

confidence: 58%

“…Most studies have been performed in mice; however, there is good evidence that increased trp degradation occurs during systemic allergen immunotherapy (SIT) also in humans (45). IDO seems to play a role in the efficacy of allergen immunotherapy: Tolerance induction against allergens is partially mediated by IDO activation during SIT (46,47). Formation of trp metabolites rather than trp deprivation itself seems to establish tolerance toward allergens (46).…”

Section: Ido and The Ido Pathway Control Allergic Inflammationmentioning

confidence: 99%

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Bubnoff

Bieber

2012

Allergy

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A series of recent studies have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), is a critical participant in allergic inflammation. Originally known for its regulatory function during pregnancy and during chronic inflammation in tumorigenesis and infection, the activity of IDO seems to positively modify the inflammatory state of atopy or allergy. The tryptophan degradation pathway is important for tolerance induction during systemic allergen immunotherapy. Here, we focus on recent findings that establish the IDO pathway as central to allergic inflammation.The indoleamine 2,3-dioxygenase (IDO) pathway has been found to contribute substantially to the control of allergic inflammation. Traditionally recognized for its immunomodulatory role in infection, pregnancy, autoimmunity, and neoplasia, the effect of IDO on allergy appears to be a another piece of puzzle in the 'hygiene hypothesis'. Early microbial exposure and thus the stimulation of the IDO pathway by distinct Toll-like receptors (TLR) may, together with other immunoregulatory pathways, shape the predisposition to and determine the outcome of allergic inflammation, autoimmunity, and probably other diseases. Current data suggest that a normal induction of IDO activity, which decreases serum tryptophan (trp) levels and increases the levels of trp metabolites, controls the allergic inflammation. The mechanism of IDO-induced tolerance induction can probably be manifold but the induction of regulatory T cells may be a major aspect of the control function over allergic inflammation. This review summarizes the current knowledge on the IDO pathway and its role in regulating immune functions with a focus on allergic diseases.Tryptophan and its degradation pathways: indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase (TDO)As an essential amino acid, tryptophan (trp) is a constituent of proteins. Inadequate dietary intake of trp and other essential amino acids can lead to a negative nitrogen balance and to a loss of muscle mass, brain size, and weight (1). Trp is an essential starting point of two biochemical pathways: (i) the enzyme tryptophan 5-hydroxylase converts trp into 5-hydroxytryptophan, which is subsequently decarboxylized to 5-hydroxytryptamine (5-HT, serotonin), an essential neurotransmitter and vasoconstrictor, and (ii) two atoms of the molecular oxygen are inserted into L-trp to form N-formylkynurenine, the first and rate-limiting step in the kynurenine pathway (Fig. 1) (2, 3). The activation of molecular oxygen and its insertion into trp are catalyzed by three

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“…The decreased concentration of tryptophan on its own could reduce the rate of cell proliferation (9,11) and ability to synthesize pro-inflammatory cytokines (12). Alternatively, toxic byproducts of tryptophan catabolism could impact the immune cells (13)(14)(15). It is also possible that the full anti-inflammatory action of the kynurenine pathway is achieved upon synergistic action of decreased tryptophan concentration and accumulation of its catabolites (16).…”

Section: Introductionmentioning

confidence: 99%

An exploratory study of the interplay between decreased concentration of tryptophan, accumulation of kynurenines, and inflammatory arthritis

Kolodziej

2012

IUBMB Life

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Tryptophan is an essential amino acid which influences a wide range of physiological processes, including mood, cognition, and immunity. In the autoimmune diseases, such as rheumatoid arthritis (RA), the induction of tryptophan catabolism may help to diminish exacerbated immune responses. In this study, using collagen‐induced arthritis (CIA) in DBA/1 mice which is an animal model of RA, the endogenous activity of the kynurenine pathway in the immune system was monitored before and after onset of the disease. An increased rate of the initiation of tryptophan catabolism via the kynurenine pathway throughout CIA has been observed. However, decreased tryptophan concentration in the lymph nodes from pre‐arthritic mice was not enough to prevent development of CIA. In contrast, resolution of inflammation coincided with the decreased concentration of tryptophan and accumulation of its catabolites: kynurenine, anthranilic acid, and 3‐hydroxyanthranilic acid in lymph nodes but not in the spleen. In addition, the lack of the accumulation of kynurenine and its downstream metabolites in the pre‐arthritic lymph nodes coincided with increased mRNA expression for genes involved in the catabolism of kynurenine (Kynureninase, kynurenine 3‐monooxygenase, and 3‐hydroxyanthranilate 3,4 dioxygenase). However, in the lymph nodes from mice with established CIA, mRNA expression for these genes was normalized. Hence, keeping in mind an exploratory character of the results, it can be postulated that an anti‐inflammatory role of the kynurenine pathway reaches its full potential only when decreased concentration of tryptophan coincides with accumulation of kynurenines driven by metabolic regulation of gene expression on the kynurenine pathway. © 2012 IUBMB IUBMB Life, 64(12): 983–987, 2012

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Indoleamine 2,3-dioxygenase–dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model

Cited by 69 publications

References 45 publications

Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

An exploratory study of the interplay between decreased concentration of tryptophan, accumulation of kynurenines, and inflammatory arthritis

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