Taher Yousef A, Piavaux Benoit J A, Gras Reneé, van Esch Betty C A M, Hofman Gerard A, Bloksma Nanne, Henricks Paul A J, van Oosterhout Antoon J M
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.
J Allergy Clin Immunol. 2008 Apr;121(4):983-91.e2. doi: 10.1016/j.jaci.2007.11.021. Epub 2008 Jan 7.
The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in immune suppression and tolerance induction.
We examined (1) whether IDO activity is required during tolerance induction by allergen immunotherapy or for the subsequent suppressive effects on asthma manifestations and (2) whether tryptophan depletion or generation of its downstream metabolites is involved.
Ovalbumin (OVA)-sensitized and OVA-challenged BALB/c mice that display increased airway responsiveness to methacholine, serum OVA-specific IgE levels, bronchoalveolar eosinophilia, and TH2 cytokine levels were used as a model of allergic asthma. Sensitized mice received subcutaneous optimal (1 mg) or suboptimal (100 microg) OVA immunotherapy.
Inhibition of IDO by 1-methyl-DL-tryptophan during immunotherapy, but not during inhalation challenge, partially reversed the suppressive effects of immunotherapy on airway eosinophilia and TH2 cytokine levels, whereas airway hyperresponsiveness and serum OVA-specific IgE levels remained suppressed. Administration of tryptophan during immunotherapy failed to abrogate its beneficial effects toward allergic airway inflammation. Interestingly, administration of tryptophan or its metabolites, kynurenine, 3-hydroxykynurenine, and xanthurenic acid, but not 3-hydroxyanthranilinic acid, quinolinic acid, and kynurenic acid, during suboptimal immunotherapy potentiated the reduction of eosinophilia. These effects coincided with reduced TH2 cytokine levels in bronchoalveolar lavage fluid, but no effects on IgE levels were detected.
During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding TH2-dependent allergic airway inflammation.
色氨酸分解代谢酶吲哚胺2,3-双加氧酶（IDO）与免疫抑制和耐受性诱导有关。
我们研究了（1）在变应原免疫治疗诱导耐受性期间或对随后哮喘表现的抑制作用中，IDO活性是否是必需的；（2）是否涉及色氨酸耗竭或其下游代谢产物的生成。
用对乙酰甲胆碱气道反应性增加、血清卵清蛋白特异性IgE水平、支气管肺泡嗜酸性粒细胞增多和TH2细胞因子水平升高的卵清蛋白（OVA）致敏和OVA激发的BALB/c小鼠作为变应性哮喘模型。致敏小鼠接受皮下最佳剂量（1mg）或次最佳剂量（100μg）的OVA免疫治疗。
在免疫治疗期间而非吸入激发期间用1-甲基-DL-色氨酸抑制IDO，部分逆转了免疫治疗对气道嗜酸性粒细胞增多和TH2细胞因子水平的抑制作用，而气道高反应性和血清OVA特异性IgE水平仍受到抑制。在免疫治疗期间给予色氨酸未能消除其对变应性气道炎症的有益作用。有趣的是，在次最佳免疫治疗期间给予色氨酸或其代谢产物犬尿氨酸、3-羟基犬尿氨酸和黄尿酸，但不给予3-羟基邻氨基苯甲酸、喹啉酸和犬尿酸，可增强嗜酸性粒细胞减少。这些作用与支气管肺泡灌洗液中TH2细胞因子水平降低一致，但未检测到对IgE水平的影响。
在免疫治疗期间，通过IDO产生的色氨酸代谢产物犬尿氨酸、3-羟基犬尿氨酸和黄尿酸有助于诱导对TH2依赖性变应性气道炎症的耐受性。
