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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Suppression of the allogeneic response by the anti-allergy drug N-(3,4-dimethoxycinnamonyl) anthranilic acid results from T-cell cycle arrest
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Suppression of the allogeneic response by the anti-allergy drug N-(3,4-dimethoxycinnamonyl) anthranilic acid results from T-cell cycle arrest

机译：抗过敏药物N-（3,4-二甲氧基肉桂酸）邻氨基苯甲酸对同种异体反应的抑制是由于T细胞周期停滞

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摘要

Previously we have shown that indoleamine 2,3-dioxygenase (IDO) and the tryptophan metabolite, 3-hydroxykynurenine (3HK) can prolong corneal allograft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan by breakdown to kynurenines, which themselves act directly on T lymphocytes. The tryptophan metabolite analogue N-(3,4-dimethoxycinnamonyl) anthranilic acid (DAA, 'Tranilast') shares the anthranilic acid core with 3HK. Systemic administration of DAA to mice receiving a fully MHC-mismatched allograft of cornea or skin resulted in significant delay in rejection (median survival of controls 12 days, 13 days for cornea and skin grafts, respectively, and of treated mice 24 days (P < 0·0001) and 17 days (P < 0·03), respectively). We provide evidence that DAA-induced suppression of the allogeneic response, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T-cell death. Cell cycle arrest was mediated by up-regulation of the cell cycle-specific inhibitors p21 and p15, and associated with a significant reduction in interleukin-2 production, allowing us to characterize a novel mechanism for DAA-induced T-cell anergy. Currently licensed as an anti-allergy drug, the oral bioavailability and safe therapeutic profile of DAA make it a candidate for the prevention of rejection of transplanted cornea and other tissues.
机译：以前我们已经证明吲哚胺2，3-二加氧酶（IDO）和色氨酸代谢物3-羟基犬尿氨酸（3HK）可以延长同种异体角膜的存活。 IDO通过分解成犬尿氨酸而消耗必需氨基酸色氨酸来调节免疫反应，犬尿氨酸本身直接作用于T淋巴细胞。色氨酸代谢物类似物N-（3,4-二甲氧基肉桂基）邻氨基苯甲酸（DAA，'Tranilast'）与3HK共享邻氨基苯甲酸核心。对接受完全MHC不匹配的角膜或皮肤同种异体移植小鼠进行全身性DAA给药会导致排斥反应的明显延迟（对照组角膜移植和皮肤移植分别为12天，13天和24天（P < 0·0001）和17天（分别为P <0·03）。我们提供的证据表明，与色氨酸代谢产物诱导的相反，DAA诱导的同种异体反应抑制是细胞周期停滞而不是T细胞死亡的结果。细胞周期阻滞是由细胞周期特异性抑制剂p21和p15的上调介导的，并与白介素2产生的显着减少有关，这使我们能够表征DAA诱导的T细胞无反应性的新机制。 DAA的口服生物利用度和安全的治疗特性目前已获批准用作抗过敏药，使其成为预防移植角膜和其他组织排斥的候选药物。

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