Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies.
Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies.
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DOI：
10.15252/emmm.201506145
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发表时间：
2016-06
影响因子：
11.1
通讯作者：
Albert ML
中科院分区：
文献类型：
--
作者：
Decalf J;Tarbell KV;Casrouge A;Price JD;Linder G;Mottez E;Sultanik P;Mallet V;Pol S;Duffy D;Albert ML
生物化学实验、动物模型和人体观察性研究均支持二肽基肽酶4（DPP 4）在CXCL 10的N末端截短中的作用，这导致产生限制T细胞和NK细胞迁移的趋化因子拮抗剂形式。受体内调节淋巴细胞运输能力的影响，我们进行了两项前瞻性临床试验，以测试DPP 4抑制对健康供体和慢性丙型肝炎患者CXCL 10加工的影响，慢性丙型肝炎患者中发现DPP 4水平升高。受试者每天接受100 mg西格列汀（一种临床批准的DPP 4抑制剂）治疗。使用超灵敏单分子测定法（Simoa）分析血浆样本，与总CXCL 10水平相比，区分全长CXCL 101 -77和NH 2截短的CXCL 103 -77。西格列汀治疗导致CXCL 103 -77浓度显著降低，CXCL 101 -77浓度相应增加，对趋化因子总水平的影响极小。这些数据提供了第一个直接证据，即人体内DPP 4抑制可以保留CXCL 10的生物活性形式，为DPP 4抑制剂提供了新的治疗机会。
Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL101–77 from the NH 2‐truncated CXCL103–77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103–77 concentration, a reciprocal increase in CXCL101–77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors.