Therapeutic benefit of pentostatin in severe IL-10-/- colitis.
Therapeutic benefit of pentostatin in severe IL-10-/- colitis.
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DOI：
10.1002/ibd.20410
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发表时间：
2008-07
影响因子：
4.9
通讯作者：
Barrett, Terrence A.
中科院分区：
文献类型：
--
作者：
Brown, Jeffrey B.;Lee, Goo;Grimm, Gery R.;Barrett, Terrence A.
关键词：
Pentostatin是一种腺苷脱氨酶（ADA）抑制剂，是一种用于治疗白血病的嘌呤类抗代谢药。ADA抑制减弱增殖淋巴细胞的扩增，并增加腺苷释放，腺苷是一种有效的抗炎分子。人类炎症性肠病（IBD）是由效应T细胞（Teff）的扩增驱动的，效应T细胞（Teff）压倒调节性T细胞（Treg）并传播先天性免疫应答。在这里，我们研究了ADA抑制对损害Teff细胞扩增和减少IL-10缺陷（IL-10−/−）小鼠中炎性细胞因子释放的治疗益处。通过给予吡罗昔康两周，在IL-10−/−小鼠中诱导结肠炎。每天用喷司他丁或磷酸盐缓冲盐水处理小鼠1周，并检查对组织炎症、淋巴细胞数量和细胞因子产生的影响。喷妥他汀使炎症减少>50%并且使血清淀粉样蛋白A水平几乎正常化。结肠和肠系膜淋巴结（MLN）中的淋巴细胞扩增（分别为3.5倍和>5倍）下降>50- 90%。结肠和MLN中的促炎因子（IL-1β、IFN-γ、IL-6、CXCL 10、TNF）下降，而FoxP 3和TGF-β不变。在体外（36小时）或体内（3小时）激活后，来自喷司他丁处理的小鼠的等量T细胞的细胞因子产生减少，表明喷司他丁独立于淋巴细胞耗竭的抗炎作用有助于其治疗益处。粘膜淋巴细胞亚群分析表明喷司他丁减少效应CD 4 + CD 69 + T细胞的数量，而保留CD 4 + CD 62 L + T细胞。避免严重淋巴细胞耗竭的喷妥他汀剂量通过损害Teff细胞扩增和减少促炎细胞因子产生同时保留调节性Treg群体和功能来有效治疗结肠炎。
Pentostatin, an adenosine deaminase (ADA) inhibitor, is a purine antimetabolite used for the treatment of leukemias. ADA inhibition blunts expansion of proliferating lymphocytes and increases adenosine release, a potent anti-inflammatory molecule. Human inflammatory bowel disease (IBD) is driven by expansion of effector T cells (Teff) that overwhelm reulatory T cells (Treg) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair Teff cell expansion and reduce inflammatory cytokine release in IL-10-deficient (IL-10−/−) mice. Colitis was induced in IL-10−/− mice by administering piroxicam for two weeks. Mice were treated with daily pentostatin or phosphate-buffered saline for 1 week and effects on tissue inflammation, lymphocyte numbers and cytokine production examined. Pentostatin reduced inflammation by >50% and nearly normalized serum amyloid A levels. Lymphocyte expansions in the colon and mesenteric lymph node (MLN) (3.5-fold and >5-fold respectively) dropped by >50–90%. Pro-inflammatory factors in the colon and MLN (IL-1β, IFN-γ, IL-6, CXCL10, TNF) dropped whereas FoxP3 and TGF-β were unchanged. Reductions in cytokine production from equivalent numbers of T cells from pentostatin-treated mice after in vitro (36h) or in vivo (3h) activation suggested anti-inflammatory effects of pentostatin independent of lymphodepletion contributed to its therapeutic benefit. Analysis of mucosal lymphocyte subsets suggested pentostatin reduced numbers of effector CD4+ CD69+ T cells, while sparing CD4+ CD62L+ T cells. Pentostatin dosages that avoid severe lymphocyte depletion effectively treat colitis by impairing Teff cell expansion and reducing pro-inflammatory cytokine production while preserving regulatory Treg populations and function.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
2.8
作者：
Köse, K;Yazici, C;Asçioglu, Ö
通讯作者：
Asçioglu, Ö
DOI：
10.1016/s0090-1229(95)90288-0
发表时间：
1995-09-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
HIRSCHHORN, R
通讯作者：
HIRSCHHORN, R
影响因子：
15.9
作者：
Fuss, IJ;Heller, F;Strober, W
通讯作者：
Strober, W
影响因子：
3.4
作者：
Hitoglou, S;Hatzistilianou, M;Catriu, D
通讯作者：
Catriu, D