A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse - Androstene hormones as regulators of regulatory T cells
A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse - Androstene hormones as regulators of regulatory T cells
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DOI：
10.1196/annals.1423.066
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Offner, H.
中科院分区：
文献类型：
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作者：
Auci, D.;Kaler, L.;Offner, H.
脱氢表雄酮（DHEA）因其在抗衰老、代谢和免疫调节等方面的作用而受到广泛关注。合成衍生物，如5-雄甾烯-16 α-氟-17-酮（HE 2500）和某些天然代谢物也在各种自身免疫和代谢疾病的动物模型中提供益处。但是，像DHEA一样，低效力和低口服生物利用度表明这些化合物在人类中的有用性有限。我们假设，HE 3286，一种新的17-乙炔基衍生物将是口服生物利用度，更有效，化学上更有用的人比它的母体化合物。我们发现，在剂量/质量基础上，HE 3286在小鼠中的口服生物利用度高达25%。在胶原诱导的关节炎（CIA）的DBA小鼠模型中，从疾病发作开始接受HE 3286（50 mg/kg）经口给药的动物显著降低CIA峰值评分和关节炎每日严重程度评分。获益与以下方面的减少相关：（1）TNF-α、IL-6和IL-17的产生;和（2）通过组织学分析判断的关节炎症、糜烂和滑膜增生减少。在任何经典的试验模型中均未发现HE 3286具有免疫抑制作用，包括丝裂原诱导的增殖、迟发型超敏反应或混合淋巴细胞反应。相反，获益与CD 4 + CD 25 + FOXp 3 + CD 127-调节性T细胞（T-reg）的数量和功能增加相关。据我们所知，这可能是第一项研究报告，口服生物可利用的合成类似物DHEA可以改善CIA小鼠模型中与类风湿性关节炎（RA）相关的正在进行的疾病，并将该发现与促炎细胞因子的减少和T-reg细胞的增加相关。靶向T-reg细胞的激素具有治疗自身免疫性、感染性和肿瘤性疾病的有趣潜力。
Dehydroepiandrosterone (DHEA) has attracted much interest because of its many antiaging, metabolic and immune-modulating effects in rodents. Synthetic derivatives, such as 5-androstene-16 alpha-fluoro-17-one (HE2500) and certain natural metabolites also provide benefit in various animal models of autoimmune and metabolic diseases. But, like DHEA, low potency and low oral bioavailability suggested limited usefulness of these compounds in humans. We hypothesized that HE3286, a novel 17-ethynyl derivative would be orally bioavailable, more potent, and chemically more useful in man than its parent compound. We found that on a dose/mass basis, HE3286 demonstrated up to 25% oral bioavailability in mice. In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-alpha, IL-6, and IL-17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. HE3286 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction. Instead, benefit was associated with increases in numbers and function of CD4+CD25+FOXp3+CD127-regulatory T cells (T-reg). To our knowledge, this is probably the first study to report that an orally bioavailable synthetic analogue of DHEA can ameliorate ongoing disease in a CIA mouse model with relevance to rheumatoid arthritis (RA) and to correlate that finding with decreases in proinflammatory cytokines and increases in T-reg cells. Hormones targeting T-reg cells hold the intriguing potential to treat autoimmune, infectious, and neoplastic diseases.