Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University & Veterans Affairs Medical Center, Cleveland, Ohio, USA.
JCI Insight. 2023 Jan 24;8(2):e163789. doi: 10.1172/jci.insight.163789.
BACKGROUNDAdverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODSSkin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTSCholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSIONHigh-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATIONclinicaltrials.gov (NCT02968446).FUNDINGNIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).
药物不良反应是不可预测的免疫事件，给临床管理带来了诸多挑战。全身性给予胆钙化醇（维生素 D3）具有免疫调节作用。在这项针对健康成年人的随机、双盲、安慰剂对照干预性试验中，我们研究了单次大剂量口服维生素 D3 对实验性化学性皮疹的临床和分子免疫调节作用。
28 名参与者接受了局部氮芥（NM）诱导的皮肤炎症。在接下来的一周内，通过临床测量、血清研究和皮肤组织分析来描述 NM 单独作用于个体时的炎症反应。所有参与者均接受了对侧手臂的重复 NM 暴露，然后接受安慰剂或 20 万国际单位胆钙化醇干预。在 6 周内，通过多组学分析、临床测量和血清研究来随访完整的皮疹反应。
胆钙化醇减轻了所有参与者的急性炎症，并实现了 6 周的持久反应。皮肤和血液的综合分析表明，NM 的反应严重程度存在意外差异，这与全身性中性粒细胞增多以及显著的组织病理学和临床差异相符。多组学和途径分析揭示了一个独特的、对 NM 反应过度的 3 个生物标志物特征（CCL20、CCL2、CXCL8），其被胆钙化醇抑制，并提示涉及 IL-17 信号通路的参与。
大剂量全身性胆钙化醇可能是治疗局部化疗严重反应的有效方法。我们的研究结果广泛表明，胆钙化醇作为一种抗炎干预措施，可抑制过度免疫反应的发展。
clinicaltrials.gov（NCT02968446）。
美国国立卫生研究院（NIH）和国家关节炎和肌肉骨骼及皮肤病研究所（NIAMS；授予 U01AR064144、U01AR071168、P30 AR075049、U54 AR079795 和 P30 AR039750（凯斯西储大学））。
