Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy
Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy
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DOI：
10.1210/jc.2005-1220
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发表时间：
2006-02-01
影响因子：
5.8
通讯作者：
Gorden, P
中科院分区：
文献类型：
--
作者：
Oral, EA;Javor, ED;Gorden, P
内容：本研究旨在探讨瘦素在免疫调节中的作用。目的：在评价瘦素对严重脂肪代谢障碍患者代谢功能影响的研究中，我们的目的是研究淋巴细胞亚群和体外外周血单个核细胞（PBMC）活化（血清瘦素水平< 4 ng/ml）。我们在美国国立卫生研究院的临床研究中心进行了一项开放标签研究，患者作为自己的对照。十个病人（年龄范围，15-63岁; 1名男性和9名女性）患有全身形式的脂肪营养不良。干预：患者用重组人瘦素治疗，以达到正常高浓度，持续4 - 8个月。瘦素水平从1.8 +/- 0.4增加到16.5 +/- 3.9 ng/dl（P < 0.001），而代谢控制改善[糖化血红蛋白（HbA（1c））从9.3 +/-0.4%降至7.1 +/-1.4%，P < 0.001，甘油三酯从平均值1490 +/- 710 mg/dl下降45 +/- 11%，P = 0.001]。在基线和治疗4个月和8个月时通过流式细胞术研究淋巴细胞亚群。在基线和4个月时，通过用植物血凝素、植物血凝素加IL-12、脂多糖和脂多糖加干扰素-γ刺激后的细胞因子释放和增殖来评价PBMC反应性。在基线时，各种T淋巴细胞亚群显著低于年龄和性别匹配的对照组;然而，CD 4/CD 8比值正常。B淋巴细胞和单核细胞的相对百分比升高，但绝对水平正常。瘦素治疗诱导T淋巴细胞亚群的显着变化，使T淋巴细胞亚群的绝对数量和所有谱系的相对百分比均正常化。此外，在体外肿瘤坏死因子-α分泌的患者PBMC显着增加到正常后4个月的瘦素治疗baseline.Conclusion：这些数据支持现有的证据表明，瘦素有适度的免疫调节作用在hypoleptinemic人类。
Context: We conducted this study to understand the role of leptin therapy in immunomodulation.Objective: Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml).Design and Setting: We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health.Patients: Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied.Intervention: Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months.Results: Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline.Conclusion: These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.