Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Clin Infect Dis. 2021 Aug 16;73(4):621-630. doi: 10.1093/cid/ciab019.
The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).
92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways.
Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways.
Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.
生长激素（GH）/胰岛素样生长因子-1（IGF-1）轴调节关键代谢途径；然而，对于增强脉冲式 GH 分泌对人类免疫功能的影响知之甚少。本研究使用蛋白质组学和基因集富集分析来评估生长激素释放激素（GHRH）类似物 tesamorelin 对人类免疫缺陷病毒（HIV）（PWH）和非酒精性脂肪性肝病（NAFLD）患者循环免疫标志物和肝组织的影响。
61 名患有 NAFLD 的 PWH 参与了一项为期 12 个月的 tesamorelin 与安慰剂的双盲、随机试验，对其血浆样本中的 92 种与免疫、趋化和代谢相关的生物标志物进行了测量。对靶向免疫途径的连续肝活检进行了基因集富集分析。
与安慰剂相比， tesamorelin 降低了与细胞毒性 T 细胞和单核细胞激活相关的相互关联蛋白。 tesamorelin 使 13 种蛋白的循环浓度显著降低，而没有蛋白增加。这些蛋白包括 4 种趋化因子（CCL3、CCL4、CCL13[MCP4]、IL8[CXCL8]）、2 种细胞因子（IL-10 和 CSF-1）和 4 种 T 细胞相关分子（CD8A、CRTAM、GZMA、ADGRG1），以及 ARG1、Gal-9 和 HGF。网络分析表明，这些蛋白的基因途径之间存在密切的相互作用，推断分析表明，密切相关的免疫激活途径簇被下调。使用肝组织进行的靶向转录组学证实了下调的免疫激活途径的器官内信号显著。
长期使用 GHRH 类似物可降低 T 细胞和单核细胞/巨噬细胞活性的标志物，表明 GH 轴的增强可能改善代谢失调、全身和器官炎症的 HIV 人群中的免疫激活。临床试验注册。NCT02196831。
