National Liver Transplantation Unit, St. Vincent's University Hospital, Dublin, Ireland.
J Gastroenterol Hepatol. 2010 Dec;25(12):1883-90. doi: 10.1111/j.1440-1746.2010.06281.x.
Neutropenia, a major side-effect of interferon-α (IFN-α) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-α might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression.
Fifty-five patients who were receiving IFN-α/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- α or the TLR7/8 agonist, CL097.
Therapeutic IFN-α caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-α treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-α; however, co-incubation with a TLR7/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls.
Suppressed G-CSF production in the presence of IFN-α may contribute to IFN-α-induced neutropenia. However, a TLR7/8 agonist elicits G-CSF secretion even in the presence of IFN-α, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-α-induced neutropenia.
干扰素-α（IFN-α）治疗的主要副作用是中性粒细胞减少症，可通过重组粒细胞集落刺激因子（G-CSF）有效治疗，G-CSF 是中性粒细胞的重要生长因子。我们假设 IFN-α 可能通过外周血单个核细胞（PBMC）抑制 G-CSF 的产生，导致中性粒细胞减少症的发生，而 Toll 样受体（TLR）激动剂可能克服这种抑制。
招募了 55 名正在接受 IFN-α/利巴韦林联合治疗慢性丙型肝炎病毒（HCV）感染的患者。记录绝对中性粒细胞计数（ANC）、单核细胞计数和治疗结果数据。通过酶联免疫吸附试验检测分离自患者和健康对照者 PBMC 在无 IFN-α或存在 IFN-α 或 TLR7/8 激动剂 CL097 18 小时培养后的上清液中 G-CSF 水平。
治疗性 IFN-α导致所有患者的中性粒细胞计数显著下降，15 名患者需要治疗性 G-CSF。IFN-α 治疗过程中 ANC 的减少与 PBMC 产生 G-CSF 的能力下降相平行。IFN-α 存在时 PBMC 的 G-CSF 产生受到抑制；然而，TLR7/8 激动剂的共孵育显著增强了来自 HCV 患者和健康对照者的细胞中 G-CSF 的分泌。
IFN-α 存在时 G-CSF 产生受抑制可能导致 IFN-α 诱导的中性粒细胞减少症。然而，TLR7/8 激动剂即使在 IFN-α 存在的情况下也能引发 G-CSF 分泌，提示 TLR 激动剂在治疗 IFN-α 诱导的中性粒细胞减少症方面可能具有治疗作用。
