Ⅰ型干扰素与细菌感染

干扰素( IFN)是免疫反应中重要的细胞因子.根据IFN作用受体的不同,IFN通常分为Ⅰ型IFN(主要包括IFN-α、IFN-β)和Ⅱ型IFN(IFN-γ),Ⅰ型IFN主要通过IFN受体A(IFNAR)介导机体抗病毒反应.近年研究表明,Ⅰ型IFN在机体抗细菌感染中也起着重要作用.文中着重对Ⅰ型IFN信号通路介导的宿主免疫在利斯特菌、链球菌、结核杆菌、炭疽芽孢杆菌、军团菌、铜绿假单胞菌等细菌感染中的作用作一综述.     

α-干扰素中和抗体对慢性乙肝患者干扰素抗病毒疗效的影响

目的 研究慢性乙型肝炎患者α-干扰素(IFN-α)中和抗体(NA)产生的情况,并探讨其对IFN抗病毒疗效的影响.方法 采用抗病毒中和生物测定法检测了48例慢性乙型肝炎患者IFN-α治疗前、治疗后3-6个月血清中NA产生的情况;同时,也检测了10名健康人血清中NA.结果 慢性乙型肝炎患者IFN-α治疗前和健康人血清中均无NA产生.48例患者IFN-α治疗6个月后,完全应答有15例,部分应答23例,无应答10例;IFN-α治疗后3个月和6个月时血清中NA阳转率分别为25%和37.5%(P>0.05).治疗后3个月时完全应答组和部分应答组NA阳转率均显著高于无应答组;同时,治疗后6个月时完全应答组NA阳转率较无应答组也显著升高.结论 IFN-α治疗后机体可产生NA;NA的产生可影响IFN-α抗病毒疗效,尤其是IFN-α治疗后早期(3个月)即产生了NA.     

TNF-Based Isolated Limb Perfusion Followed by Consolidation Biotherapy with Systemic Low-dose Interferon Alpha 2b in Patients with In-transit Melanoma Metastases: A Pilot Trial

BACKGROUND: Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP. METHODS: A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B). RESULTS: In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP. CONCLUSIONS: These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.     

IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C

Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behaviour. Previous studies suggest that altered basal ganglia function may contribute to IFN-alpha-induced neuropsychological and behavioural changes. To further examine IFN-alpha effects on neuropsychological functions related to basal ganglia (as well as other brain regions), and explore the relationship between altered neuropsychological function and IFN-alpha-induced depression and fatigue, a selected subset of the Cambridge Neuropsychological Test Automated Battery was administered to 32 hepatitis C patients at baseline (Visit 1) and following 12 weeks (Visit 2) of either no treatment (n = 12) or treatment with IFN-alpha plus ribavirin (n = 20). Symptoms of depression and fatigue were assessed using the Montgomery-Asberg Depression Rating Scale and the Multidimensional Fatigue Inventory. Compared to control subjects, patients treated with IFN-alpha/ribavirin exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task and slower response times in the rapid visual information processing task, a task of sustained attention. Decreased motor speed on the five-choice movement segments of the reaction time task was in turn correlated with increased symptoms of depression and fatigue (R = 0.47, p < 0.05 and R = 0.48, p < 0.05, respectively). IFN-alpha/ribavirin treatment had no effects on executive function, decision time in the reaction time task, or target detection accuracy in the sustained attention task. Motor slowing and its correlation with psychiatric symptoms suggest that altered basal ganglia function may contribute to the pathogenesis of IFN-alpha-induced behavioural changes.     

IFN-α: A key therapeutic target for multiple autoimmune rheumatic diseases

Interferon (IFN)-α has emerged as a major therapeutic target for several autoimmune rheumatic diseases. In this review, we focus on clinical and preclinical advances in anti-IFN-α treatments in systemic lupus erythematosus (SLE), primary Sjögren syndrome (pSS), systemic sclerosis (SSc), and dermatomyositis (DM), for which a high medical need persists. Promising achievements were obtained following direct IFN-α neutralization, targeting its production through the cytosolic nucleic acid sensor pathways or by blocking its downstream effects through the type I IFN receptor. We further focus on molecular profiling and data integration approaches as crucial steps to select patients most likely to benefit from anti-IFN-α therapies within a precision medicine approach.     

肝素对肝纤维化大鼠模型作用的疗效观察

目的建立肝纤维化大鼠模型,对肝素、干扰素和复方丹参的抗肝纤维的疗效进行评价。方法应用CCl4建立肝纤维化大鼠模型,分别给予不同剂量的肝素、干扰素和丹参进行抗肝纤维化干预治疗。8周后处死大鼠,留取血清检测HA、IV-C、LN、PCⅢ等,留取肝组织,行HE和Massson三色染色。结果肝素治疗组、复方丹参治疗组的各项血清学指标水平与肝纤维化大鼠造模组相比均有显著性差异。α干扰素治疗组与肝纤维化大鼠造模组相比,HA和PCⅢ水平有显著性下降,ⅣC、LN水平无显著性差异。肝素治疗组的HA、ⅣC、LN、PCⅢ水平均较复方丹参治疗组、α干扰素治疗组为低。胶原纤维染色显示,肝素可明显抑制肝纤维化的发展,作用效果优于干扰素和复方丹参。结论肝素、α干扰素、丹参具有抗肝纤维化作用,但以肝素的作用效果为最强。     

Interferon-alpha-2 in the treatment of idiopathic myelofibrosis

Summary We investigated the effect of human recombinant DNA-derived IFN-alpha-2 given in a dose of 1–2×10⁶ units daily by subcutaneous injection to five patients with advanced idiopathic myelofibrosis (IM). Transfusion dependent anemia and symptomatic splenomegaly were taken as inclusion criteria for this pilot study. Two patients succumbed, one and three months after starting interferon-treatment because of pneumonia and traumatic cranial injury, respectively. While on IFN-treatment no improvement of cytopenia or reduction of splenomegaly was seen in four of the patients. In one patient, however, the requirement for erythrocyte transfusions decreased from 5 to 1.7 monthly upon IFN-treatment. After two, four and six months respectively IFN-treatment had to be stopped in these cases because of progressive thrombocytopenia and/or neutropenia. These observations suggest, that IFN-alpha might be of only marginal value in the treatment of advanced idiopathic myelofibrosis.Abbreviations IM idiopathic myelofibrosis - IFN interferon - rIFN recombinant interferon-alpha-2 - PDGF platelet derived growth factor     

难治性慢性丙型肝炎强化治疗疗效研究

目的探讨难治性慢性丙型肝炎强化治疗疗效,通过优化治疗剂量和疗程来提高慢性丙型肝炎患者对干扰素联合利巴韦林治疗的持续病毒应答率。方法对常规治疗的干扰素剂量（聚乙二醇干扰素α每周皮下注射1次）和利巴韦林（每天10．5mg／kg）经治的无应答和部分患者,根据患者的意愿进行标准干扰素α10 MU隔日注射1次或聚乙二醇干扰素α-2a（PEG—IFN α-2a）360μg每周注射1次,并根据体重每天给予15mg／kg的利巴韦林的强化剂量治疗,在治疗的0、4、12周和以后的每间隔12周、治疗结束后的24周进行HCV RNA含量检测,根据患者治疗过程中的病毒应答情况给予72～96周的疗程,以持续病毒应答（sustained viral response,SVR）作为疗效的评判指标。结果18例患者完成全程治疗和观察,12例获得持续病毒学应答,5例治疗无效,1例复发。3例患者获得RVR,RVR获得者的cEVR和SVR均为3／3,RVR组治疗前的病毒载量显著低于未获得RVR组（t=4．687,P〈0．001）。15例无快速病毒应答者,8例获得完全早期病毒应答,9例获得SVR。聚乙二醇干扰素α-2a 360μg每周注射1次的SVR为4／5。11例获得cEVR患者均获得SVR,7例无cEVR的患者,仅1例获得SVR。结论强化剂量的干扰素和RBV可以使较高比例的既往规范抗病毒治疗无应答、部分应答获得SVR。在强化治疗过程中根据病毒的应答情况及时调整和延长HCV RNA阴性的疗程是提高难治性慢性丙型肝炎持续病毒应答率的重要措施。     

双抗体夹心ELISA定量检测重组人干扰素α1b方法的建立与评价

目的 建立双抗体夹心ELISA法定量检测重组人干扰素α1b的方法.方法 筛选具有不同抗原结合位点的抗重组人干扰素α1b单克隆抗体,分别作为包被抗体和辣根过氧化酶标记抗体,建立双抗体夹心ELISA法定量检测不同批次重组人干扰素α1b含量,评价该法的检出限、精确度、重复性、特异性.结果 所建立的ELISA最低检出限为10 ng/ml,检测线性范围10～100 ng/ml,R2 =0.992,测定值与实际值偏差＞5％,板间变异系数均小于10％.结论 该方法灵敏度高,特异性强,准确性和重复性好,可用于重组人干扰素α1b成品的定量检测.     

慢性乙型肝炎患者聚乙二醇α干扰素与α干扰素治疗中应用利可君的临床研究

目的 探讨聚乙二醇α干扰素和α干扰素治疗慢乙肝患者期间应用利可君是否可降低外周血细胞下降的不良反应,提高干扰素的抗病毒疗效.方法 2002年1月至2010年2月住院的395例经干扰素治疗的e抗原阳性的慢乙肝患者,分组:A组:干扰素治疗过程中加用利可君的患者,B组:干扰素治疗中未用利可君的患者.结果 (1)中性粒细胞数下降＜1×109/L的全组患者有35.9％,其中A组29.6％,B组42.8％,P=0.01;≤0.75 × 109/L A组12.6％,B组26.4％,P=0.02;≤0.5 ×109/LA组4.8％,B组16.4％,P=0.04.(2)A组中8.2％治疗过程干扰素减量,所有患者完成治疗,B组为23.3％干扰素减量,2.1％中途停药.另外A组中40.3％干扰素加量超过常规剂量,B组中仅5.2％.(3)血小板减少＜ 100×109/LA组8.7％的患者,B组11.1％;≤80×109/LA组有5.3％,B组7.9％;≤50×109/L A组有1.0％,B组2.6％,A组有减少血小板下降的趋势.(4)在治疗结束时,A组HBVDNA＜ 100IU/ml的患者为67.4％,e抗原转阴率为54.3％,e抗原血清学转换率为40.7％;B组分别为53.9％,41.2％,26.9％,两组比较P值分别为0.02、0.01、0.01.结论 慢性乙型肝炎患者在用干扰素抗病毒治疗期间加用利可君可防治以中性粒细胞数下降为表现的外周血细胞下降的不良反应,有减少血小板下降的趋势,进而可提高患者抗病毒的疗效.