系统性红斑狼疮患者血清GM-CSF及其抗体的变化及意义

目的:探讨人重组粒细胞-巨噬细胞集落刺激因子(GM-CSF)和GM-CSF抗体(GM-CSF Ab)水平在系统性红斑狼疮(SLE)发病中尤其是导致血液学损害发生的可能作用机制.方法:①用酶联免疫吸附法(ELISA)测定40例SLE(SLE组,按白细胞计数又分为白细胞减少组20例,白细胞正常组20例)、11例其他结缔组织病(病例对照组)及20例健康体检者(健康对照组)血清GM-CSF和GM-CSF Ab的水平;②按SLEDAI评分将SLE组分为活动期组16例,非活动期组24例,用ELISA测定两组血清GM-CSF和GM-CSF Ab的水平;③将SLE组治疗足10个月者12例用ELISA测定血清GM-CSF和GM-CSF Ab的水平进行治疗前后配对比较.④分析SLE组血清GM-CSF及GM-CSF Ab水平与临床指标(SLEDAI评分、血白细胞计数)的相关性.结果:①白细胞减少组血清GM-CSF及GM-CSF Ab水平高于白细胞正常组、病例对照组和正常对照组(P<0.05),白细胞正常组血清GM-CSF及GM-CSF Ab水平也高于疾病对照组和正常对照组(P<0.05);②活动期组血清GM-CSF及GM-CSF Ab水平高于非活动期组(P<0.05);③12例完成治疗的SLE患者治疗后血清GM-CSF及GM-CSF Ab水平低于治疗前(P<0.05);④SLE组血清GM-CSF及GM-CSF Ab水平与SLEDAI评分呈显著正相关(P<0.01),与SLE血白细胞计数呈显著负相关(P<0.05).结论:血清GM-CSF及GM-CSF Ab水平与SLE,尤其与合并血液学损害的SLE患者疾病活动性有关,可能用来作为合并血液学损害的SLE患者的生物治疗靶点.     

系统性红斑狼疮患者血管生成因子的表达及临床意义

目的探讨血管生成因子中胎盘生长因子(PIGF)、碱性成纤维细胞生长因子(bFGF)、血管内皮生长因子(VEGF)在系统性红斑狼疮(SLE)患者外周血的表达及相互关系。方法采用ELISA法检测54例SLE患者(SLE组)及28例健康人(对照组)血清PIGF、bFGF、VEGF的水平并分析其相关性;同时常规检测血沉、SLE活动性指数(SLEDAI)评分和补体C3等。根据SLEDAI评分,将SLE患者分为活动期组和缓解期组。结果 SLE组PIGF、bFGF、VEGF水平均明显高于对照组(P<0.05);活动期组PIGF、bFGF、VEGF及缓解期组PIGF、bFGF水平均明显高于对照组(P<0.05)。活动期组PIGF、bFGF、VEGF水平与缓解期组相比无统计学差异(P>0.05)。SLE组的PIGF与VEGF、bFGF和VEGF水平均呈正相关(P<0.05),PIGF、VEGF水平与血沉、SLEDAI评分亦呈正相关。结论血清PIGF、bFGF、VEGF可能参与了SLE的发病机理。     

粒细胞-巨噬细胞集落刺激因子在呼吸道感染患儿血清中的变化

目的:检测粒细胞-巨噬细胞集落刺激因子(GM-CSF)在呼吸道感染患儿血清中的变化,为临床诊断细菌性呼吸道感染提供可靠依据.方法:采用放射免疫法检测61例呼吸道感染患儿(观察组)血清GM-CSF水平以及血清中C反应蛋白(CRP)和外周血白细胞、中性粒细胞计数的变化,并与22例正常儿童(对照组)进行比较.结果:①观察组GM-CSF平均值高于对照组,存在显著差异(P＜0.05);②观察组60例检测CRP,阳性8例,与GM-CSF相比,两者存在显著差异(P＜0.05);③观察组GM-CSF与白细胞、中性粒细胞计数比较,存在正相关(P＜0.01).结论:GM-CSF是反应细菌感染的重要指标,对指导抗生素的合理应用具有重要意义.     

系统性红斑狼疮病人血清人附睾分泌蛋白 4和抗双链 DNA抗体水平与病情活动性的相关性

目的 探讨系统性红斑狼疮(SLE)病人血清人附睾分泌蛋白4(HE4)和抗双链DNA抗体(抗dsDNA抗体)水平与病情活动性的相关性.方法 选取2017年1月至2018年12月在德阳市人民医院风湿免疫科进行诊治的74例SLE病人作为受试对象,另选取同期在该院进行体检的57例健康者作为对照组;按照SLE病情活动指数(SLEDAI)评分将74例SLE病人分为非活动期组35例(SLEDAI<10分)和活动期组39例(SLEDAI≥10分).采用酶联免疫吸附测定(ELISA)双抗体夹心法检测血清HE4、抗dsDNA抗体水平.分析SLE病人血清HE4水平与抗dsDNA抗体及病情活动性的关系,并采用受试者工作特征曲线(ROC曲线)评估血清HE4、抗dsDNA抗体水平区分非活动期及活动期SLE病人的价值.结果 SLE病人血清HE4、抗dsDNA抗体水平分别为(83.44±26.53)pmol/L、(1.53±0.49)μg/L,均明显高于对照组的(39.16±8.25)pmol/L、(0.42±0.13)μg/L(P<0.05).SLE病人抗dsDNA抗体阳性血清HE4水平显著高于抗dsDNA抗体阴性者(P<0.05).SLE活动期病人SLEDAI评分、血清HE4水平分别为(14.95±4.07)分、(95.76±29.55)pmol/L,均显著高于非活动期病人的(6.52±2.13)分、(60.34±18.12)pmol/L(P<0.05),且SLE病人血清HE4水平与抗dsDNA抗体水平、SLEDAI评分均呈正相关(P<0.05).SLE病人血清HE4水平与补体(C3、C4)水平呈负相关(P<0.05),与免疫球蛋白(IgA、IgG、IgM)、抗核抗体(ANA)滴度及24 h尿蛋白定量均呈正相关(P<0.05).ROC曲线分析表明血清HE4水平、抗dsDNA抗体水平均可区分非活动期及活动期SLE病人(P<0.05),且血清HE4水平效能优于血清抗dsDNA抗体水平.结论 SLE病人血清HE4、抗dsDNA抗体水平升高与疾病活动程度呈正相关,二者水平升高有利于区分活动期及非活动期SLE病人.     

粒细胞-巨噬细胞集落刺激因子对高氧暴露新生大鼠的影响

目的探讨粒细胞-巨噬细胞集落刺激因子(GM-CSF)对高氧引起的新生大鼠肺损伤的干预作用。方法 32只大鼠随机均分为四组:95%氧浓度+GM-CSF 9μg/kg(A)组、GM-CSF9μg/kg(B)组、95%氧浓度+生理盐水(C)组和生理盐水(D)组。7d后计算肺湿质量与干质量比(W/D),检测支气管肺泡灌洗液(BALF)中白细胞数量、单核细胞趋化蛋白1(MCP-1)及白细胞介素8(IL-8)水平,RT-PCR检测肺组织中MCP-1mRNA表达,HE染色进行肺损伤病理评分。结果与C、D组相比,A、B组肺损伤评分及W/D、BALF中白细胞和中性粒细胞计数、MCP-1及IL-8水平、MCP-1mRNA表达均明显增加(P<0.05);除MCP-1水平及其mRNA表达外,A组上述各指标与B组比较差异有统计学意义(P<0.05)。结论 GM-CSF对高氧暴露引起的新生大鼠肺损伤具有保护作用,这可能与损伤部位炎症反应受抑制有关。     

Effect of granulocyte macrophage colony-stimulating factor on hyperoxia-exposed newborn rats

目的 探讨粒细胞-巨噬细胞集落刺激因子(GM-CSF)对高氧引起的新生大鼠肺损伤的干预作用.方法 32只大鼠随机均分为四组:95％氧浓度+GM-CSF 9 μg/kg(A)组、GM-CSF9 μg/kg(B)组、95％氧浓度+生理盐水(C)组和生理盐水(D)组.7d后计算肺湿质量与干质量比(W/D),检测支气管肺泡灌洗液(BALF)中白细胞数量、单核细胞趋化蛋白1(MCP-1)及白细胞介素8(IL-8)水平,RT-PCR检测肺组织中MCP-1 mRNA表达,HE染色进行肺损伤病理评分.结果 与C、D组相比,A、B组肺损伤评分及W/D、BALF中白细胞和中性粒细胞计数、MCP-1及IL-8水平、MCP-1 mRNA表达均明显增加(P＜0.05);除MCP-1水平及其mRNA表达外,A组上述各指标与B组比较差异有统计学意义(P＜0.05).结论 GM-CSF对高氧暴露引起的新生大鼠肺损伤具有保护作用,这可能与损伤部位炎症反应受抑制有关.     

白芍总苷治疗系统性红斑狼疮合并白细胞减少症患者33例

目的:了解白芍总苷治疗合并有白细胞减少症的系统性红斑狼疮(SLE)患者的疗效及安全性.方法:选择处于活动期并有白细胞减少症的SLE患者33例为治疗组,采用1:1配比病例对照研究的方法比较两组治疗前及治疗12周后血红蛋白定量、白细胞与淋巴细胞和血小板计数、以及与SLE活动有关指标的变化.结果:治疗组用白芍总苷治疗12周后血红蛋白定量、周围血白细胞及淋巴细胞和血小板计数与对照组相比无显著差异(P均＞0.05);但平均血沉水平、血清抗ds-DNA抗体的阳性率,平均SLE疾病活动指数(SLEDAI)和每日平均应用强的松的剂量以及感染的发生率显著低于对照组;而血清补体水平显著高于对照组(P均＜0.05).两组不良反应的发生率无显著差异(P＞0.05).结论:白芍总苷用于治疗合并有白细胞减少症的SLE患者安全、有效,并且可以降低SLE患者感染的发生率.     

GM-CSF与P-选择素在充血性心力衰竭中的研究

目的检测充血性心力衰竭(CHF)患者血清粒细胞-巨噬细胞集落刺激因子(GMCSF)及P-选择素(P-sd)的水平,并探讨它们在CHF中的关系.方法CHF患者59例和年龄、性别相匹配的健康对照组19例,根据NYHA分级将CHF患者分成心功能Ⅱ、Ⅲ、Ⅳ级3组,测定血清GM-CSF及血浆P-sel水平.GM-CSF采用放射免疫法检测,P-sel用ELISA法检测.结果CHF组血清GM-CSF及血浆P-sel水平与对照组比较差异有显著意义(P＜0.01),CHF患者在心功能Ⅱ、Ⅲ、Ⅳ级各组GM-CSF、P-sel较对照组升高差异有显著意义(P＜0.01),且Ⅲ、Ⅳ级组与Ⅱ级组比较显著升高(P＜0.01),其中GM-CSF在心功能Ⅳ级组较Ⅲ级组升高有统计学意义(P＜0.05).不同病因的CHF患者之间差异无显著意义(P＞0.05).CHF患者血清GM-CSF与血浆P-sel呈显著正相关(r=0.7035,P＜0.01).结论(1)CHF患者外周血GM-CSF、、P--sel水平增高,提示它们可能参与了CHF的病理生理过程;(2)GM-CSF可能与CHF时血小板活化有关.     

系统性红斑狼疮380例外周血淋巴细胞亚群变化及临床意义

目的：探讨 T 淋巴细胞亚群、B 淋巴细胞及 NK 细胞的变化在系统性红斑狼疮(SLE)发生和发展中的作用。方法选取解放军264医院和山西医科大学第二医院诊治的 SLE 380例及健康体检者58例,SLE 患者分为稳定期组157例、轻度活动期组79例、中度活动期组82例、重度活动期组62例。检测各组外周血中 T、B 淋巴细胞、NK细胞、Th、Ts 细胞计数及百分比,并分析 SLE 患者外周血淋巴细胞亚群与 SLE 疾病活动指数(SLEDAI)的相关性。结果活动期 SLE T、Th 及 NK 细胞计数及百分比、Ts 细胞计数低于健康对照组和稳定期组,B 细胞百分比高于健康对照组和稳定期组(P <0．05)。 T、Th、Ts、NK 细胞计数、T 细胞百分比与 SLEDAI 评分呈负相关,B 细胞百分比与 SLE-DAI 评分呈正相关(r =-0.347、-0.311、-0.326、-0.351、-0.318、0.455,P <0．05)。结论外周血淋巴细胞亚群的变化可以为 SLE 患者病情评估及诊治效果提供依据。     

系统性红斑狼疮患者血清白细胞介素-15的检测及其临床意义

目的检测系统性红斑狼疮(SLE)患者血清白细胞介素(IL)-15水平,并进一步分析其临床意义。方法IL-15检测采用酶联免疫吸附试验(ELISA)方法。结果①SLE组患者血清IL-15水平显著高于正常对照组(P<0.05),活动期SLE患者血清IL-15水平显著高于缓解期患者(P<0.05)。②发生临床肾损害者IL-15水平明显高于无肾损害者(P<0.05)。③出现抗dsDNA抗体阳性、低补体C3血症、高IgG血症者血清IL-15水平均分别显著高于无上述表现者。④活动期SLE患者血清IL-15水平与抗dsDNA抗体呈正相关关系,但与系统性红斑狼疮活动性指标(SLEDAI)无相关关系。结论SLE患者血清IL-15水平显著增高,IL-15可能参与SLE的病理生理过程;IL-15可能与SLE的肾损害有关。     

Immobilisation of GM-CSF onto particulate vaccine carrier systems

Physical connection of vaccine carriers with immunostimulating cytokines may provide an interesting possibility to enhance the immune response of protective or therapeutic vaccines. As a first evaluation, various aluminium hydroxide adjuvants and poly(D,L-lactide-co-glycolide) (PLGA) microparticulates with modified positively and negatively charged surfaces were prepared to adsorb granulocyte-macrophage colony-stimulating factor (GM-CSF) under different pH conditions. Negatively charged surfaces were chosen to resemble physiological binding of GM-CSF to extracellular glycosaminoglycans, while modified positively charged surfaces may enhance GM-CSF adsorption due to electrostatic interaction. Release of GM-CSF was checked in vitro in a simulated interstitial environment. Anionic and cationic surfaces efficiently attracted GM-CSF to the carrier surface independently of the pH, while the composition of the carrier largely influenced the release of GM-CSF over time. Thus, the adsorption of GM-CSF to aluminium hydroxide adjuvants and PLGA microparticulates provides a simple and efficient possibility to physically connect the cytokine with these commonly used and potential vaccine carriers and may enable its localised delivery to the side of action.     

FIVB plus GM-CSF in metastatic colorectal cancer

The response rate of patients with metastatic colorectal cancer to the 4-drug combination [5-Fluorouracil (5-FU), dacarbazine, vincristine and bis-chloronitrosourea given 5 weekly (FIVB)] was better than the response rate to 5-FU. The dose limiting toxicity of the FIVB was myelosuppression. The present study investigates the effect of FIVB given with GM-CSF so that drug cycles could be given every 4 weeks.Thirty-five ambulatory patients with measurable metastatic colorectal cancer were treated with FIVB plus GM-CSF 4 weekly. All patients were evaluable for toxicity. Among the 163 cycles given only 4 were delayed because of leucopenia and 8 cycles were delayed because of gastrointestinal (GI) toxicity. A 50% dose reduction was given to 10 patients who had Grade 2 and 3 GI toxicity. Four of the 35 patients developed thromboembolic complications, 2 of which were lethal. Two patients were not evaluable for response as they were removed from study early because of toxicity. There were 2 complete responses and 6 partial responses. The median time to treatment failure was 3.8 months and median survival time 9.9 months.The addition of GM-CSF to FIVB decreased the expected leucopenia allowing drug treatment to be given 4 weekly to most patients. GI toxicity was dose limiting. Despite the increased dose intensity that could be delivered (to two thirds of patients), response rates were not definitely increased, no survival benefit was seen and important thromboembolic complications occurred.     

Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung disease as a major regulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a disease characterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in the patient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonary inflammation, neutrophil recruitment and release of pro-inflammatory mediators in the bronchoalveolar lavage fluid of the diseased mice. 2 h prior to LPS administration, mice were systemically treated with the murine GM-CSF neutralizing antibody mAb 22E9 per intraperitoneal injection. Intranasal challenge with LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha (TNF-alpha), keratinocyte cytokine and macrophage inflammatory protein-2 (MIP-2) were also observed at this time point. GM-CSF was no longer detectable in bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSF neutralizing antibody dose-dependently inhibited the accumulation of neutrophils and reduced TNF-alpha and MIP-2 protein levels in bronchoalveolar lavage fluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.     

粒细胞-巨噬细胞集落刺激因子在初发和复发性鼻息肉中的表达

目的研究粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulation factor,GM-CSF）在初发鼻息肉和复发鼻息肉组织中的表达,探讨其在初发鼻息肉和复发鼻息肉发病机制中的作用。方法选择初发鼻息肉组40例、复发鼻息肉组40例,正常下鼻甲黏膜对照组20例,下鼻甲黏膜组织标本来自鼻中隔偏曲伴下鼻甲肥大的患者。采用免疫组织化学方法观察GM-CSF在初发鼻息肉组和复发鼻息肉组和正常下鼻甲黏膜中的表达,比较GM-CSF在初发性和复发性鼻息肉2组间和两组组内不同性别中表达的差异性。结果 GM-CSF阳性细胞主要表达在黏膜下层及血管周围,在初发性鼻息肉和复发性鼻息肉组间比较差异有统计学意义（P〈0.05）,2组内不同性别间比较差异无统计学意义（P〉0.05）。在正常下鼻甲黏膜中无明显表达。结论 GM-CSF能够延长炎性细胞的存活时间,抑制炎性细胞的死亡,参加它们的趋化和浸润。致使大量GM-CSF向黏膜中聚集,促使局部炎症长期地存在,病变范围逐渐累及整个鼻腔以及多个和多组鼻窦,导致鼻息肉的形成和复发。     

Phase II trial of GM-CSF in advanced prostate cancer

Objectives. Prostate-specific antigen onlydisease progression following definitivetherapy is significant therapeutic dilemma. The benefit of hormonal therapy remainsunproven and is associated with significanttoxicity, more pronounced with chronic use. Biochemical progression following hormonaltherapy has no standard treatment. Newapproaches to the management of this subsetof patients are needed. A previous studyin advanced prostate cancer demonstratedbiologic activity of granulocytemacrophage-colony stimulating factor. Thepurpose of this study was to evaluate theactivity of granulocyte macrophage-colonystimulating factor in a less heavilypretreated population. Materials and methods. Sixteenpatients with advanced prostate cancer, 7hormonally naïve, and 9 androgenindependent, were treated with granulocytemacrophage-colony stimulating factoradministered subcutaneously at 250 gthree times a week for up to 6 months. Prostate-specific antigen measurements wereobtained every 2 weeks. Results. No patient achieved anobjective response. Six patientsdemonstrated a 10–15% decline in theirbaseline prostate-specific antigen whichwas maintained during the entire treatmentperiod. Five of these 6 patientsdemonstrated a rise in theirprostate-specific antigen following studycompletion. Therapy was well tolerated,with only 1 grade 3 event which was nottreatment-related. Conclusions. Granulocytemacrophage-colony stimulating factordemonstrates modest biologic evidence ofactivity in prostate cancer as manifestedby prostate-specific antigen response. Further investigation of the mechanism ofactivity and additional clinical evaluationof this agent seems warranted.     

GM-CSF与DNA疫苗研究进展

粒细胞-巨噬细胞集落刺激因子(GM-CSF)不仅促进骨髓细胞的增殖分化,还可富集免疫部位的抗原呈递细胞,增强细胞功能,激活一系列免疫活性细胞,明显增强疫苗的免疫效能.GM-CSF作为佐剂,以蛋白或编码质粒等形式被广泛应用于疫苗研究,对DNA疫苗免疫效能的影响引起广泛关注.本文综述了近年来GM-CSF用于DNA疫苗研究的进展状况.     

GM-CSF modulates pulmonary resistance to influenza A infection

Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9 × 10⁴ ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM^−/−) mice compared to GM^−/− mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO^−/− alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.     

Phase I trial of diaziquone (AZQ) plus GM-CSF

Summary Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I trial using AZQ in combination with GM-CSF to determine if the maximal tolerated dose (MTD) of AZQ could be escalated. Using GM-CSF on a standard schedule, we were unable to escalate the previously determined MTD of diaziquone with the use of this colony stimulating factor.