头孢克洛独特的免疫学特性.ppt

头孢克洛独特的免疫学特性,抗生素参与机体免疫反应,间接效应 直接效应,间接效应,杀死细菌 改变肠道菌群,抗原性 防止细菌毒素效应,直接效应,激活宿主防御机制(多形核白细胞) 激活巨噬细胞－吞噬细胞伸出伪足包围细菌并吞入 激活调理作用－激活补体系统，使细菌易被吞噬并抑制细菌酶或毒素产生 激活趋化作用－使白细胞向细菌移动,影响生物学效应的抗菌药,对宿主防御系统无活性 （一般的β内酰胺类抗生素） 抑制免疫功能 （四环素类） 与免疫系统协同作用 （大环内酯类、喹诺酮类） 增强免疫功能 （某些头孢烯β内酰胺类）,影响体外免疫反应的抗菌药,增强吞噬细胞功能的β内酰胺类,文献报道,希刻劳当体外试验敏感，临床和细菌学的疗效为95% 当体外药敏耐药，临床疗效为84%。,Leuenberger P,Vrantchev S,Cefactor versus amoxicillin in the treatment of bacterial pneumonia:a comparative double-blind study. Eur J Clin Microbiology.1983;2(11):11-6. Zeluff B, Catchpole M,Lowe P,et al. Cefadroxil compared with cefaclor in the treatment of streptococcal pneumonia in adults. Drugs. 1986;32 Suppl; 3:39-42. Schleupner CJ, Anthony WC, Tan J, et al. Blinded comparison of cefuroxime to cefaclor for lower respiratory tract infections. Arch intern Med. 1988; 148(2):343-42. Oberlin JA. Hyslop DL, Cefaclor treatment of upper and; ower respiratory tract infections caused by moraxella catarrhalis. Pediatr infect DIS J, 1990;9(1):41-4. Wettengel R, Vetter N, Waardenburg FA. Clarithromycir versus cefaclor for the treatment of mild-to-moderate acute bacterial bronchitis. J Antimicrob Chemother. 1993;31:963-72. O’Doherty B. An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections. J Antimicrob Chemother 1996;37(Suppl C):71-81. Turik MA, Johns D Jr, Comparison of cefaclor and cefuroxime axetil in the treatment of acute otitis media with effusion in children who failed amoxicillin therapy. J Chemother, 1998;10(4):306-12. Haczynski J, Bardadin J,Gryczynska D, et al. A comparative study of cefaclor vs. amoxicillin/clavulanate in tonsillopharyngitis. Med Sci Monitor. 2001;7(5):1016-22. Esposito S,Marchisio P,Bosos S, et al. Comparative efficacy and safety of 5-day cefaclor and 10-day amoxicillin teeatment of group A streptococcal pharyngitis in children. Int J Antimicrobial Agents. 2002;20(1)28-33. Haczynski J, Chmielik M, Bien S et al. A comparative study of cefaclor vs. Amoxicillin/ clavulanate in pediatric pharyngotonsillitis. Med Sci Monit. 2003;9(3):P129-35. Catania S, Gallo A. Clinical efficacy and tolerability of short course therapy with cefaclor compared with long-term therapy for treatment of acute otitis media in children. Infez Med. 2004;12(4):259-65. Aggarwal M, Sinha R, Murali MV, et al. Comparative efficacy and safety evaluation of cefaclor vs amoxycillin + clavulanate in children with Acute Otitis Media (AOM). Indian J Pediatr.2005;72(3):233-8.,希刻劳治疗社区呼吸道感染临床疗效值得信赖,94％,97％,98％,97％,96％,98％,98％,90％,94％,临床有效率％,,为什么体外药敏部分细菌对希刻劳不敏感，但治疗后的临床疗效却很好？,头孢克洛的免疫调节作用,体外研究,希刻劳具有体内增效抗菌特性,Ref:J Chemother,1998;10(2):91-96 .,在人体内,希刻劳与中性白细胞的相互作用,使希刻劳抗菌活性显著加强（ 对于肺炎链球菌的MBC仅为原来1/8）,加入中性粒细胞前,加入中性粒细胞后,,MBC降低 到1/8,头孢克洛对金葡菌体内外疗效比较(第一组),希刻劳具有体内增效抗菌特性,头孢克罗对金葡菌体内及体外疗效比较(第二组),希刻劳具有体内增效抗菌特性,希刻劳体内疗效明显大于体外药敏试验,实验表明：希刻劳对革兰氏阳性菌体外的MBC要明显大于体内,◆ 头孢克洛可增强吞噬细胞的趋化及氧化作用。 ◆ 头孢克洛可抑制白细胞合成丙三烯，抑制氧自由基形成和组胺释放。,艾效曼,赵莹,张秀珍.头孢克洛免疫调节功能体外实验,头孢克洛对流感嗜血杆菌体内和体外模拟试验,希刻劳具有体内增效抗菌特性,头孢克洛对卡他莫拉菌菌体内和体外模拟试验,希刻劳具有体内增效抗菌特性,实验表明：希刻劳对革兰氏阴性菌体外的MBC要明显大于体内,◆ 头孢克洛可增强吞噬细胞的趋化及氧化作用。 ◆ 头孢克洛可抑制白细胞合成丙三烯，抑制氧自由基形成和组胺释放。,艾效曼，胡云建，张秀珍修改.头孢克洛对流感嗜血杆菌和卡他莫拉菌体内模拟实验,希刻劳体内疗效明显大于体外药敏试验,头孢克洛体内模拟试验MBC值比较ug/ml,希刻劳体内疗效明显大于体外药敏试验,头孢克洛对细胞因子的免疫调节作用,体内研究,感染引起的全身炎症反应及随后机体的代偿性抗炎症反应是导致脏器功能损伤的主要原因,Sergio Zanotti,Sseem Kumar,Anand Kumar,Cytokine modulation in sepsis and septic shock.Expert Opin Investig.Drugs 2002,11(8):1061-1075,细菌感染治疗结果的决定因素,药物的抗菌作用,宿主的免疫功能,+,通过体外药敏试验来判断,,,通过免疫功能测定 先天免疫 获得性免疫,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,有些抗菌药具有免疫调节作用,抗生素对宿主先天免疫和获得性免疫的作用可能影响治疗结果 头孢地嗪免疫调节作用最大 头孢噻肟有免疫抑制作用 头孢克洛也具有免疫调节作用 体外增强粒细胞的吞噬作用和杀菌活性 体外增强巨噬细胞的吞噬作用和杀菌活性 体外增强多形核中性粒细胞(PMN)的活性 可能对免疫细胞因子也有调节作用,免疫指数定义,头孢克洛的免疫调节作用可影响机体免疫防御机制,希刻劳被证实有提高机体免疫反应的作用,◆ 抗生素能提高机体的细胞免疫和体液免疫。 ◆ 抗生素能降低细菌的毒力因子或使其更易被免疫攻击。 ◆ 抗生素能帮助机体免疫功能的恢复。,1、 JM.T. HAMILTON-MILLER Department of MedicalMicrobiology, Royal Free and University College Medical School. London, U.K. Immunopharmacology of Antibiotics:Direct and Indirect Immunomodulation of Defence Mechanisms LEADING ARTICLE Journal of chemotherapy Vol 2001;13(2):107-111,头孢克洛对免疫的调节作用,动物试验,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,细胞因子与免疫功能,I型细胞因子：促炎症细胞因子 IFN-γ、TNF-α、IL-1、IL-2、IL-12、IL-18 刺激细胞介导的免疫效应细胞，如巨噬细胞、细胞毒性T细胞以及NK细胞 上调迟发型超敏反应 调节免疫，参与清除胞内病原体 2型细胞因子 IL-4、IL-5、IL-6、IL-10、IL-13 主要调节体液免疫应答，刺激IgG1和IgE的生成 下调巨噬细胞、细胞毒性T细胞以及NK细胞的功能活性 3型细胞因子 TGF-β 主要调节体液免疫应答，刺激IgG1和IgE的生成 下调巨噬细胞、细胞毒性T细胞以及NK细胞的功能活性,实验方法,大鼠口服头孢克洛 剂量是10、50或100mg/kg/d 疗程3天或6天 对照组口服磷酸盐缓冲液(PBS) 吸入CO2处死动物 取动物脾脏，制备细胞悬液 进行免疫试验 淋巴细胞增殖试验 测定各种细胞因子水平,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,主要结果,头孢克洛刺激淋巴细胞增殖,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,细胞增殖指数,P=0.001,P=0.001,P=0.002,P=0.045,*P值是与头孢克洛组与赋形剂组相比t检验的结果,P=0.002,头孢克洛刺激淋巴细胞增殖,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,细胞增殖指数,P<0.001,P<0.001,P<0.001,P=0.001,P=0.001,P=0.004,*P值是与头孢克洛组与赋形剂组相比t检验的结果,头孢克洛刺激TNF-α的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,头孢克洛刺激TNF-α的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,头孢克洛刺激IFN-γ的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，头孢克洛组与赋形剂组相比t检验的结果,*,*,头孢克洛刺激IFN-γ的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，头孢克洛组与赋形剂组相比t检验的结果,*,头孢克洛刺激IL-2的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P=0.001，头孢克洛组与赋形剂组相比t检验的结果,*,头孢克洛刺激IL-2的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，**p=0.007，头孢克洛组与赋形剂组相比t检验的结果,*,*,*,头孢克洛降低IL-4水平,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，**p=0.003，头孢克洛组与赋形剂组相比t检验的结果,*,*,**,头孢克洛降低IL-4水平,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，**p=0.001，头孢克洛组与赋形剂组相比t检验的结果,*,**,*,头孢克洛降低IL-6水平,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,头孢克洛降低IL-6水平,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，**p=0.008，***p=0.014，头孢克洛组与赋形剂组相比t检验的结果,*,**,***,头孢克洛刺激IL-10的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,*P≤0.001，头孢克洛组与赋形剂组相比t检验的结果,*,*,头孢克洛刺激IL-10的合成,Mangano K, et al. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy 2006, 18(6):641-647,pg/ml,总结,头孢克洛可增强大鼠脾脏淋巴细胞的增殖作用 头孢克洛刺激大鼠脾脏细胞生成1型促炎症细胞因子 IFN-γ IL-2 下调2型抗炎症细胞因子的水平 IL-4 IL-6 用头孢克洛3天后暂时增强大鼠脾脏细胞分泌IL-10，但用药6天后未见IL-10升高,结论,头孢克洛可刺激大鼠脾脏细胞在离体条件下生成1型促炎症细胞因子，如IFN-γ和IL-2，同时还可下调2型抗炎症细胞因子(如IL-4和IL-6)的生成。 IFN-γ和IL-2可产生多种免疫刺激作用，如促进T细胞分化，上调MHC的表达，或活化细胞毒性T淋巴细胞。同时，IL-2和IFN-γ还可刺激NK细胞和巨噬细胞，对先天特异性免疫产生重要作用。 头孢克洛的免疫药理作用可能会与其抗菌作用产生重要的累加作用，甚至是产生协同作用。,结论,头孢克洛短期治疗可能使免疫应答一定程度上偏向于分泌1型细胞因子 头孢克洛的这种免疫药理作用可能与其抗菌作用产生重要的累加作用，甚至协同作用 可在临床研究中进一步确定头孢克洛的这种免疫药理作用及其临床意义,,Thank You,