中药引发过敏反应的危险因素及中成药致敏成分研究
|
摘要
随着中药临床应用的日益广泛,中成药的安全性问题尤其是中药注射剂引发的过敏反应,越来越引起医药界的高度重视。个别中药注射剂不良反应所引发的社会效应使人们担忧中成药的安全性,甚至使人们产生某些误解,这对中药研究领域提出了严峻的挑战。目前,我国在中成药临床安全用药领域的研究相当薄弱,对中药引发过敏反应的危险因素认识不清,缺乏有效用于中药过敏反应的临床前评价方法,且未对中药致敏成分开展系统性筛查研究,阻碍了药品质量的提高,甚至影响现代中药产业的跨越发展。因此,筛查与评价中成药(尤其是中药注射剂)致敏成分已成为中药现代化研究领域的重要任务,其关键科学问题有：1、中药引发过敏反应的危险因素有哪些?2、如何从海量的文献数据中寻找信息,从相互孤立的“碎片化”信息中辨析隐含的规律,从而发现可疑的中药致敏成分?3、如何建立评价中药注射剂静脉给药致敏性的动物模型?4、如何研究发现中成药的致敏成分?
针对上述重要科学命题,本文以中药引发过敏反应的危险因素及中成药致敏成分为主要研究内容,在中药过敏反应研究领域中采用网络药理学技术,首次构建了中药致敏原网络模型,对中药引发过敏反应的危险因素和可疑致敏成分进行探查；同时,创建了评价静脉给药引发过敏反应的动物模型,并将其应用于绿原酸静脉给药致敏性研究。本论文主要研究结果与学术贡献如下：
1.文献回顾性研究结果表明,中药引发过敏反应的主要危险因素有过敏史、剂型、给药途径、配制溶媒及联合用药等；中药注射剂是中药引发过敏反应的主要剂型,极易引发过敏性休克等严重不良反应；过敏史、给药途径、配制溶媒以及过敏出现时间为中药注射剂引发过敏性休克的显著性危险因素。本项研究采用回顾性研究方法对中药过敏反应的文献报道进行了系统性研究,对中药引发过敏反应的主要危险因素进行分析,为中药致敏成分筛查与评价研究提供基础资料。
2.中药致敏原网络分析结果显示,金银花、黄芩、连翘、栀子等为临床高致敏的可疑中药材,且栀子、鱼腥草、板兰根等为致过敏性休克发生的高风险药材；β-谷甾醇、绿原酸、棕榈酸等成分与中药过敏反应的发生高度相关。本研究采用网络药理学研究方法,首次构建了中药致敏原网络模型,为辨析海量文献数据背后隐含的规律性知识提供方法,并发现了一些可疑的中药致敏成分,为中药毒理学研究开辟了新的思路。
3.静脉给药致敏性评价动物模型研究结果显示,所建立的模型具有较高灵敏度与特异性,阳性药可显著促进PLN增殖,诱导TNP-特异性AFCs形成,而阴性对照药对PLN未产生显著性影响；同时,PLN参数可有效判别过敏反应的T细胞类型。本项研究建立了用于筛查与评价静脉给药中药致敏成分的小鼠模型,为解决中药注射剂致敏性评价难题提供了新的科学手段。
4.绿原酸致敏性研究结果显示,绿原酸类化合物静脉给药具有显著的致敏性,且其结构特性与过敏反应发生的强度、类型存在构效关系。本项研究为绿原酸静脉给药引发过敏反应提供了基础实验依据。
5.绿原酸致敏的潜在分子机制研究结果显示,其可能通过与大分子物质共价结合形成完整抗原,刺激DCs成熟分化而启动抗原呈递；同时,促进DCs中Tim4蛋白表达增加,打破Treg细胞的免疫耐受平衡,从而引发Th2型过敏反应。本项研究结果表明Treg细胞介导的免疫平衡失调可能是绿原酸致敏的重要分子机制,为阐明绿原酸致敏机制提供实验依据。
With the increasing applications of Traditional Chinese Medicine (TCM) in clinical treatments, the safety issues of Chinese medicine products (CMP), especially the sensitization induced by Traditional Chinese Medicine Injectables (TCMIs), raise more attentions among the clinicians. The social effects associated with adverse reactions of individual TCM initiated concerns among the public, even some misunderstanding about the safety of CMP, which put forward severe challenges on toxicological studies of TCM. Currently, studies related to clinical safety of CMP are relatively insufficient, such as scarce knowledges about risk factors of sensitization induced by TCM, ineffective methods to evaluate the sensitizations preclinically, and unavailablity of systematic screening of sensitized components of TCM, which significantly hampers the process to improve the quality of CMP, and even influences the developments of modern TCM industry. Therefore, screening and evaluation of the sensitized components of CMP (especially TCMIs) has become an important task in the TCM-related research fields, several key scientific questions to be addressed are the following:1. What are the risk factors of sensitization induced by TCM?2. How to extract valuable information from massive literature data, therefore elucidating the underlying mechanisms from these isolated knowledges, and eventually identifying suspicious sensitized components of TCM?3. How to establish reliable animal models to evaluate the sensitization of TCMIs administered intravenously?4. How to identify the sensitized components of CMP?
Among these important scientific questions, I focus on the risk factors of sensitization induced by TCM and sensitized components of CMP in this study. The network pharmacology technology was applied to construct the network model of TCM allergen for the first time. The significant risk factors and potentially sensitized components of TCM were found through this method. Furthermore, an animal model was established for the evaluation of sensitization induced by TCMIs administered intravenously. Chlorogenic acid was used as the test compound to demonstrate the reliability of this model. The main findings and academic contributions of this study are listed below:
1. Retrospective review of literatures indicated that allergic history, dosage forms, routes of administration, solvents, drug combination are the major risk factors of TCM to trigger sensitization. TCMIs is the main dosage form of TCM to induce sesitization that are linked with serious adverse reactions such as anaphylactic shock. Furthermore, the allergic history, routes of administration, solvents, and the time point for the first appearance after injections are significantly associated with the risk of anaphylactic shock induced by TCMIs. In current work, a retrospective review method was utilized to systemically analyze the reports about sensitization induced TCM. Results of this study uncovered the major risk factors invovled in sensitization of TCMIs, which also provides reliable experimental information for screening and evaluation of the sensitized components of TCM.
2. Analysis on the TCM allergen network suggested that several TCMs could easily induce sensitizations clinically, such as honeysuckle, scutellaria, forsythia, and gardenia, etc. And gardenia, houttuynial, as well as isatidis, were the herbs with high risk to induce anaphylatic shock. Furthermore, beta-sitosterol, chlorogenic acid, and palmitic acid were highly correlated with sensitizations induced by TCM. The network pharmacology technology was used to construct the network model of TCM allergen for the first time, which provides valuble information about potential mechanisms of sensitization and makes it possible to identify potential sensitized components of TCM. This work demonstrated a new avenue to investigate the toxicology of TCM.
3. Results from animal studies indicated that current animal model showed good sensitivity and specificity for the evaluation of the sensitization through intravenous administration. Through this model, positive compounds would significantly promote the PLN proliferation and induce TNP-specific AFCs formation, while none of these reactions were observed for negative compounds. In addition, the types of T cell differentiations in sensitization may also be distinguished by PLN parameters. In the present study, a mouse model for screening and evaluation of the sensitized components of TCM was established, which provides a new way to evaluate the sensitization of TCMIs experimentally.
4. Chlorogenic acid was evaluated by the animal model and results indicated that chlorogenic acids can significantly induce sensitization. And there are structure-activity relationships between structural characteristics of these compounds and the intensity and types of sensitization. The current work provided convincing experimental evidence for the sensitization induced by chlorogenic acid through intravenous administration.
5. A potential sensitized mechanism of chorogenic acid was proposed. Several lines of experimental data indicated that this compound induced a Th2type sensitization probably through the covalent interactions with macromolecules to form a complete antigen, which then stimulated the DCs maturation to launch antigen-presenting, and promoted the expression of Tim4in DCs to break the immune tolerance balance of Treg cells. Based on these results, altered immune balances mediated by Treg cell might be the important molecular mechanism for the sensitization induced by chlorogenic acid, which provided important experimental evidence to elucidate the mechanisms of sensitization induced by chlorogenic acid.
针对上述重要科学命题,本文以中药引发过敏反应的危险因素及中成药致敏成分为主要研究内容,在中药过敏反应研究领域中采用网络药理学技术,首次构建了中药致敏原网络模型,对中药引发过敏反应的危险因素和可疑致敏成分进行探查；同时,创建了评价静脉给药引发过敏反应的动物模型,并将其应用于绿原酸静脉给药致敏性研究。本论文主要研究结果与学术贡献如下：
1.文献回顾性研究结果表明,中药引发过敏反应的主要危险因素有过敏史、剂型、给药途径、配制溶媒及联合用药等；中药注射剂是中药引发过敏反应的主要剂型,极易引发过敏性休克等严重不良反应；过敏史、给药途径、配制溶媒以及过敏出现时间为中药注射剂引发过敏性休克的显著性危险因素。本项研究采用回顾性研究方法对中药过敏反应的文献报道进行了系统性研究,对中药引发过敏反应的主要危险因素进行分析,为中药致敏成分筛查与评价研究提供基础资料。
2.中药致敏原网络分析结果显示,金银花、黄芩、连翘、栀子等为临床高致敏的可疑中药材,且栀子、鱼腥草、板兰根等为致过敏性休克发生的高风险药材；β-谷甾醇、绿原酸、棕榈酸等成分与中药过敏反应的发生高度相关。本研究采用网络药理学研究方法,首次构建了中药致敏原网络模型,为辨析海量文献数据背后隐含的规律性知识提供方法,并发现了一些可疑的中药致敏成分,为中药毒理学研究开辟了新的思路。
3.静脉给药致敏性评价动物模型研究结果显示,所建立的模型具有较高灵敏度与特异性,阳性药可显著促进PLN增殖,诱导TNP-特异性AFCs形成,而阴性对照药对PLN未产生显著性影响；同时,PLN参数可有效判别过敏反应的T细胞类型。本项研究建立了用于筛查与评价静脉给药中药致敏成分的小鼠模型,为解决中药注射剂致敏性评价难题提供了新的科学手段。
4.绿原酸致敏性研究结果显示,绿原酸类化合物静脉给药具有显著的致敏性,且其结构特性与过敏反应发生的强度、类型存在构效关系。本项研究为绿原酸静脉给药引发过敏反应提供了基础实验依据。
5.绿原酸致敏的潜在分子机制研究结果显示,其可能通过与大分子物质共价结合形成完整抗原,刺激DCs成熟分化而启动抗原呈递；同时,促进DCs中Tim4蛋白表达增加,打破Treg细胞的免疫耐受平衡,从而引发Th2型过敏反应。本项研究结果表明Treg细胞介导的免疫平衡失调可能是绿原酸致敏的重要分子机制,为阐明绿原酸致敏机制提供实验依据。
With the increasing applications of Traditional Chinese Medicine (TCM) in clinical treatments, the safety issues of Chinese medicine products (CMP), especially the sensitization induced by Traditional Chinese Medicine Injectables (TCMIs), raise more attentions among the clinicians. The social effects associated with adverse reactions of individual TCM initiated concerns among the public, even some misunderstanding about the safety of CMP, which put forward severe challenges on toxicological studies of TCM. Currently, studies related to clinical safety of CMP are relatively insufficient, such as scarce knowledges about risk factors of sensitization induced by TCM, ineffective methods to evaluate the sensitizations preclinically, and unavailablity of systematic screening of sensitized components of TCM, which significantly hampers the process to improve the quality of CMP, and even influences the developments of modern TCM industry. Therefore, screening and evaluation of the sensitized components of CMP (especially TCMIs) has become an important task in the TCM-related research fields, several key scientific questions to be addressed are the following:1. What are the risk factors of sensitization induced by TCM?2. How to extract valuable information from massive literature data, therefore elucidating the underlying mechanisms from these isolated knowledges, and eventually identifying suspicious sensitized components of TCM?3. How to establish reliable animal models to evaluate the sensitization of TCMIs administered intravenously?4. How to identify the sensitized components of CMP?
Among these important scientific questions, I focus on the risk factors of sensitization induced by TCM and sensitized components of CMP in this study. The network pharmacology technology was applied to construct the network model of TCM allergen for the first time. The significant risk factors and potentially sensitized components of TCM were found through this method. Furthermore, an animal model was established for the evaluation of sensitization induced by TCMIs administered intravenously. Chlorogenic acid was used as the test compound to demonstrate the reliability of this model. The main findings and academic contributions of this study are listed below:
1. Retrospective review of literatures indicated that allergic history, dosage forms, routes of administration, solvents, drug combination are the major risk factors of TCM to trigger sensitization. TCMIs is the main dosage form of TCM to induce sesitization that are linked with serious adverse reactions such as anaphylactic shock. Furthermore, the allergic history, routes of administration, solvents, and the time point for the first appearance after injections are significantly associated with the risk of anaphylactic shock induced by TCMIs. In current work, a retrospective review method was utilized to systemically analyze the reports about sensitization induced TCM. Results of this study uncovered the major risk factors invovled in sensitization of TCMIs, which also provides reliable experimental information for screening and evaluation of the sensitized components of TCM.
2. Analysis on the TCM allergen network suggested that several TCMs could easily induce sensitizations clinically, such as honeysuckle, scutellaria, forsythia, and gardenia, etc. And gardenia, houttuynial, as well as isatidis, were the herbs with high risk to induce anaphylatic shock. Furthermore, beta-sitosterol, chlorogenic acid, and palmitic acid were highly correlated with sensitizations induced by TCM. The network pharmacology technology was used to construct the network model of TCM allergen for the first time, which provides valuble information about potential mechanisms of sensitization and makes it possible to identify potential sensitized components of TCM. This work demonstrated a new avenue to investigate the toxicology of TCM.
3. Results from animal studies indicated that current animal model showed good sensitivity and specificity for the evaluation of the sensitization through intravenous administration. Through this model, positive compounds would significantly promote the PLN proliferation and induce TNP-specific AFCs formation, while none of these reactions were observed for negative compounds. In addition, the types of T cell differentiations in sensitization may also be distinguished by PLN parameters. In the present study, a mouse model for screening and evaluation of the sensitized components of TCM was established, which provides a new way to evaluate the sensitization of TCMIs experimentally.
4. Chlorogenic acid was evaluated by the animal model and results indicated that chlorogenic acids can significantly induce sensitization. And there are structure-activity relationships between structural characteristics of these compounds and the intensity and types of sensitization. The current work provided convincing experimental evidence for the sensitization induced by chlorogenic acid through intravenous administration.
5. A potential sensitized mechanism of chorogenic acid was proposed. Several lines of experimental data indicated that this compound induced a Th2type sensitization probably through the covalent interactions with macromolecules to form a complete antigen, which then stimulated the DCs maturation to launch antigen-presenting, and promoted the expression of Tim4in DCs to break the immune tolerance balance of Treg cells. Based on these results, altered immune balances mediated by Treg cell might be the important molecular mechanism for the sensitization induced by chlorogenic acid, which provided important experimental evidence to elucidate the mechanisms of sensitization induced by chlorogenic acid.
引文
[1]姚苑梅,徐玉红,吴斌,等.1768例中药制剂不良反应报告分析[J].中国药物警戒,2011(9)：566-569.
[2]Rooney A A, Luebke R W, Selgrade M K, et al. Immunotoxicology and its application in risk assessment[J]. EXS,2012,101:251-287.
[3]李世荫,周劲松.中药的变态反应[J].药物流行病学杂志,2002(6)：318-325.
[4]王奇,赖世隆,温泽淮,等.2002年版《国家基本药物目录》中药注射剂类药品不良反应文献调查分析[J].中国药物警戒,2007(3)：137-141.
[5]Zegers M, de Bruijne M C, Wagner C, et al. Adverse events and potentially preventable deaths in Dutch hospitals:results of a retrospective patient record review study[J]. Qual Saf Health Care,2009,18(4):297～302.
[6]Pourpak Z, Fazlollahi M R, Fattahi F. Understanding adverse drug reactions and drug allergies:principles, diagnosis and treatment aspects[J]. Recent Pat Inflamm Allergy Drug Discov,2008,2(1):24-46.
[7]Gennis M A, Vemuri R, Burns E A, et al. Familial occurrence of hypersensitivity to phenytoin[J]. Am J Med,1991,91(6): 631-634.
[8]Shiohara T, Kano Y, Takahashi R, et al. Drug-induced hypersensitivity syndrome:recent advances in the diagnosis, pathogenesis and management[J]. Chem Immunol Allergy,2012,97:122-138.
[9]Sicherer S H. Advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insect venom[J]. J Allergy Clin Immunol,2003,111(3 Suppl):S829-S834.
[10]De Swert L F. Risk factors for allergy[J]. Eur J Pediatr,1999,158(2):89～94.
[11]Hattevig G, Kjellman B, Bjorksten B. Clinical symptoms and IgE responses to common food proteins and inhalants in the first 7 years of life[J]. Clin Allergy,1987,17(6):571-578.
[12]Barbee R A, Halonen M, Kaltenborn W, et al. A longitudinal study of serum IgE in a community cohort:correlations with age, sex, smoking, and atopic status[J]. J Allergy Clin Immunol,1987,79(6):919～927.
[13]Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction[J]. Allergy,1990,45(8):587-596.
[14]Ronchetti R, Jesenak M, Rennerova Z, et al. Relationship between atopic asthma and the population prevalence rates for asthma or atopy in children:atopic and nonatopic asthma in epidemiology[J]. Allergy Asthma Proc,2009,30(1):55-63.
[15]Gamboa P M. The epidemiology of drug allergy-related consultations in Spanish Allergology services:Alergologica-2005[J], J Investig Allergol Clin Immunol,2009,19 Suppl 2:45-50.
[16]Gomes E R, Demoly P. Epidemiology of hypersensitivity drug reactions[J]. Curr Opin Allergy Clin Immunol,2005,5(4): 309～316.
[17]Montastruc J L. Lapeyre-Mestre M, Bagheri H. et al. Gender differences in adverse drug reactions:analysis of spontaneous reports to a Regional Pharmacovigilance Centre in France[J]. Fundam Clin Pharmacol.2002,16(5):343-346.
[18]Kando J C, Yonkers K A, Cole J O. Gender as a risk factor for adverse events to medications[J]. Drugs,1995,50(1):1-6.
[19]Sears M R, Burrows B. Flannery E M. et al. Atopy in childhood. I. Gender and allergen related risks for development of hay fever and asthma[Jl. Clin Exp Allergy.1993.23(11):941-948.
[20]Kuehr J. Frischer T. Karmaus W. et al. Early childhood risk factors for sensitization at school age[J]. J Allergy Clin Immunol. 1992.90(3 Pt 1):358～363.
[21]Omenaas E, Bakke P, Elsayed S, et al. Total and specific serum IgE levels in adults:relationship to sex. age and environmental factors[J]. Clin Exp Allergy.1994.24(6):530-539.
[22]Bharadwaj M. Illing P, Theodossis A, et al. Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex[J]. Annu Rev Pharmacol Toxicol.2012.52:401-431.
[23]Chandra R K. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hvdrolysate. soy. and conventional cow's milk formulas[J]. J Pediatr Gastroenterol Nutr.1997.24(4):380-388.
[24]Thong B Y. Tan T C. Epidemiology and risk factors for drug allergy[J]. Br J Clin Pharmacol,2011,71(5):684-700.
[25]Man C B, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese[J]. Epilepsia,2007,48(5):1015-1018.
[26]Chung W H. Hung S I, Hong H S, et al. Medical genetics:a marker for Stevens-Johnson syndrome[J]. Nature, 2004,428(6982):486.
[27]Hughes A R, Mosteller M, Bansal A T, et al. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations[J]. Pharmacogenomics.2004.5(2):203-211.
[28]Hung S I, Chung W H, Liou L B, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol[J]. Proc Natl Acad Sci U S A,2005,102(11):4134-4139.
[29]Lonjou C, Thomas L, Borot N, et al. A marker for Stevens-Johnson syndrome...:ethnicity matters[J]. Pharmacogenomics J, 2006,6(4):265-268.
[301 Mallal S. Phillips E, Carosi G. et al. HLA-B*5701 screening for hypersensitivity to abacavir[J]. N Engl J Mcd,2008,358(6): 568-579.
[31]Huang C 2, Yang J, Qiao H L. et al. Polymorphisms and haplotype analysis of IL-4Ralpha Q576R and 175V in patients with penicillin allergy[J]. Eur J Clin Pharmacol,2009,65(9):895-902.
[32]Qiao H L, Yang J, Zhang Y W. Relationships between specific serum IgE, cytokines and polymorphisms in the IL-4, IL-4Ralpha in patients with penicillins allergy[J]. Allergy,2005,60(8):1053-1059.
[33]Qiao H L, Yang J, Zhang Y W. Specific serum IgE levels and FcepsilonRIbeta genetic polymorphism in patients with penicillins allergy[J]. Allergy,2004,59(12):1326-1332.
[34]Shirakawa T, Hashimoto T, Furuyama J, et al. Linkage between severe atopy and chromosome 11q13 in Japanese families[J]. Clin Genet,1994,46(3):228-232.
[35]Vercelli D. Discovering susceptibility genes for asthma and allergy[J]. Nat Rev Immunol.2008,8(3):169～182.
[36]Marsh D G, Neely J D, Breazeale D R, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations [J]. Science,1994,264(5162):1152-1156.
[37]Gosavi D D, Reddy P S. Drug Allergy[J]. International Journal of Research in Pharmaceutical and Biomedical Sciences, 2012,3(2):834-840.
[38]Pope J, Jerome D, Fenlon D, et al. Frequency of adverse drug reactions in patients with systemic lupus erythematosus[J]. J Rheumatol,2003,30(3):480-484.
[39]Lehloenya R J, Wallace J, Todd G, et al. Multiple drug hypersensitivity reactions to anti-tuberculosis drugs:five cases in HlV-infected patients[J]. Int J Tuberc Lung Dis,2012,16(9):1260-1264.
[40]Phillips E, Mallal S. Drug hypersensitivity in HIV[J]. Curr Opin Allergy Clin Immunol,2007,7(4):324-330.
[41]Brown T, Confrancesco J J. Update from the 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV[J]. Hopkins HIV Rep,2005,17(1):4-5,8.
[42]Kourorian Z, Fattahi F, Pourpak Z, et al. Adverse drug reactions in an Iranian department of adult infectious diseases[J]. East Mediterr Health J,2009,15(6):1351～1357.
[43]Varkey P, Cunningham J, O'Meara J, et al. Multidisciplinary approach to inpatient medication reconciliation in an academic setting[J]. Am J Health Syst Pharm,2007,64(8):850～854.
[44]Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine[J]. Br J Clin Pharmacol,2000,49(2):158-167.
[45]Riedl M A, Casillas A M. Adverse drug reactions:types and treatment options[J]. Am Fam Physician,2003,68(9): 1781～1790.
[46]Mahgoub A, Idle J R, Smith R L. Genetically determined variability in drug metabolism:dual slow acetylation and drug oxidation traits[J]. Lancet,1979,2(8134):154.
[47]Clark D W. Genetically determined variability in acetylation and oxidation. Therapeutic implications[J]. Drugs,1985,29(4): 342～375.
[48]Britschgi M, von Greyerz S, Burkhart C, et al. Molecular aspects of drug recognition by specific T cells[J]. Curr Drug Targets,2003,4(1):1-11.
[49]Demoly P. [Drug allergies and drug hypersensitivities][J]. Rev Prat,2007,57(12):1326～1330.
[50]Adkinson N J. Risk factors for drug allergy[J]. J Allergy Clin Immunol,1984,74(4 Pt 2):567-572.
[51]Demoly P, Viola M, Gomes E, et al. Epidemiology and Causes of Drug Hypersensitivity[J]. Pichler WJ (ed):Drug Hypersensitivity. Basel, Karger,2007(pp):2-17.
[52]Cetinkaya F, Cag Y. Penicillin sensitivity among children without a positive history for penicillin allergy[J]. Pediatr Allergy Immunol,2004.15(3):278-280.
[53]Pichichero M E, Pichichero D M. Diagnosis of penicillin, amoxicillin, and cephalosporin allergy:reliability of examination assessed by skin testing and oral challenge[J]. J Pediatr,1998,132(1):137～143.
[54]Johansson S G, Bieber T. Dahl R, et al. Revised nomenclature for allergy for global use:Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003[J]. J Allergy Clin Immunol,2004,113(5):832～836.
[55]Nagasaka H, Komatsu H, Ohura T, et al. Nitric oxide synthesis in ornithine transcarbamylase deficiency, possible involvement of low no synthesis in clinical manifestations of urea cycle defect[J]. J Pediatr,2004,145(2):259～262.
[561 Posadas S J, Pichler W J. Delayed drug hypersensitivity reactions-new concepts[J], Clin Exp Allergy,2007,37(7):989～999.
[57]龚非力基础免疫学[M]武汉:湖北科学技术出版社,1998：10-14.
[581 VervloetD, Durham S. Adverse reactions to drugs[J]. BMJ.1998.316(7143):1511～1514.
[59]Descotes J, Choquet-Kastylevsky G. Gell and Coombs's classification:is it still valid?[J]. Toxicology.2001.158(1-2):43-49.
[60]Metcalfe D D. Baram D, Mekori Y A. Mast cells[J]. Physiol Rev,1997,77(4):1033～1079.
[611 Hagen J W, Magro C M, Crowson A N. Emerging adverse cutaneous drug reactions[J]. Dermatol Clin,2012,30(4):695～730.
[621 Schnyder B. Pichler W J. Mechanisms of drug-induced allergy[J]. Mayo Clin Proc,2009.84(3):268～272.
[63]Warkentin T E. Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis[J]. N Engl J Med, 2007.356(9):891～893.
[64]Aster R H. Drug-induced immune cytopenias[J]. Toxicology,2005.209(2):149-153.
[65]Deshazo R D, Kemp S F. Allergic reactions to drugs and biologic agents[J]. JAMA.1997,278(22):1895-1906.
[66]Roychowdhury S, Svensson C K. Mechanisms of drug-induced delayed-type hypersensitivity reactions in the skin[J]. AAPS J,2005,7(4):E834-E846.
[67]Merk H F, Baron J, Hertl M, et al. Lymphocyte activation in allergic reactions elicited by small-molecular-weight compounds[J]. Int Arch Allergy Immunol,1997,113(1-3):173-176.
[68]Kuljanac I. Mechanisms of drug hypersensitivity reactions and the skin[J]. Recent Pat lnflamm Allergy Drug Discov, 2008,2(1):64～71.
[69]Pichler W J. Delayed drug hypersensitivity reactions[J]. Ann Intern Med,2003,139(8):683-693.
[70]De Week A L, Sanz M L, Gamboa P M, et al. Diagnosis of immediate-type beta-lactam allergy in vitro by flow-cytometric basophil activation test and sulfidoleukotriene production:a multicenter study[J[. J Investig Allergol Clin Immunol,2009,19(2): 91-109.
[71]Budinger L, Hertl M. Immunologic mechanisms in hypersensitivity reactions to metal ions:an overview[J]. Allergy, 2000,55(2):108～115.
[72]Steinman R M. The dendritic cell system and its role in immunogenicity[J]. Annu Rev Immunol,1991,9:271～296.
[73]Farkas L, Kvale E O, Johansen F E, et al. Plasmacytoid dendritic cells activate allergen-specific TH2 memory cells: modulation by CpG oligodeoxynucleotides[J]. J Allergy Clin Immunol,2004,114(2):436-443.
[74]Benson M, Adner M, Cardell L O. Cytokines and cytokine receptors in allergic rhinitis:how do they relate to the Th2 hypothesis in allergy?[J]. Clin Exp Allergy,2001,31(3):361-367.
[75]Suzuki Y, Ra C. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment:aspirin modulation of IgE-dependent mast cell activation:role of aspirin-induced exacerbation of immediate allergy[J], J Pharmacol Sci,2009,110(3):237～244.
[76]Li X M, Brown L. Efficacy and mechanisms of action of traditional Chinese medicines for treating asthma and allergy [J]. J Allergy Clin Immunol,2009,123(2):297-306,307～308.
[77]Pumphrey R. Anaphylaxis:can we tell who is at risk of a fatal reaction?[J]. Curr Opin Allergy Clin Immunol,2004,4(4): 285-290.
[78]Kvedariene V, Martins P, Rouanet L, et al. Diagnosis of iodinated contrast media hypersensitivity:results of a 6-year period[J]. Clin Exp Allergy,2006,36(8):1072-1077.
[79]Caubet J C, Pichler W J, Eigenmann P A. Educational case series:Mechanisms of drug allergy[J]. Pediatr Allergy Immunol, 2011,22(6):559-567.
[80]Steinman R M. Lasker Basic Medical Research Award. Dendritic cells:versatile controllers of the immune system[J]. Nat Med,2007,13(10):1155-1159.
[81]Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce T(H)2 and tolerogenic responses[J]. Nat Immunol,2010,11(8):647-655.
[82]Joffre O P, Segura E, Savina A, et al. Cross-presentation by dendritic cells[J]. Nat Rev Immunol,2012.
[83]Manicassamy S, Ravindran R, Deng J, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity[J]. Nat Med,2009,15(4):401-409.
[84]Lucas M, Zhang X, Prasanna V, et al. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus[J].J Immunol,2005,175(1):469～477.
[85]Hawlisch H, Belkaid Y, Baelder R, et al. C5a negatively regulates toll-like receptor 4-induced immune responses[J]. Immunity,2005,22(4):415-426.
[86]Agrawal S, Agrawal A, Doughty B, et al. Cutting edge:different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos[J]. J Immunol,2003,171(10):4984-4989.
[87]Dillon S, Agrawal A, Van Dyke T, et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells[J]. J Immunol,2004,172(8): 4733-4743.
[88]Arima K, Watanabe N, Hanabuchi S, et al. Distinct signal codes generate dendritic cell functional plasticity[J]. Sci Signal, 2010,3(105):a4.
[89]Nurtanio N, Yang P C. Role of TIM-4 in innate or adaptive immune response[J]. N Am J Med Sci,2011,3(5):217～221.
[90]Coombes J L, Siddiqui K R, Arancibia-Carcamo C V, et al. A functionally specialized population of mucosal CD103+DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism[J]. J Exp Med,2007,204(8):1757-1764.
[91]Lund F E, Randall T D. Effector and regulatory B cells:modulators of CD4(+) T cell immunity[J]. Nat Rev Immunol, 2010,10(4):236-247.
[92]Mosmann T R, Cherwinski H, Bond M W, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol,1986.136(7):2348-2357.
[93]Angkasekwinai P, Park H, Wang Y H, et al. Interleukin 25 promotes the initiation of proallergic type 2 responses[J]. J Exp Med,2007,204(7):1509-1517.
[94]Yoshimoto T, Yasuda K, Tanaka H, et al. Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class Ⅱ complexes to CD4+ T cells[J]. Nat Immunol.2009,10(7):706-712.
[95]Soumelis V, Reche P A, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP[J]. Nat Immunol,2002,3(7):673～680.
[96]Eisenbarth S C, Piggott D A, Huleatt J W, et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen[J]. J Exp Med,2002,196(12):1645-1651.
[97]Yamane H, Zhu J, Paul W E. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment[J]. J Exp Med,2005,202(6):793～804.
[98]Zhu J, Guo L, Watson C J, et al. Stat6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion[J]. J Immunol,2001,166(12):7276-7281.
[99]Kurata H, Lee H J, O'Garra A. et al. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells[J]. Immunity,1999,11(6):677-688.
[100]Amsen D, Antov A, Jankovic D, et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch[J]. Immunity,2007,27(1):89～99.
[101]Yu Q, Sharma A, Oh S Y, et al. T cell factor I initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma[J]. Nat Immunol,2009,10(9):992-999.
[102]Rochman Y, Spolski R, Leonard W J. New insights into the regulation of T cells by gamma(c) family cytokines[J]. Nat Rev Immunol,2009,9(7):480～490.
[103]Cote-Sierra J, Foucras G, Guo L, et al. Interleukin 2 plays a central role in Th2 differentiation[J]. Proc Natl Acad Sci U S A, 2004,101(11):3880-3885.
[104]Zhu J, Min B, Hu-Li J, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses[J]. Nat Immunol,2004,5(11):1157-1165.
[105]Zhu J, Cote-Sierra J, Guo L, et al. Stat5 activation plays a critical role in Th2 differentiation[J]. Immunity,2003,19(5): 739-748.
[106]Paul W E, Zhu J. How are T(H)2-type immune responses initiated and amplified?[J]. Nat Rev Immunol,2010,10(4): 225-235.
[107]Zhu J, Davidson T S, Wei G, et al. Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells[J].J Exp Med,2009,206(2):329-341.
[1081 Chen D, Martinez G. T cells:the usual subsets[J]. Nature Reviews Immunology,2012, (Poster).
[109]Mcheyzer-Williams L J, Mcheyzer-Williams M G. Antigen-specific memory B cell development[J]. Annu Rev Immunol, 2005,23:487-513.
[110]Rawlings D J, Schwartz M A, Jackson S W, et al. Integration of B cell responses through Toll-like receptors and antigen receptors[J]. Nat Rev Immunol,2012,12(4):282-294.
[111]Defranco A L. The complexity of signaling pathways activated by the BCR[J]. Curr Opin Immunol,1997,9(3):296-308.
[112]Dal Porto J M, Gauld S B, Merrell K T, et al. B cell antigen receptor signaling 101[J]. Mol Immunol,2004,41(6-7): 599-613.
[113]Mcheyzer-Williams M G. Combinations of interleukins 2,4 and 5 regulate the secretion of murine immunoglobulin isotypes[J].Eur J Immunol,1989,19(11):2025-2030.
[114]Yoshida K, Matsuoka M, Usuda S, et al. Immunoglobulin switch circular DNA in the mouse infected with Nippostrongylus brasiliensis:evidence for successive class switching from mu to epsilon via gamma 1[J]. Proc Natl Acad Sci U S A,1990,87(20): 7829～7833.
[115]Ozaki K, Spolski R, Feng C G, et al. A critical role for IL-21 in regulating immunoglobulin production[J]. Science, 2002,298(5598):1630-1634.
[116]Cazac B B, Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo[J]. Immunity,2000,13(4): 443-451.
[117]Falcone F H, Zillikens D, Gibbs B F. The 21st century renaissance of the basophil? Current insights into its role in allergic responses and innate immunity[J]. Exp Dermatol,2006,15(11):855～864.
[118]Patil S U, Shreffler W G. Immunology in the Clinic Review Series; focus on allergies:basophils as biomarkers for assessing immune modulation[J]. Clin Exp Immunol,2012,167(1):59-66.
[119]Abraham S N, Malaviya R. Mast cells in infection and immunity[J]. Infect Immun,1997,65(9):3501～3508.
[120]Galli S J, Tsai M. Mast cells in allergy and infection:versatile effector and regulatory cells in innate and adaptive immunity[J]. Eur J Immunol,2010,40(7):1843～1851.
[121]Mclachlan J B, Hart J P, Pizzo S V, et al. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection[J]. Nat Immunol,2003,4(12):1199～1205.
[122]Amaral M M, Davio C, Ceballos A, et al. Histamine improves antigen uptake and cross-presentation by dendritic cells[J]. J Immunol,2007,179(6):3425-3433.
[123]Kalesnikoff J, Galli S J. New developments in mast cell biology[J]. Nat Immunol,2008,9(11):1215-1223.
[124]Abraham S N, St J A. Mast cell-orchestrated immunity to pathogens[J]. Nat Rev Immunol,2010,10(6):440-452.
[125]Thakurdas S M, Melicoff E, Sansores-Garcia L, et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections[J]. J Biol Chem,2007,282(29):20809～20815.
[126]Metcalfe D D, Baram D, Mekori Y A. Mast cells[J]. Physiol Rev,1997,77(4):1033～1079.
[127]Ley K, Laudanna C, Cybulsky M I, et al. Getting to the site of inflammation:the leukocyte adhesion cascade updated[J]. Nat Rev Immunol,2007,7(9):678～689.
[128]Davis D M. Mechanisms and functions for the duration of intercellular contacts made by lymphocytes[J]. Nat Rev Immunol, 2009,9(8):543～555.
[129]Gomez E, Torres M J, Mayorga C, et al. Immunologic evaluation of drug allergy[J]. Allergy Asthma Immunol Res, 2012.4(5):251～263.
[130]Ishizaka K. Ishizaka T, Hornbrook M M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity wth gamma-E-globulin antibody[J]. J Immunol,1966,97(6):840～853.
[131]Fontaine C, Mayorga C, Bousquet P J, et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy[J]. Allergy.2007,62(1):47～52.
[132]Sanz M L, Gamboa P M, De Week A L. Cellular tests in the diagnosis of drug hypersensitivity[J]. Curr Pharm Des, 2008.14(27):2803-2808.
[133]Ebo D G, Hagendorens M M. Schuerwegh A J, et al. Flow-assisted quantification of in vitro activated basophils in the diagnosis of wasp venom allergy and follow-up of wasp venom immunotherapy[J]. Cytometry B Clin Cytom,2007,72(3): 196-203.
[134]Ebo D G, Sainte-Laudy J, Bridts C H, et al. Flow-assisted allergy diagnosis, current applications and future perspectives[J]. Allergy.2006.61(9):1028-1039.
[135]Romano A. Torres M J. Castells M. et al. Diagnosis and management of drug hypersensitivity reactions[J]. J Allergy Clin Immunol,2011,127(3 Suppl):S67-S73.
[136]Luque 1. Leyva L, Jose T M, et al. In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions[J]. Allergy,2001,56(7):611-618.
[137]Nyfeler B, Pichler W J. The lymphocyte transformation test for the diagnosis of drug allergy:sensitivity and specificity [J]. Clin Exp Allergy,1997,27(2):175-181.
[138]Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption[J]. Allergy,2007,62(12):1439-1444.
[139]Gruchalla R S, Pirmohamed M. Clinical practice. Antibiotic allergy[J]. N Engl J Med,2006.354(6):601-609.
[140]Beeler A, Zaccaria L, Kawabata T, et al. CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity[J]. Allergy,2008,63(2):181～188.
[141]Torres M J, Blanca M, Fernandez J, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics[J]. Allergy, 2003,58(10):961～972.
[142]石良,王锡昌,刘源,等.食物过敏原免疫学检测技术研究进展[J].分析测试学报,2010(9)：981-986.
[143]Nguyen B, Tanious F A, Wilson W D. Biosensor-surface plasmon resonance:quantitative analysis of small molecule-nucleic acid interactions[J]. Methods,2007,42(2):150-161.
[144]Liu Y, Wilson W D. Quantitative analysis of small molecule-nucleic acid interactions with a biosensor surface and surface plasmon resonance detection[J]. Methods Mol Biol,2010,613:1-23.
[145]Achilleos C, Tailhardat M, Courtellemont P, et al. Investigation of surface plasmon resonance biosensor for skin sensitizers studies[J]. Toxicol In Vitro,2009,23(2):308-318.
[146]Cao L, Lin H, Mirsky V M. Surface plasmon resonance biosensor for enrofloxacin based on deoxyribonucleic acid[J]. Anal Chim Acta,2007,589(1):1～5.
[147]Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity[J]. Allergy,2002,57(1):45～51.
[148]Borch J E, Andersen K E, Bindslev-Jensen C. The prevalence of suspected and challenge-verified penicillin allergy in a university hospital population[J]. Basic Clin Pharmacol Toxicol,2006,98(4):357-362.
[149]Romano A, Blanca M, Torres M J, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics[J]. Allergy, 2004,59(11):1153～1160.
[150]Hayakawa R. Contact dermatitis[J]. Nagoya J Med Sci,2000,63(3-4):83～90.
[151]Aptula A O, Patlewicz G, Roberts D W, et al. Non-enzymatic glutathione reactivity and in vitro toxicity:a non-animal approach to skin sensitization[J]. Toxicol In Vitro,2006,20(2):239～247.
[152]Ettmayer P, Mayer P, Kalthoff F, et al. A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation[J]. Am J Respir Crit Care Med,2006,173(6):599-606.
[153]Schoeters E, Verheyen G R, Nelissen 1, et al. Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization[J].Mol Immunol,2007,44(12):3222-3233.
[1541 Metz M, Magerl M, Kuhl N F, et al. Mast cells determine the magnitude of bacterial toxin-induced skin infiammation[J]. Exp Dermatol,2009,18(2):160-166.
[155]Royer B, Varadaradjalou S, Saas P, et al. Inhibition of IgE-induced activation of human mast cells by IL-10[J]. Clin Exp Allergy,2001,31(5):694-704.
[156]Scola A M, Loxham M, Charlton S J, et al. The long-acting beta-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells[J]. Br J Pharmacol,2009,158(1):267-276.
[157]Alm P E, Bloom G D. What-if any-is the role of adrenergic mechanisms in histamine release from mast cells?[J]. Agents Actions,1981,11(1-2):60-66.
[158]Wicklein D, Stocker M, Klockenbring T, et al. In contrast to specific B cells, human basophils are unaffected by the toxic activity of an allergen toxin due to lack of internalization of immunoglobulin E-bound allergen[J]. Clin Exp Allergy,2006,36(4): 531-542.
[1591 Ennis M, Nehring E, Schneider C. Adverse reactions to drugs:in vitro studies with isolated cells[J]. Inflamm Res,2004,53 Suppl 2:S105～S108.
[160]Ganeshan K, Neilsen C V, Hadsaitong A, et al. Impairing oral tolerance promotes allergy and anaphylaxis:a new murine food allergy model[J]. J Allergy Clin Immunol,2009,123(1):231-238.
[161]Nierkens S, Aalbers M, Bol M, et al. Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens[J]. Toxicol Sci,2005,83(2):273～281.
[162]Okunuki H, Teshima R, Harikai N, et al. Oral sensitization of W/W(v) mice with ovalbumin and possible involvement of the decrease in gammadelta-T cells[J]. Biol Pharm Bull,2003,26(9):1260～1265.
[163]Hastings K L. Pre-clinical methods for detecting the hypersensitivity potential of pharmaceuticals:regulatory considerations[J]. Toxicology,2001.158(1-2):85-89.
[164]Matsuda T, Matsubara T, Hino S. Immunogenic and allergenic potentials of natural and recombinant innocuous proteins[J]. J Biosci Bioeng,2006,101(3):203-211.
[165]郑宏,尹极峰,温浩啮齿类动物速发型过敏反应模型建立及其影响因素研究进展[J].地方病通报,1999(2)：103-105
[166]Lee B, Trung T H, Bae E A. et al. Mangiferin inhibits passive cutaneous anaphylaxis reaction and pruritus in mice[J]. Planta Med,2009,75(13):1415～1417.
[167]Magnusson B. Kligman A M. The identification of contact allergens by animal assay. The guinea pig maximization test[J]. J Invest Dermatol.1969.52(3):268～276.
[168]Hattori H, Yamaguchi F, Wagai N, et al. An assessment of antigenic potential of beta-lactam antibiotics, low molecular weight drugs, using guinea pig models[J]. Toxicology,1997,123(1-2):149～160.
[169]Liden C, Boman A. Contact allergy to colour developing agents in the guinea pig[J]. Contact Dermatitis,1988,19(4): 290-295.
[170]Tuschl H, Landsteiner H T, Kovac R. Application of the popliteal lymph node assay in immunotoxicity testing, complementation of the direct popliteal lymph node assay with flow cytometric analyses[J]. Toxicology.2002,172(1):35～48.
[171]van Loveren H. Cockshott A, Gebel T. et al. Skin sensitization in chemical risk assessment:report of a WHO/IPCS international workshop focusing on dose-response assessment[J]. Regul Toxicol Pharmacol.2008.50(2):155-199.
[172]薛彬.我国免疫毒理学现况及展望[J].卫生毒理学杂志,2000(1)：8-9
[173]张碧华.胡欣,傅得兴,等.浅谈中药注射剂的风险因素及其控制[J].中国药物警戒,2009(6)：335-339.
[174]张新亮.清开灵注射液静脉点滴不良反应2例[J].兰州医学院学报,2003(2)：30
[175]龚慕辛.王立斌.清开灵注射液致329例过敏反应文献分析[J].时珍国医国药,2007(9)：2175-2176.
[176]Zegers M, de Bruijne M C, Wagner C, et al. Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals[J]. BMC Health Serv Res.2007,7:27.
[177]刘锐锋,李元文,萧健鹏,等.中药注射剂引起过敏性休克危险因素的非条件Logistic回归分析[J].今日药学,2010(5).
[178]Hopkins A L. Network pharmacology[J]. Nat Biotechnol,2007.25(10):1110-1111.
[179]Hopkins A L. Network pharmacology:the next paradigm in drug discovery[J]. Nat Chem Biol.2008,4(11):682-690.
[180]Lim J. Hao T. Shaw C. et al.A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration[J]. Cell,2006,125(4):801-814.
[181]Ma'Ayan A, Jenkins S L, Goldfarb J. et al. Network analysis of FDA approved drugs and their targets[J]. Mt Sinai J Med, 2007,74(1):27-32.
[182]Xie L, Li J, Xie L, et al. Drug discovery using chemical systems biology:identification of the protein-ligand binding network to explain the side effects of CETP inhibitors[J]. PLoS Comput Biol,2009,5(5):e1000387.
[183]Jonsson P F, Bates P A. Global topological features of cancer proteins in the human interactome[J]. Bioinformatics, 2006,22(18):2291-2297.
[184]Sharan R, Ideker T. Modeling cellular machinery through biological network comparison[J]. Nat Biotechnol,2006,24(4): 427～433.
[185]Bader S, Kuhner S, Gavin A C. Interaction networks for systems biology[J]. FEBS Lett,2008,582(8):1220～1224.
[186]Shannon P, Markiel A, Ozier O, et al. Cytoscape:a software environment for integrated models of biomolecular interaction networks[J]. Genome Res,2003,13(11):2498-2504.
[187]Costanzo M, Baryshnikova A, Bellay J, et al. The genetic landscape of a cell[J]. Science,2010,327(5964):425～431.
[188]Cline M S, Smoot M, Cerami E, et al. Integration of biological networks and gene expression data using Cytoscape[J]. Nat Protoc,2007,2(10):2366～2382.
[189]Hopkins A L. Network pharmacology[J]. Nat Biotechnol,2007,25(10):1110～1111.
[190]Seebacher J, Gavin A C, SnapShot:Protein-protein interaction networks[J]. Cell,2011,144(6):1000,1000-1001.
[191]Simons F E, Frew A J, Ansotegui I J, et al. Risk assessment in anaphylaxis:current and future approaches[J]. J Allergy Clin Immunol,2007,120(1 Suppl):S2-S24.
[192]刘兆华,刘兆平,周庚寅.胭窝淋巴结试验在药物超敏反应研究中的应用[J].中国药理学与毒理学杂志,2009(1)：70-75.
[193]Gleichmann E, Gleichmann H. Graft-versus-host reaction:a pathogenetic principle for the development of drug allergy, autoimmunity, and malignant lymphoma in non-chimeric individuals. Hypothesis[J]. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol,1976,85(2):91～109.
[194]Samuelsen M, Nygaard U C, Lovik M. Allergy adjuvant effect of particles from wood smoke and road traffic[J]. Toxicology, 2008,246(2-3):124～131.
[195]Gutting B W, Updyke L W, Amacher D E. Diclofenac activates T cells in the direct popliteal lymph node assay and selectively induces IgG(1) and IgE against co-injected TNP-OVA[J]. Toxicol Lett,2002,131(3):167-180.
[196]Carey J B, Allshire A, van Pelt F N. Immune modulation by cadmium and lead in the acute reporter antigen-popliteal lymph node assay[J]. Toxicol Sci,2006,91(1):113-122.
[197]Aida T, Kimura T, Ishikawa N, et al. Evaluation of allergenic potential of low-molecular compounds by mouse popliteal lymph node assay[J]. J Toxicol Sci,1998,23(5):425-432.
[198]Nierkens S, Aalbers M, Bol M, et al. Differential requirement for CD28/CTLA-4-CD80/CD86 interactions in drug-induced type 1 and type 2 immune responses to trinitrophenyl-ovalbumin[J]. J Immunol,2005,175(6):3707～3714.
[199]Lovik M, Alberg T, Nygaard U C, et al. Popliteal lymph node (PLN) assay to study adjuvant effects on respiratory allergy[J]. Methods,2007,41(1):72～79.
[200]Kammuller M E, Thomas C, De Bakker J M, et al. The popliteal lymph node assay in mice to screen for the immune disregulating potential of chemicals--a preliminary study[J]. Int J Immunopharmacol,1989,11(3):293-300.
[201]Gehrs B C, Smialowicz R J. Persistent suppression of delayed-type hypersensitivity in adult F344 rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin[J]. Toxicology,1999,134(1):79-88.
[202]Ravel G, Descotes J. Popliteal lymph node assay:facts and perspectives[J]. J Appl Toxicol,2005,25(6):451-458.
[203]Isola D, Kimber I, Sarlo K, et al. Chemical respiratory allergy and occupational asthma:what are the key areas of uncertainty?[J]. J Appl Toxicol,2008,28(3):249-253.
[204]Pieters R, Albers R. Screening tests for autoimmune-related immunotoxicity[J]. Environ Health Perspect,1999.107 Suppl 5: 673-677.
[205]Albers R, Broeders A, van der Pijl A, et al. The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals[J]. Toxicol Appl Pharmacol,1997,143(1):102～109.
[2061 Nierkens S, van Helden P, Bol M, et al. Selective requirement for CD40-CD154 in drug-induced type 1 versus type 2 responses to trinitrophenyl-ovalbumin[J]. J Immunol,2002.168(8):3747-3754.
[207]Nierkens S. Aalbers M, Bol M. et al. Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens[J]. Toxicol Sci,2005,83(2):273-281.
[208]Yoshida A, Aoki R, Kimoto-Nira H. et al. Oral administration of live Lactococcus lactis C59 suppresses IgE antibody production in ovalbumin-sensitized mice via the regulation of interleukin-4 production[J]. FEMS Immunol Med Microbiol. 2011.61(3):315-322.
[209]Oliver M R. Tan D T. Scott R B. Colonic motor response to IgE-mediated mast cell degranulation in the Hooded-Lister rat[J]. Neurogastroenterol Motil,1996.8(2):121～130.
[210]Doyle R J. Smith C S. Cronholm L S. Histamine hypersensitivity in mice induced by concanavalin A[J]. J Allergy Clin Immunol,1978.61(2):108-114.
[211]Gutting B W, Updyke L W, Amacher D E. Investigating the TNP-OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans[J]. J Appl Toxicol,2002,22(3):177～183.
[212]Gutting B W, Schomaker S J, Kaplan A H, et al. A comparison of the direct and reporter antigen popliteal lymph node assay for the detection of immunomodulation by low molecular weight compounds[J]. Toxicol Sci,1999,51(1):71-79.
[213]Tanojo H, Wester R C, Shainhouse J Z, et al. Diclofenac metabolic profile following in vitro percutaneous absorption through viable human skin[J]. Eur J Drug Metab Pharmacokinet,1999,24(4):345～351.
[214]Dearman R J, Betts C J, Caddick H T, et al. Cytokine profiling of chemical allergens in mice:impact of mitogen on selectivity of response[J]. J Appl Toxicol,2009,29(3):233～241.
[215]Layton L L, Panzani R, Greene F C, et al. Atopic hypersensitivity to a protein of the green coffee bean and absence of allergic reactions to chlorogenic acid, low-molecular-weight components of green coffee, or to roasted coffee[J]. Int Arch Allergy Appl Immunol,1965,28(1):116-127.
[216]Layton L L, Greene F C, Panzani R. ALLERGY TO GREEN COFFEE. FAILURE OF PATIENTS ALLERGIC TO GREEN COFFEE TO REACT TO CHLOROGENIC ACID, ROASTED COFFEE, OR ORANGE[J]. J Allergy,1965,36:84-91.
[217]Freedman S O. ANTIGENIC PROPERTIES OF CHLOROGENIC ACID[J]. J Allergy,1964,35:97-107.
[218]Freedman S O, Siddiqi A I, Krupey J, et al. Identification of a simple chemical compound (chlorogenic acid) as an allergen in plant materials causing human atopic disease[J]. Trans Assoc Am Physicians,1962,75:99～106.
[219]李钦,张信岳,陈国神.含绿原酸的清热解毒类中药注射剂不良反应及其机理探讨[J].中国现代应用药学,2009(7)：555-558.
[220]裴振峨,翟伟,马军丽,等.北京地区1015例中药注射剂不良反应报告分析[J].临床药物治疗杂志,2009(2)：39-41.
[221]Naisbitt D J, Gordon S F, Pirmohamed M, et al. Immunological principles of adverse drug reactions:the initiation and propagation of immune responses elicited by drug treatment[J]. Drug Saf,2000,23(6):483～507.
[222]Xie C, Zhong D F, Chen X Y. [Metabolites of injected chlorogenic acid in rats][J]. Yao Xue Xue Bao,2011,46(1):88～95.
[223]Pirmohamed M, Naisbitt D J, Gordon F, et al. The danger hypothesis-potential role in idiosyncratic drug reactions[J]. Toxicology,2002,181-182:55-63.
[224]Nizard R S, Biau D, Porcher R, et al. A meta-analysis of patellar replacement in total knee arthroplasty[J]. Clin Orthop Relat Res,2005(432):196～203.
[225]Carnathan G W, Metcalf L E, Cochrane R L, et al. Relationship between progesterone suppression and pregnancy in rats[J]. J Pharm Pharmacol,1987,39(5):401-404.
[226]van der Worp H B, Sena E S, Donnan G A, et al. Hypothermia in animal models of acute ischaemic stroke:a systematic review and meta-analysis[J]. Brain,2007,130(Pt 12):3063-3074.
[227]Pound P, Ebrahim S, Sandercock P, et al. Where is the evidence that animal research benefits humans?[J]. BMJ, 2004,328(7438):514-517.
[228]Izrailev S, Zhu F, Agrafiotis D K. A distance geometry heuristic for expanding the range of geometries sampled during conformational search[J]. J Comput Chem,2006,27(16):1962～1969.
[229]Mercader A G, Duchowicz P R, Fernandez F M, et al. Replacement method and enhanced replacement method versus the genetic algorithm approach for the selection of molecular descriptors in QSPR/QSAR theories[J]. J Chem Inf Model,2010,50(9): 1542～1548.
[230]Pourbasheer E, Riahi S, Ganjali M R, et al. QSAR study of C allosteric binding site of HCV NS5B polymerase inhibitors by support vector machine[J]. Mol Divers,2011,15(3):645-653.
[231]de Molfetta F A, Angelotti W F, Romero R A, et al. A neural networks study of quinone compounds with trypanocidal activity[J]. J Mol Model,2008,14(10):975-985.
[232]Rastija V, Medic-Saric M. QSAR study of antioxidant activity of wine polyphenols[J]. Eur J Med Chem,2009,44(1): 400～408.
[233]Mercader A G, Duchowicz P R, Fernandez F M, et al. Replacement method and enhanced replacement method versus the genetic algorithm approach for the selection of molecular descriptors in QSPR/QSAR theories[J]. J Chem Inf Model,2010,50(9): 1542～1548.
[234]Weber K C, Da S A. A chemometric study of the 5-HT(1A) receptor affinities presented by arylpiperazine compounds[J]. Eur J Med Chem,2008,43(2):364-372.
[235]Todeschini R, Vighi M, Finizio A, et al.3D-modelling and prediction by WHIM descriptors. Part 8. Toxicity and physico-chemical properties of environmental priority chemicals by 2D-TI and 3D-WHIM descriptors[J]. SAR QSAR Environ Res, 1997,7(1-4):173～193.
[236]Rasulev B F, Abdullaev N D, Syrov V N, et al. A Quantitative Structure-Activity Relationship (QSAR) study of the antioxidant activity of flavonoids[J]. Qsar & Combinatorial Science,2005,24(9):1056-1065.
[237]国家食品药品监督管理局.中药、天然药物免疫毒性(过敏性、光过敏性)研究的技术指导原则[M].[Z]GPT5-1,2005.
[238]Casp.10 questions to help you make sense of qualitative research[M].2006.
[239]王志国,王丹巧,于友华,等.清开灵注射液中绿原酸致敏性的研究[J].2011
[240]张信岳,陈爱君,李钦,等绿原酸主动全身过敏与被动皮肤过敏的实验研究[J] 2011
[241]林敏,钱华勤,张彤.等.绿原酸致过敏反应的买验研究[J].2010
[242]郭姗姗.王意忠,金亚宏,等.BN大鼠用于评价中药注射液速发型过敏反应模型的建立及适用性评价[J].中国中药杂志,2011(14)：1845-1849
[243]黄晓舞,廖红波,刘屏,等CGA-BSA致豚鼠过敏反应及其机制的研究[J].中国中药杂志,2010(09)：1181-1184
[244]罗飞,包旭,林大胜.等.绿原酸对动物的致敏性研究[J].华西药学杂志,2009(02)：181-183
[245]何洲.绿原酸与清开灵注射液过敏反应相关性的研究.北京中医药大学,2011.
[246]吴晓冬,杨华蓉,林大胜,等.绿原酸致敏性的综合研究与评价[J]中国甲药杂志,2010(24)：3357-3361
[247]李瑾翡,黎旸,陈琪,等.注射用双黄连的免疫毒性研究[J]中药新药与临床药理,2008(03)：172-174
[248]张瑞霞,汤纳平,等.绿原酸和双黄连粉针剂致敏性比较评价[J]世界科学技术(甲医药现代化).2010(06)：1005-1008
[249]Gong J. Liu F T, Chen S S. Polyphenolic antioxidants enhance lgE production[J]. Immunol Invest,2004,33(3):295-307.
[250]Lin M, Gong W, Wang Y, et al. Structure-Activity Differences of Chlorogenic Acid and Its Isomers on Sensitization via Intravenous Exposure[J]. Int J Toxicol,2012.
[251]Liu Z, Liu Z, Shi Y, et al. Evaluation of the immunosensitizing potential of chlorogenic acid using a popliteal lymph node assay in BALB/c mice[J]. Food Chem Toxicol,2010,48(4):1059-1065.
[252]Nizard R S, Biau D, Porcher R, et al. A meta-analysis of patellar replacement in total knee arthroplasty[J]. Clin Orthop Relat Res,2005(432):196～203.
[253]Friedrich J O, Adhikari N K, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data[J]. BMC Med Res Methodol,2007,7:5.
[254]国家药典委员会2010版中华人民共和国药典一部.北京：2010
[255]Frew A. General principles of investigating and managing drug allergy [J]. Br J Clin Pharmacol,2011,71(5):642-646.
[256]Inaba K, Inaba M. Antigen recognition and presentation by dendritic cells[J]. Int J Hematol,2005,81(3):181-187.
[2571 Banchereau J, Steinman R M. Dendritic cells and the control of immunity[J]. Nature,1998,392(6673):245-252.
[258]Meyers J H, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation[J]. Nat Immunol,2005,6(5):455-464.
[259]Umetsu S E, Lee W L, Mcintire J J, et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance[J]. Nat Immunol,2005,6(5):447-454.
[260]Meyers J H, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation[J]. Nat Immunol,2005,6(5):455-464.
[261]Kuchroo V K, Meyers J H, Umetsu D T, et al. TIM family of genes in immunity and tolerance[J]. Adv Immunol,2006,91: 227-249.
[262]Liu T, He S H, Zheng P Y, et al. Staphylococcal enterotoxin B increases TIM4 expression in human dendritic cells that drives naive CD4 T cells to differentiate into Th2 cells[J]. Mol Immunol,2007,44(14):3580-3587.
[2]Rooney A A, Luebke R W, Selgrade M K, et al. Immunotoxicology and its application in risk assessment[J]. EXS,2012,101:251-287.
[3]李世荫,周劲松.中药的变态反应[J].药物流行病学杂志,2002(6)：318-325.
[4]王奇,赖世隆,温泽淮,等.2002年版《国家基本药物目录》中药注射剂类药品不良反应文献调查分析[J].中国药物警戒,2007(3)：137-141.
[5]Zegers M, de Bruijne M C, Wagner C, et al. Adverse events and potentially preventable deaths in Dutch hospitals:results of a retrospective patient record review study[J]. Qual Saf Health Care,2009,18(4):297～302.
[6]Pourpak Z, Fazlollahi M R, Fattahi F. Understanding adverse drug reactions and drug allergies:principles, diagnosis and treatment aspects[J]. Recent Pat Inflamm Allergy Drug Discov,2008,2(1):24-46.
[7]Gennis M A, Vemuri R, Burns E A, et al. Familial occurrence of hypersensitivity to phenytoin[J]. Am J Med,1991,91(6): 631-634.
[8]Shiohara T, Kano Y, Takahashi R, et al. Drug-induced hypersensitivity syndrome:recent advances in the diagnosis, pathogenesis and management[J]. Chem Immunol Allergy,2012,97:122-138.
[9]Sicherer S H. Advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insect venom[J]. J Allergy Clin Immunol,2003,111(3 Suppl):S829-S834.
[10]De Swert L F. Risk factors for allergy[J]. Eur J Pediatr,1999,158(2):89～94.
[11]Hattevig G, Kjellman B, Bjorksten B. Clinical symptoms and IgE responses to common food proteins and inhalants in the first 7 years of life[J]. Clin Allergy,1987,17(6):571-578.
[12]Barbee R A, Halonen M, Kaltenborn W, et al. A longitudinal study of serum IgE in a community cohort:correlations with age, sex, smoking, and atopic status[J]. J Allergy Clin Immunol,1987,79(6):919～927.
[13]Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction[J]. Allergy,1990,45(8):587-596.
[14]Ronchetti R, Jesenak M, Rennerova Z, et al. Relationship between atopic asthma and the population prevalence rates for asthma or atopy in children:atopic and nonatopic asthma in epidemiology[J]. Allergy Asthma Proc,2009,30(1):55-63.
[15]Gamboa P M. The epidemiology of drug allergy-related consultations in Spanish Allergology services:Alergologica-2005[J], J Investig Allergol Clin Immunol,2009,19 Suppl 2:45-50.
[16]Gomes E R, Demoly P. Epidemiology of hypersensitivity drug reactions[J]. Curr Opin Allergy Clin Immunol,2005,5(4): 309～316.
[17]Montastruc J L. Lapeyre-Mestre M, Bagheri H. et al. Gender differences in adverse drug reactions:analysis of spontaneous reports to a Regional Pharmacovigilance Centre in France[J]. Fundam Clin Pharmacol.2002,16(5):343-346.
[18]Kando J C, Yonkers K A, Cole J O. Gender as a risk factor for adverse events to medications[J]. Drugs,1995,50(1):1-6.
[19]Sears M R, Burrows B. Flannery E M. et al. Atopy in childhood. I. Gender and allergen related risks for development of hay fever and asthma[Jl. Clin Exp Allergy.1993.23(11):941-948.
[20]Kuehr J. Frischer T. Karmaus W. et al. Early childhood risk factors for sensitization at school age[J]. J Allergy Clin Immunol. 1992.90(3 Pt 1):358～363.
[21]Omenaas E, Bakke P, Elsayed S, et al. Total and specific serum IgE levels in adults:relationship to sex. age and environmental factors[J]. Clin Exp Allergy.1994.24(6):530-539.
[22]Bharadwaj M. Illing P, Theodossis A, et al. Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex[J]. Annu Rev Pharmacol Toxicol.2012.52:401-431.
[23]Chandra R K. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hvdrolysate. soy. and conventional cow's milk formulas[J]. J Pediatr Gastroenterol Nutr.1997.24(4):380-388.
[24]Thong B Y. Tan T C. Epidemiology and risk factors for drug allergy[J]. Br J Clin Pharmacol,2011,71(5):684-700.
[25]Man C B, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese[J]. Epilepsia,2007,48(5):1015-1018.
[26]Chung W H. Hung S I, Hong H S, et al. Medical genetics:a marker for Stevens-Johnson syndrome[J]. Nature, 2004,428(6982):486.
[27]Hughes A R, Mosteller M, Bansal A T, et al. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations[J]. Pharmacogenomics.2004.5(2):203-211.
[28]Hung S I, Chung W H, Liou L B, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol[J]. Proc Natl Acad Sci U S A,2005,102(11):4134-4139.
[29]Lonjou C, Thomas L, Borot N, et al. A marker for Stevens-Johnson syndrome...:ethnicity matters[J]. Pharmacogenomics J, 2006,6(4):265-268.
[301 Mallal S. Phillips E, Carosi G. et al. HLA-B*5701 screening for hypersensitivity to abacavir[J]. N Engl J Mcd,2008,358(6): 568-579.
[31]Huang C 2, Yang J, Qiao H L. et al. Polymorphisms and haplotype analysis of IL-4Ralpha Q576R and 175V in patients with penicillin allergy[J]. Eur J Clin Pharmacol,2009,65(9):895-902.
[32]Qiao H L, Yang J, Zhang Y W. Relationships between specific serum IgE, cytokines and polymorphisms in the IL-4, IL-4Ralpha in patients with penicillins allergy[J]. Allergy,2005,60(8):1053-1059.
[33]Qiao H L, Yang J, Zhang Y W. Specific serum IgE levels and FcepsilonRIbeta genetic polymorphism in patients with penicillins allergy[J]. Allergy,2004,59(12):1326-1332.
[34]Shirakawa T, Hashimoto T, Furuyama J, et al. Linkage between severe atopy and chromosome 11q13 in Japanese families[J]. Clin Genet,1994,46(3):228-232.
[35]Vercelli D. Discovering susceptibility genes for asthma and allergy[J]. Nat Rev Immunol.2008,8(3):169～182.
[36]Marsh D G, Neely J D, Breazeale D R, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations [J]. Science,1994,264(5162):1152-1156.
[37]Gosavi D D, Reddy P S. Drug Allergy[J]. International Journal of Research in Pharmaceutical and Biomedical Sciences, 2012,3(2):834-840.
[38]Pope J, Jerome D, Fenlon D, et al. Frequency of adverse drug reactions in patients with systemic lupus erythematosus[J]. J Rheumatol,2003,30(3):480-484.
[39]Lehloenya R J, Wallace J, Todd G, et al. Multiple drug hypersensitivity reactions to anti-tuberculosis drugs:five cases in HlV-infected patients[J]. Int J Tuberc Lung Dis,2012,16(9):1260-1264.
[40]Phillips E, Mallal S. Drug hypersensitivity in HIV[J]. Curr Opin Allergy Clin Immunol,2007,7(4):324-330.
[41]Brown T, Confrancesco J J. Update from the 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV[J]. Hopkins HIV Rep,2005,17(1):4-5,8.
[42]Kourorian Z, Fattahi F, Pourpak Z, et al. Adverse drug reactions in an Iranian department of adult infectious diseases[J]. East Mediterr Health J,2009,15(6):1351～1357.
[43]Varkey P, Cunningham J, O'Meara J, et al. Multidisciplinary approach to inpatient medication reconciliation in an academic setting[J]. Am J Health Syst Pharm,2007,64(8):850～854.
[44]Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine[J]. Br J Clin Pharmacol,2000,49(2):158-167.
[45]Riedl M A, Casillas A M. Adverse drug reactions:types and treatment options[J]. Am Fam Physician,2003,68(9): 1781～1790.
[46]Mahgoub A, Idle J R, Smith R L. Genetically determined variability in drug metabolism:dual slow acetylation and drug oxidation traits[J]. Lancet,1979,2(8134):154.
[47]Clark D W. Genetically determined variability in acetylation and oxidation. Therapeutic implications[J]. Drugs,1985,29(4): 342～375.
[48]Britschgi M, von Greyerz S, Burkhart C, et al. Molecular aspects of drug recognition by specific T cells[J]. Curr Drug Targets,2003,4(1):1-11.
[49]Demoly P. [Drug allergies and drug hypersensitivities][J]. Rev Prat,2007,57(12):1326～1330.
[50]Adkinson N J. Risk factors for drug allergy[J]. J Allergy Clin Immunol,1984,74(4 Pt 2):567-572.
[51]Demoly P, Viola M, Gomes E, et al. Epidemiology and Causes of Drug Hypersensitivity[J]. Pichler WJ (ed):Drug Hypersensitivity. Basel, Karger,2007(pp):2-17.
[52]Cetinkaya F, Cag Y. Penicillin sensitivity among children without a positive history for penicillin allergy[J]. Pediatr Allergy Immunol,2004.15(3):278-280.
[53]Pichichero M E, Pichichero D M. Diagnosis of penicillin, amoxicillin, and cephalosporin allergy:reliability of examination assessed by skin testing and oral challenge[J]. J Pediatr,1998,132(1):137～143.
[54]Johansson S G, Bieber T. Dahl R, et al. Revised nomenclature for allergy for global use:Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003[J]. J Allergy Clin Immunol,2004,113(5):832～836.
[55]Nagasaka H, Komatsu H, Ohura T, et al. Nitric oxide synthesis in ornithine transcarbamylase deficiency, possible involvement of low no synthesis in clinical manifestations of urea cycle defect[J]. J Pediatr,2004,145(2):259～262.
[561 Posadas S J, Pichler W J. Delayed drug hypersensitivity reactions-new concepts[J], Clin Exp Allergy,2007,37(7):989～999.
[57]龚非力基础免疫学[M]武汉:湖北科学技术出版社,1998：10-14.
[581 VervloetD, Durham S. Adverse reactions to drugs[J]. BMJ.1998.316(7143):1511～1514.
[59]Descotes J, Choquet-Kastylevsky G. Gell and Coombs's classification:is it still valid?[J]. Toxicology.2001.158(1-2):43-49.
[60]Metcalfe D D. Baram D, Mekori Y A. Mast cells[J]. Physiol Rev,1997,77(4):1033～1079.
[611 Hagen J W, Magro C M, Crowson A N. Emerging adverse cutaneous drug reactions[J]. Dermatol Clin,2012,30(4):695～730.
[621 Schnyder B. Pichler W J. Mechanisms of drug-induced allergy[J]. Mayo Clin Proc,2009.84(3):268～272.
[63]Warkentin T E. Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis[J]. N Engl J Med, 2007.356(9):891～893.
[64]Aster R H. Drug-induced immune cytopenias[J]. Toxicology,2005.209(2):149-153.
[65]Deshazo R D, Kemp S F. Allergic reactions to drugs and biologic agents[J]. JAMA.1997,278(22):1895-1906.
[66]Roychowdhury S, Svensson C K. Mechanisms of drug-induced delayed-type hypersensitivity reactions in the skin[J]. AAPS J,2005,7(4):E834-E846.
[67]Merk H F, Baron J, Hertl M, et al. Lymphocyte activation in allergic reactions elicited by small-molecular-weight compounds[J]. Int Arch Allergy Immunol,1997,113(1-3):173-176.
[68]Kuljanac I. Mechanisms of drug hypersensitivity reactions and the skin[J]. Recent Pat lnflamm Allergy Drug Discov, 2008,2(1):64～71.
[69]Pichler W J. Delayed drug hypersensitivity reactions[J]. Ann Intern Med,2003,139(8):683-693.
[70]De Week A L, Sanz M L, Gamboa P M, et al. Diagnosis of immediate-type beta-lactam allergy in vitro by flow-cytometric basophil activation test and sulfidoleukotriene production:a multicenter study[J[. J Investig Allergol Clin Immunol,2009,19(2): 91-109.
[71]Budinger L, Hertl M. Immunologic mechanisms in hypersensitivity reactions to metal ions:an overview[J]. Allergy, 2000,55(2):108～115.
[72]Steinman R M. The dendritic cell system and its role in immunogenicity[J]. Annu Rev Immunol,1991,9:271～296.
[73]Farkas L, Kvale E O, Johansen F E, et al. Plasmacytoid dendritic cells activate allergen-specific TH2 memory cells: modulation by CpG oligodeoxynucleotides[J]. J Allergy Clin Immunol,2004,114(2):436-443.
[74]Benson M, Adner M, Cardell L O. Cytokines and cytokine receptors in allergic rhinitis:how do they relate to the Th2 hypothesis in allergy?[J]. Clin Exp Allergy,2001,31(3):361-367.
[75]Suzuki Y, Ra C. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment:aspirin modulation of IgE-dependent mast cell activation:role of aspirin-induced exacerbation of immediate allergy[J], J Pharmacol Sci,2009,110(3):237～244.
[76]Li X M, Brown L. Efficacy and mechanisms of action of traditional Chinese medicines for treating asthma and allergy [J]. J Allergy Clin Immunol,2009,123(2):297-306,307～308.
[77]Pumphrey R. Anaphylaxis:can we tell who is at risk of a fatal reaction?[J]. Curr Opin Allergy Clin Immunol,2004,4(4): 285-290.
[78]Kvedariene V, Martins P, Rouanet L, et al. Diagnosis of iodinated contrast media hypersensitivity:results of a 6-year period[J]. Clin Exp Allergy,2006,36(8):1072-1077.
[79]Caubet J C, Pichler W J, Eigenmann P A. Educational case series:Mechanisms of drug allergy[J]. Pediatr Allergy Immunol, 2011,22(6):559-567.
[80]Steinman R M. Lasker Basic Medical Research Award. Dendritic cells:versatile controllers of the immune system[J]. Nat Med,2007,13(10):1155-1159.
[81]Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce T(H)2 and tolerogenic responses[J]. Nat Immunol,2010,11(8):647-655.
[82]Joffre O P, Segura E, Savina A, et al. Cross-presentation by dendritic cells[J]. Nat Rev Immunol,2012.
[83]Manicassamy S, Ravindran R, Deng J, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity[J]. Nat Med,2009,15(4):401-409.
[84]Lucas M, Zhang X, Prasanna V, et al. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus[J].J Immunol,2005,175(1):469～477.
[85]Hawlisch H, Belkaid Y, Baelder R, et al. C5a negatively regulates toll-like receptor 4-induced immune responses[J]. Immunity,2005,22(4):415-426.
[86]Agrawal S, Agrawal A, Doughty B, et al. Cutting edge:different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos[J]. J Immunol,2003,171(10):4984-4989.
[87]Dillon S, Agrawal A, Van Dyke T, et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells[J]. J Immunol,2004,172(8): 4733-4743.
[88]Arima K, Watanabe N, Hanabuchi S, et al. Distinct signal codes generate dendritic cell functional plasticity[J]. Sci Signal, 2010,3(105):a4.
[89]Nurtanio N, Yang P C. Role of TIM-4 in innate or adaptive immune response[J]. N Am J Med Sci,2011,3(5):217～221.
[90]Coombes J L, Siddiqui K R, Arancibia-Carcamo C V, et al. A functionally specialized population of mucosal CD103+DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism[J]. J Exp Med,2007,204(8):1757-1764.
[91]Lund F E, Randall T D. Effector and regulatory B cells:modulators of CD4(+) T cell immunity[J]. Nat Rev Immunol, 2010,10(4):236-247.
[92]Mosmann T R, Cherwinski H, Bond M W, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol,1986.136(7):2348-2357.
[93]Angkasekwinai P, Park H, Wang Y H, et al. Interleukin 25 promotes the initiation of proallergic type 2 responses[J]. J Exp Med,2007,204(7):1509-1517.
[94]Yoshimoto T, Yasuda K, Tanaka H, et al. Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class Ⅱ complexes to CD4+ T cells[J]. Nat Immunol.2009,10(7):706-712.
[95]Soumelis V, Reche P A, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP[J]. Nat Immunol,2002,3(7):673～680.
[96]Eisenbarth S C, Piggott D A, Huleatt J W, et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen[J]. J Exp Med,2002,196(12):1645-1651.
[97]Yamane H, Zhu J, Paul W E. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment[J]. J Exp Med,2005,202(6):793～804.
[98]Zhu J, Guo L, Watson C J, et al. Stat6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion[J]. J Immunol,2001,166(12):7276-7281.
[99]Kurata H, Lee H J, O'Garra A. et al. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells[J]. Immunity,1999,11(6):677-688.
[100]Amsen D, Antov A, Jankovic D, et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch[J]. Immunity,2007,27(1):89～99.
[101]Yu Q, Sharma A, Oh S Y, et al. T cell factor I initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma[J]. Nat Immunol,2009,10(9):992-999.
[102]Rochman Y, Spolski R, Leonard W J. New insights into the regulation of T cells by gamma(c) family cytokines[J]. Nat Rev Immunol,2009,9(7):480～490.
[103]Cote-Sierra J, Foucras G, Guo L, et al. Interleukin 2 plays a central role in Th2 differentiation[J]. Proc Natl Acad Sci U S A, 2004,101(11):3880-3885.
[104]Zhu J, Min B, Hu-Li J, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses[J]. Nat Immunol,2004,5(11):1157-1165.
[105]Zhu J, Cote-Sierra J, Guo L, et al. Stat5 activation plays a critical role in Th2 differentiation[J]. Immunity,2003,19(5): 739-748.
[106]Paul W E, Zhu J. How are T(H)2-type immune responses initiated and amplified?[J]. Nat Rev Immunol,2010,10(4): 225-235.
[107]Zhu J, Davidson T S, Wei G, et al. Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells[J].J Exp Med,2009,206(2):329-341.
[1081 Chen D, Martinez G. T cells:the usual subsets[J]. Nature Reviews Immunology,2012, (Poster).
[109]Mcheyzer-Williams L J, Mcheyzer-Williams M G. Antigen-specific memory B cell development[J]. Annu Rev Immunol, 2005,23:487-513.
[110]Rawlings D J, Schwartz M A, Jackson S W, et al. Integration of B cell responses through Toll-like receptors and antigen receptors[J]. Nat Rev Immunol,2012,12(4):282-294.
[111]Defranco A L. The complexity of signaling pathways activated by the BCR[J]. Curr Opin Immunol,1997,9(3):296-308.
[112]Dal Porto J M, Gauld S B, Merrell K T, et al. B cell antigen receptor signaling 101[J]. Mol Immunol,2004,41(6-7): 599-613.
[113]Mcheyzer-Williams M G. Combinations of interleukins 2,4 and 5 regulate the secretion of murine immunoglobulin isotypes[J].Eur J Immunol,1989,19(11):2025-2030.
[114]Yoshida K, Matsuoka M, Usuda S, et al. Immunoglobulin switch circular DNA in the mouse infected with Nippostrongylus brasiliensis:evidence for successive class switching from mu to epsilon via gamma 1[J]. Proc Natl Acad Sci U S A,1990,87(20): 7829～7833.
[115]Ozaki K, Spolski R, Feng C G, et al. A critical role for IL-21 in regulating immunoglobulin production[J]. Science, 2002,298(5598):1630-1634.
[116]Cazac B B, Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo[J]. Immunity,2000,13(4): 443-451.
[117]Falcone F H, Zillikens D, Gibbs B F. The 21st century renaissance of the basophil? Current insights into its role in allergic responses and innate immunity[J]. Exp Dermatol,2006,15(11):855～864.
[118]Patil S U, Shreffler W G. Immunology in the Clinic Review Series; focus on allergies:basophils as biomarkers for assessing immune modulation[J]. Clin Exp Immunol,2012,167(1):59-66.
[119]Abraham S N, Malaviya R. Mast cells in infection and immunity[J]. Infect Immun,1997,65(9):3501～3508.
[120]Galli S J, Tsai M. Mast cells in allergy and infection:versatile effector and regulatory cells in innate and adaptive immunity[J]. Eur J Immunol,2010,40(7):1843～1851.
[121]Mclachlan J B, Hart J P, Pizzo S V, et al. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection[J]. Nat Immunol,2003,4(12):1199～1205.
[122]Amaral M M, Davio C, Ceballos A, et al. Histamine improves antigen uptake and cross-presentation by dendritic cells[J]. J Immunol,2007,179(6):3425-3433.
[123]Kalesnikoff J, Galli S J. New developments in mast cell biology[J]. Nat Immunol,2008,9(11):1215-1223.
[124]Abraham S N, St J A. Mast cell-orchestrated immunity to pathogens[J]. Nat Rev Immunol,2010,10(6):440-452.
[125]Thakurdas S M, Melicoff E, Sansores-Garcia L, et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections[J]. J Biol Chem,2007,282(29):20809～20815.
[126]Metcalfe D D, Baram D, Mekori Y A. Mast cells[J]. Physiol Rev,1997,77(4):1033～1079.
[127]Ley K, Laudanna C, Cybulsky M I, et al. Getting to the site of inflammation:the leukocyte adhesion cascade updated[J]. Nat Rev Immunol,2007,7(9):678～689.
[128]Davis D M. Mechanisms and functions for the duration of intercellular contacts made by lymphocytes[J]. Nat Rev Immunol, 2009,9(8):543～555.
[129]Gomez E, Torres M J, Mayorga C, et al. Immunologic evaluation of drug allergy[J]. Allergy Asthma Immunol Res, 2012.4(5):251～263.
[130]Ishizaka K. Ishizaka T, Hornbrook M M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity wth gamma-E-globulin antibody[J]. J Immunol,1966,97(6):840～853.
[131]Fontaine C, Mayorga C, Bousquet P J, et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy[J]. Allergy.2007,62(1):47～52.
[132]Sanz M L, Gamboa P M, De Week A L. Cellular tests in the diagnosis of drug hypersensitivity[J]. Curr Pharm Des, 2008.14(27):2803-2808.
[133]Ebo D G, Hagendorens M M. Schuerwegh A J, et al. Flow-assisted quantification of in vitro activated basophils in the diagnosis of wasp venom allergy and follow-up of wasp venom immunotherapy[J]. Cytometry B Clin Cytom,2007,72(3): 196-203.
[134]Ebo D G, Sainte-Laudy J, Bridts C H, et al. Flow-assisted allergy diagnosis, current applications and future perspectives[J]. Allergy.2006.61(9):1028-1039.
[135]Romano A. Torres M J. Castells M. et al. Diagnosis and management of drug hypersensitivity reactions[J]. J Allergy Clin Immunol,2011,127(3 Suppl):S67-S73.
[136]Luque 1. Leyva L, Jose T M, et al. In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions[J]. Allergy,2001,56(7):611-618.
[137]Nyfeler B, Pichler W J. The lymphocyte transformation test for the diagnosis of drug allergy:sensitivity and specificity [J]. Clin Exp Allergy,1997,27(2):175-181.
[138]Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption[J]. Allergy,2007,62(12):1439-1444.
[139]Gruchalla R S, Pirmohamed M. Clinical practice. Antibiotic allergy[J]. N Engl J Med,2006.354(6):601-609.
[140]Beeler A, Zaccaria L, Kawabata T, et al. CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity[J]. Allergy,2008,63(2):181～188.
[141]Torres M J, Blanca M, Fernandez J, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics[J]. Allergy, 2003,58(10):961～972.
[142]石良,王锡昌,刘源,等.食物过敏原免疫学检测技术研究进展[J].分析测试学报,2010(9)：981-986.
[143]Nguyen B, Tanious F A, Wilson W D. Biosensor-surface plasmon resonance:quantitative analysis of small molecule-nucleic acid interactions[J]. Methods,2007,42(2):150-161.
[144]Liu Y, Wilson W D. Quantitative analysis of small molecule-nucleic acid interactions with a biosensor surface and surface plasmon resonance detection[J]. Methods Mol Biol,2010,613:1-23.
[145]Achilleos C, Tailhardat M, Courtellemont P, et al. Investigation of surface plasmon resonance biosensor for skin sensitizers studies[J]. Toxicol In Vitro,2009,23(2):308-318.
[146]Cao L, Lin H, Mirsky V M. Surface plasmon resonance biosensor for enrofloxacin based on deoxyribonucleic acid[J]. Anal Chim Acta,2007,589(1):1～5.
[147]Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity[J]. Allergy,2002,57(1):45～51.
[148]Borch J E, Andersen K E, Bindslev-Jensen C. The prevalence of suspected and challenge-verified penicillin allergy in a university hospital population[J]. Basic Clin Pharmacol Toxicol,2006,98(4):357-362.
[149]Romano A, Blanca M, Torres M J, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics[J]. Allergy, 2004,59(11):1153～1160.
[150]Hayakawa R. Contact dermatitis[J]. Nagoya J Med Sci,2000,63(3-4):83～90.
[151]Aptula A O, Patlewicz G, Roberts D W, et al. Non-enzymatic glutathione reactivity and in vitro toxicity:a non-animal approach to skin sensitization[J]. Toxicol In Vitro,2006,20(2):239～247.
[152]Ettmayer P, Mayer P, Kalthoff F, et al. A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation[J]. Am J Respir Crit Care Med,2006,173(6):599-606.
[153]Schoeters E, Verheyen G R, Nelissen 1, et al. Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization[J].Mol Immunol,2007,44(12):3222-3233.
[1541 Metz M, Magerl M, Kuhl N F, et al. Mast cells determine the magnitude of bacterial toxin-induced skin infiammation[J]. Exp Dermatol,2009,18(2):160-166.
[155]Royer B, Varadaradjalou S, Saas P, et al. Inhibition of IgE-induced activation of human mast cells by IL-10[J]. Clin Exp Allergy,2001,31(5):694-704.
[156]Scola A M, Loxham M, Charlton S J, et al. The long-acting beta-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells[J]. Br J Pharmacol,2009,158(1):267-276.
[157]Alm P E, Bloom G D. What-if any-is the role of adrenergic mechanisms in histamine release from mast cells?[J]. Agents Actions,1981,11(1-2):60-66.
[158]Wicklein D, Stocker M, Klockenbring T, et al. In contrast to specific B cells, human basophils are unaffected by the toxic activity of an allergen toxin due to lack of internalization of immunoglobulin E-bound allergen[J]. Clin Exp Allergy,2006,36(4): 531-542.
[1591 Ennis M, Nehring E, Schneider C. Adverse reactions to drugs:in vitro studies with isolated cells[J]. Inflamm Res,2004,53 Suppl 2:S105～S108.
[160]Ganeshan K, Neilsen C V, Hadsaitong A, et al. Impairing oral tolerance promotes allergy and anaphylaxis:a new murine food allergy model[J]. J Allergy Clin Immunol,2009,123(1):231-238.
[161]Nierkens S, Aalbers M, Bol M, et al. Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens[J]. Toxicol Sci,2005,83(2):273～281.
[162]Okunuki H, Teshima R, Harikai N, et al. Oral sensitization of W/W(v) mice with ovalbumin and possible involvement of the decrease in gammadelta-T cells[J]. Biol Pharm Bull,2003,26(9):1260～1265.
[163]Hastings K L. Pre-clinical methods for detecting the hypersensitivity potential of pharmaceuticals:regulatory considerations[J]. Toxicology,2001.158(1-2):85-89.
[164]Matsuda T, Matsubara T, Hino S. Immunogenic and allergenic potentials of natural and recombinant innocuous proteins[J]. J Biosci Bioeng,2006,101(3):203-211.
[165]郑宏,尹极峰,温浩啮齿类动物速发型过敏反应模型建立及其影响因素研究进展[J].地方病通报,1999(2)：103-105
[166]Lee B, Trung T H, Bae E A. et al. Mangiferin inhibits passive cutaneous anaphylaxis reaction and pruritus in mice[J]. Planta Med,2009,75(13):1415～1417.
[167]Magnusson B. Kligman A M. The identification of contact allergens by animal assay. The guinea pig maximization test[J]. J Invest Dermatol.1969.52(3):268～276.
[168]Hattori H, Yamaguchi F, Wagai N, et al. An assessment of antigenic potential of beta-lactam antibiotics, low molecular weight drugs, using guinea pig models[J]. Toxicology,1997,123(1-2):149～160.
[169]Liden C, Boman A. Contact allergy to colour developing agents in the guinea pig[J]. Contact Dermatitis,1988,19(4): 290-295.
[170]Tuschl H, Landsteiner H T, Kovac R. Application of the popliteal lymph node assay in immunotoxicity testing, complementation of the direct popliteal lymph node assay with flow cytometric analyses[J]. Toxicology.2002,172(1):35～48.
[171]van Loveren H. Cockshott A, Gebel T. et al. Skin sensitization in chemical risk assessment:report of a WHO/IPCS international workshop focusing on dose-response assessment[J]. Regul Toxicol Pharmacol.2008.50(2):155-199.
[172]薛彬.我国免疫毒理学现况及展望[J].卫生毒理学杂志,2000(1)：8-9
[173]张碧华.胡欣,傅得兴,等.浅谈中药注射剂的风险因素及其控制[J].中国药物警戒,2009(6)：335-339.
[174]张新亮.清开灵注射液静脉点滴不良反应2例[J].兰州医学院学报,2003(2)：30
[175]龚慕辛.王立斌.清开灵注射液致329例过敏反应文献分析[J].时珍国医国药,2007(9)：2175-2176.
[176]Zegers M, de Bruijne M C, Wagner C, et al. Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals[J]. BMC Health Serv Res.2007,7:27.
[177]刘锐锋,李元文,萧健鹏,等.中药注射剂引起过敏性休克危险因素的非条件Logistic回归分析[J].今日药学,2010(5).
[178]Hopkins A L. Network pharmacology[J]. Nat Biotechnol,2007.25(10):1110-1111.
[179]Hopkins A L. Network pharmacology:the next paradigm in drug discovery[J]. Nat Chem Biol.2008,4(11):682-690.
[180]Lim J. Hao T. Shaw C. et al.A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration[J]. Cell,2006,125(4):801-814.
[181]Ma'Ayan A, Jenkins S L, Goldfarb J. et al. Network analysis of FDA approved drugs and their targets[J]. Mt Sinai J Med, 2007,74(1):27-32.
[182]Xie L, Li J, Xie L, et al. Drug discovery using chemical systems biology:identification of the protein-ligand binding network to explain the side effects of CETP inhibitors[J]. PLoS Comput Biol,2009,5(5):e1000387.
[183]Jonsson P F, Bates P A. Global topological features of cancer proteins in the human interactome[J]. Bioinformatics, 2006,22(18):2291-2297.
[184]Sharan R, Ideker T. Modeling cellular machinery through biological network comparison[J]. Nat Biotechnol,2006,24(4): 427～433.
[185]Bader S, Kuhner S, Gavin A C. Interaction networks for systems biology[J]. FEBS Lett,2008,582(8):1220～1224.
[186]Shannon P, Markiel A, Ozier O, et al. Cytoscape:a software environment for integrated models of biomolecular interaction networks[J]. Genome Res,2003,13(11):2498-2504.
[187]Costanzo M, Baryshnikova A, Bellay J, et al. The genetic landscape of a cell[J]. Science,2010,327(5964):425～431.
[188]Cline M S, Smoot M, Cerami E, et al. Integration of biological networks and gene expression data using Cytoscape[J]. Nat Protoc,2007,2(10):2366～2382.
[189]Hopkins A L. Network pharmacology[J]. Nat Biotechnol,2007,25(10):1110～1111.
[190]Seebacher J, Gavin A C, SnapShot:Protein-protein interaction networks[J]. Cell,2011,144(6):1000,1000-1001.
[191]Simons F E, Frew A J, Ansotegui I J, et al. Risk assessment in anaphylaxis:current and future approaches[J]. J Allergy Clin Immunol,2007,120(1 Suppl):S2-S24.
[192]刘兆华,刘兆平,周庚寅.胭窝淋巴结试验在药物超敏反应研究中的应用[J].中国药理学与毒理学杂志,2009(1)：70-75.
[193]Gleichmann E, Gleichmann H. Graft-versus-host reaction:a pathogenetic principle for the development of drug allergy, autoimmunity, and malignant lymphoma in non-chimeric individuals. Hypothesis[J]. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol,1976,85(2):91～109.
[194]Samuelsen M, Nygaard U C, Lovik M. Allergy adjuvant effect of particles from wood smoke and road traffic[J]. Toxicology, 2008,246(2-3):124～131.
[195]Gutting B W, Updyke L W, Amacher D E. Diclofenac activates T cells in the direct popliteal lymph node assay and selectively induces IgG(1) and IgE against co-injected TNP-OVA[J]. Toxicol Lett,2002,131(3):167-180.
[196]Carey J B, Allshire A, van Pelt F N. Immune modulation by cadmium and lead in the acute reporter antigen-popliteal lymph node assay[J]. Toxicol Sci,2006,91(1):113-122.
[197]Aida T, Kimura T, Ishikawa N, et al. Evaluation of allergenic potential of low-molecular compounds by mouse popliteal lymph node assay[J]. J Toxicol Sci,1998,23(5):425-432.
[198]Nierkens S, Aalbers M, Bol M, et al. Differential requirement for CD28/CTLA-4-CD80/CD86 interactions in drug-induced type 1 and type 2 immune responses to trinitrophenyl-ovalbumin[J]. J Immunol,2005,175(6):3707～3714.
[199]Lovik M, Alberg T, Nygaard U C, et al. Popliteal lymph node (PLN) assay to study adjuvant effects on respiratory allergy[J]. Methods,2007,41(1):72～79.
[200]Kammuller M E, Thomas C, De Bakker J M, et al. The popliteal lymph node assay in mice to screen for the immune disregulating potential of chemicals--a preliminary study[J]. Int J Immunopharmacol,1989,11(3):293-300.
[201]Gehrs B C, Smialowicz R J. Persistent suppression of delayed-type hypersensitivity in adult F344 rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin[J]. Toxicology,1999,134(1):79-88.
[202]Ravel G, Descotes J. Popliteal lymph node assay:facts and perspectives[J]. J Appl Toxicol,2005,25(6):451-458.
[203]Isola D, Kimber I, Sarlo K, et al. Chemical respiratory allergy and occupational asthma:what are the key areas of uncertainty?[J]. J Appl Toxicol,2008,28(3):249-253.
[204]Pieters R, Albers R. Screening tests for autoimmune-related immunotoxicity[J]. Environ Health Perspect,1999.107 Suppl 5: 673-677.
[205]Albers R, Broeders A, van der Pijl A, et al. The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals[J]. Toxicol Appl Pharmacol,1997,143(1):102～109.
[2061 Nierkens S, van Helden P, Bol M, et al. Selective requirement for CD40-CD154 in drug-induced type 1 versus type 2 responses to trinitrophenyl-ovalbumin[J]. J Immunol,2002.168(8):3747-3754.
[207]Nierkens S. Aalbers M, Bol M. et al. Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens[J]. Toxicol Sci,2005,83(2):273-281.
[208]Yoshida A, Aoki R, Kimoto-Nira H. et al. Oral administration of live Lactococcus lactis C59 suppresses IgE antibody production in ovalbumin-sensitized mice via the regulation of interleukin-4 production[J]. FEMS Immunol Med Microbiol. 2011.61(3):315-322.
[209]Oliver M R. Tan D T. Scott R B. Colonic motor response to IgE-mediated mast cell degranulation in the Hooded-Lister rat[J]. Neurogastroenterol Motil,1996.8(2):121～130.
[210]Doyle R J. Smith C S. Cronholm L S. Histamine hypersensitivity in mice induced by concanavalin A[J]. J Allergy Clin Immunol,1978.61(2):108-114.
[211]Gutting B W, Updyke L W, Amacher D E. Investigating the TNP-OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans[J]. J Appl Toxicol,2002,22(3):177～183.
[212]Gutting B W, Schomaker S J, Kaplan A H, et al. A comparison of the direct and reporter antigen popliteal lymph node assay for the detection of immunomodulation by low molecular weight compounds[J]. Toxicol Sci,1999,51(1):71-79.
[213]Tanojo H, Wester R C, Shainhouse J Z, et al. Diclofenac metabolic profile following in vitro percutaneous absorption through viable human skin[J]. Eur J Drug Metab Pharmacokinet,1999,24(4):345～351.
[214]Dearman R J, Betts C J, Caddick H T, et al. Cytokine profiling of chemical allergens in mice:impact of mitogen on selectivity of response[J]. J Appl Toxicol,2009,29(3):233～241.
[215]Layton L L, Panzani R, Greene F C, et al. Atopic hypersensitivity to a protein of the green coffee bean and absence of allergic reactions to chlorogenic acid, low-molecular-weight components of green coffee, or to roasted coffee[J]. Int Arch Allergy Appl Immunol,1965,28(1):116-127.
[216]Layton L L, Greene F C, Panzani R. ALLERGY TO GREEN COFFEE. FAILURE OF PATIENTS ALLERGIC TO GREEN COFFEE TO REACT TO CHLOROGENIC ACID, ROASTED COFFEE, OR ORANGE[J]. J Allergy,1965,36:84-91.
[217]Freedman S O. ANTIGENIC PROPERTIES OF CHLOROGENIC ACID[J]. J Allergy,1964,35:97-107.
[218]Freedman S O, Siddiqi A I, Krupey J, et al. Identification of a simple chemical compound (chlorogenic acid) as an allergen in plant materials causing human atopic disease[J]. Trans Assoc Am Physicians,1962,75:99～106.
[219]李钦,张信岳,陈国神.含绿原酸的清热解毒类中药注射剂不良反应及其机理探讨[J].中国现代应用药学,2009(7)：555-558.
[220]裴振峨,翟伟,马军丽,等.北京地区1015例中药注射剂不良反应报告分析[J].临床药物治疗杂志,2009(2)：39-41.
[221]Naisbitt D J, Gordon S F, Pirmohamed M, et al. Immunological principles of adverse drug reactions:the initiation and propagation of immune responses elicited by drug treatment[J]. Drug Saf,2000,23(6):483～507.
[222]Xie C, Zhong D F, Chen X Y. [Metabolites of injected chlorogenic acid in rats][J]. Yao Xue Xue Bao,2011,46(1):88～95.
[223]Pirmohamed M, Naisbitt D J, Gordon F, et al. The danger hypothesis-potential role in idiosyncratic drug reactions[J]. Toxicology,2002,181-182:55-63.
[224]Nizard R S, Biau D, Porcher R, et al. A meta-analysis of patellar replacement in total knee arthroplasty[J]. Clin Orthop Relat Res,2005(432):196～203.
[225]Carnathan G W, Metcalf L E, Cochrane R L, et al. Relationship between progesterone suppression and pregnancy in rats[J]. J Pharm Pharmacol,1987,39(5):401-404.
[226]van der Worp H B, Sena E S, Donnan G A, et al. Hypothermia in animal models of acute ischaemic stroke:a systematic review and meta-analysis[J]. Brain,2007,130(Pt 12):3063-3074.
[227]Pound P, Ebrahim S, Sandercock P, et al. Where is the evidence that animal research benefits humans?[J]. BMJ, 2004,328(7438):514-517.
[228]Izrailev S, Zhu F, Agrafiotis D K. A distance geometry heuristic for expanding the range of geometries sampled during conformational search[J]. J Comput Chem,2006,27(16):1962～1969.
[229]Mercader A G, Duchowicz P R, Fernandez F M, et al. Replacement method and enhanced replacement method versus the genetic algorithm approach for the selection of molecular descriptors in QSPR/QSAR theories[J]. J Chem Inf Model,2010,50(9): 1542～1548.
[230]Pourbasheer E, Riahi S, Ganjali M R, et al. QSAR study of C allosteric binding site of HCV NS5B polymerase inhibitors by support vector machine[J]. Mol Divers,2011,15(3):645-653.
[231]de Molfetta F A, Angelotti W F, Romero R A, et al. A neural networks study of quinone compounds with trypanocidal activity[J]. J Mol Model,2008,14(10):975-985.
[232]Rastija V, Medic-Saric M. QSAR study of antioxidant activity of wine polyphenols[J]. Eur J Med Chem,2009,44(1): 400～408.
[233]Mercader A G, Duchowicz P R, Fernandez F M, et al. Replacement method and enhanced replacement method versus the genetic algorithm approach for the selection of molecular descriptors in QSPR/QSAR theories[J]. J Chem Inf Model,2010,50(9): 1542～1548.
[234]Weber K C, Da S A. A chemometric study of the 5-HT(1A) receptor affinities presented by arylpiperazine compounds[J]. Eur J Med Chem,2008,43(2):364-372.
[235]Todeschini R, Vighi M, Finizio A, et al.3D-modelling and prediction by WHIM descriptors. Part 8. Toxicity and physico-chemical properties of environmental priority chemicals by 2D-TI and 3D-WHIM descriptors[J]. SAR QSAR Environ Res, 1997,7(1-4):173～193.
[236]Rasulev B F, Abdullaev N D, Syrov V N, et al. A Quantitative Structure-Activity Relationship (QSAR) study of the antioxidant activity of flavonoids[J]. Qsar & Combinatorial Science,2005,24(9):1056-1065.
[237]国家食品药品监督管理局.中药、天然药物免疫毒性(过敏性、光过敏性)研究的技术指导原则[M].[Z]GPT5-1,2005.
[238]Casp.10 questions to help you make sense of qualitative research[M].2006.
[239]王志国,王丹巧,于友华,等.清开灵注射液中绿原酸致敏性的研究[J].2011
[240]张信岳,陈爱君,李钦,等绿原酸主动全身过敏与被动皮肤过敏的实验研究[J] 2011
[241]林敏,钱华勤,张彤.等.绿原酸致过敏反应的买验研究[J].2010
[242]郭姗姗.王意忠,金亚宏,等.BN大鼠用于评价中药注射液速发型过敏反应模型的建立及适用性评价[J].中国中药杂志,2011(14)：1845-1849
[243]黄晓舞,廖红波,刘屏,等CGA-BSA致豚鼠过敏反应及其机制的研究[J].中国中药杂志,2010(09)：1181-1184
[244]罗飞,包旭,林大胜.等.绿原酸对动物的致敏性研究[J].华西药学杂志,2009(02)：181-183
[245]何洲.绿原酸与清开灵注射液过敏反应相关性的研究.北京中医药大学,2011.
[246]吴晓冬,杨华蓉,林大胜,等.绿原酸致敏性的综合研究与评价[J]中国甲药杂志,2010(24)：3357-3361
[247]李瑾翡,黎旸,陈琪,等.注射用双黄连的免疫毒性研究[J]中药新药与临床药理,2008(03)：172-174
[248]张瑞霞,汤纳平,等.绿原酸和双黄连粉针剂致敏性比较评价[J]世界科学技术(甲医药现代化).2010(06)：1005-1008
[249]Gong J. Liu F T, Chen S S. Polyphenolic antioxidants enhance lgE production[J]. Immunol Invest,2004,33(3):295-307.
[250]Lin M, Gong W, Wang Y, et al. Structure-Activity Differences of Chlorogenic Acid and Its Isomers on Sensitization via Intravenous Exposure[J]. Int J Toxicol,2012.
[251]Liu Z, Liu Z, Shi Y, et al. Evaluation of the immunosensitizing potential of chlorogenic acid using a popliteal lymph node assay in BALB/c mice[J]. Food Chem Toxicol,2010,48(4):1059-1065.
[252]Nizard R S, Biau D, Porcher R, et al. A meta-analysis of patellar replacement in total knee arthroplasty[J]. Clin Orthop Relat Res,2005(432):196～203.
[253]Friedrich J O, Adhikari N K, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data[J]. BMC Med Res Methodol,2007,7:5.
[254]国家药典委员会2010版中华人民共和国药典一部.北京：2010
[255]Frew A. General principles of investigating and managing drug allergy [J]. Br J Clin Pharmacol,2011,71(5):642-646.
[256]Inaba K, Inaba M. Antigen recognition and presentation by dendritic cells[J]. Int J Hematol,2005,81(3):181-187.
[2571 Banchereau J, Steinman R M. Dendritic cells and the control of immunity[J]. Nature,1998,392(6673):245-252.
[258]Meyers J H, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation[J]. Nat Immunol,2005,6(5):455-464.
[259]Umetsu S E, Lee W L, Mcintire J J, et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance[J]. Nat Immunol,2005,6(5):447-454.
[260]Meyers J H, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation[J]. Nat Immunol,2005,6(5):455-464.
[261]Kuchroo V K, Meyers J H, Umetsu D T, et al. TIM family of genes in immunity and tolerance[J]. Adv Immunol,2006,91: 227-249.
[262]Liu T, He S H, Zheng P Y, et al. Staphylococcal enterotoxin B increases TIM4 expression in human dendritic cells that drives naive CD4 T cells to differentiate into Th2 cells[J]. Mol Immunol,2007,44(14):3580-3587.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |