跳到主要內容

臺灣博碩士論文加值系統

(3.235.56.11) 您好!臺灣時間:2021/07/29 04:44
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:鐘文宏
研究生(外文):Wen-Hung Chung
論文名稱:史帝文生強生症候群和毒性表皮溶解症的基因體學及免疫學研究
論文名稱(外文):Genomic and immunologic studies of Stevens-Johnson syndrome and toxic epidermal necrolysis
指導教授:陳垣崇陳垣崇引用關係
指導教授(外文):Yuan-Tsong Chen
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
畢業學年度:97
語文別:英文
論文頁數:183
中文關鍵詞:史帝文生強生症毒性表皮溶解症卡巴氮平人類白血球抗原藥物基因體學顆粒溶解素
外文關鍵詞:Stevens-Johnson syndrometoxic epidermal necrolysiscarbamazepinehuman leukocyte antigenpharmacogeneticsgranulysin
相關次數:
  • 被引用被引用:0
  • 點閱點閱:328
  • 評分評分:
  • 下載下載:59
  • 收藏至我的研究室書目清單書目收藏:0
史帝文生強生症和毒性表皮溶解症是由於服用過敏藥物而造成大量表皮壞死的致死性藥物不良反應,其個體的易感受基因或疾病的危險訊息尚未清楚。我們進行卡巴氮平及異嘌呤醇引發史帝文生強生症、毒性表皮溶解症或藥物過敏症候群的藥物基因體學研究,利用病例-對照組關聯性研究及候選基因方法,發現卡巴氮平引發史帝文生強生症、毒性表皮溶解症和人類白血球抗原:HLA-B*1502基因有強烈相關聯,而異嘌呤醇引發史帝文生強生症、毒性表皮溶解症及藥物過敏症候群和人類白血球抗原:HLA-B*5801基因有強烈相關聯。為了要進一步確認卡巴氮平引發史帝文生強生症、毒性表皮溶解症的易感受基因,我們利用211個單一核苷酸多型性標誌和20個短串聯重複多型性標誌在含有4百萬鹼基的主要組織相容複合體區域做微細定位,發現卡巴氮平引發史帝文生強生症和毒性表皮溶解症的易感受基因是位於rs3130690/HLA-B*1502/MICA*019之間共82000個鹼基之內,在這個區域內HLA-B*1502是唯一的基因。這些資料顯示HLA-B*1502是卡巴氮平引發史帝文生強生症和毒性表皮溶解症的主要易感受基因。除此之外,我們也研究史帝文生強生症和毒性表皮溶解症的免疫媒介因子,發現由史帝文生強生症和毒性表皮溶解症的皮膚病灶處分離出的水泡液細胞主要是由毒殺性T淋巴球和自然殺手細胞所組成,水泡液和水泡液細胞兩者都有細胞毒性。基因表現分析發現顆粒溶解素是表現最多的毒性分子,並且利用定量聚合酵素連鎖反應及免疫組織化學染色進一步確定。在水泡液中,顆粒溶解素的濃度高於打洞素、顆粒酵素B或溶解性Fas配合體的濃度2000~3000倍,若將顆粒溶解素從水泡液中去除則會減少細胞毒性。在水泡液中的顆粒溶解素是15-kDa分泌型,打到小鼠皮膚會產生史帝文生強生症和毒性表皮溶解症相似症狀。這些發現證明分泌型的顆粒溶解素是是造成史帝文生強生症和毒性表皮溶解症表皮細胞大量壞死的主要分子,並且揭示由毒殺性T淋巴球和自然殺手細胞所媒介的細胞毒性是不須要直接細胞接觸的機制。
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific susceptible genes/danger signals involved remain unclear. We carried out pharmacogenomics studies on carbamazepine (CBZ)/allopurinol-induced SJS/TEN, and hypersensitivity syndrome (HSS). By using the candidate gene approach in case-control designed association studies, we found that CBZ-induced SJS/TEN is strongly associated with human leukocyte antigen, HLA-B*1502, and allopurinol-induced SJS/TEN/HSS with HLA-B*5801, respectively. To verify the susceptible gene for CBZ-induced SJS/TEN, we further performed fine mapping in 4-Mb of the major histocompatibility complex (MHC) region using 211 SNPs and 20 short tandem repeat polymorphisms (STRP). Our data revealed that the susceptible gene for CBZ-induced SJS/TEN is located within 82 kb (rs3130690/HLA-B*1502/MICA*019), where HLA-B*1502 gene is the only one in this region. These data suggest that HLA-B*1502 is the major susceptible gene for CBZ-SJS/TEN. In addition, we studied the immune mediators of SJS/TEN. We found that blister cells from skin lesions of SJS/TEN primarily consisted of cytotoxic T lymphocytes and natural killer cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most expressed cytotoxic molecule, confirmed by qPCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand and depleting granulysin from the blister fluid reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form and injection into mouse skin resulted in features mimicking SJS/TEN. Our findings demonstrate the secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS/TEN and highlight a mechanism for cytotoxic T lymphocyte or natural killer cells-mediated cytotoxicity that does not require the direct cellular contact.
CONTENTS
PAGE
I ABSTRACT
I-1 Chinese abstract…………………………………………... 5
I-2 English abstract…………………………………………… 7
II INTRODUCTION
II-1 Drug hypersensitivity……………………………………... 9
II-2 Clinical features of SJS/TEN……………………………... 10
II-3 Epidemiology of SJS/TEN………………………………... 11
II-4 The pathogenesis of SJS/TEN……………………………. 13
II-5 Prior studies of HLA association and drug hypersensitivity 14
II-6 Carbamazepine-induced drug hypersensitivity…………… 16
II-7 Allopurinol-induced drug hypersensitivity……………….. 18
II-8 Specific aims……………………………………………… 19
III MATERIALS AND METHODS
III-1 Patients and control subjects recruitment………………… 20
III-2 DNA isolation and STRP genotyping…………………….. 23
III-3 SNP genotyping on MHC region and metabolic enzymes for CBZ-cADRs…………………………………………... 24
III-4 SNP genotyping on MHC region and metabolic enzymes for allopurinol-cADRs……………………………………. 25
III-5 HLA Genotyping………………………………………….. 25
III-6 Statistical analyses for genomic studies…………………... 27
III-7 Immunophenotyping of SJS/TEN blister cells.................... 27
III-8 In vitro cytotoxicity assays……………………………….. 28
III-9 Affymetrix expression microarray and analysis………….. 29
III-10 Quantitative RT-PCR and copy number determination of mRNA…………………………………………………….. 30
III-11 Immunoblots and immunohistochemistry staining……….. 31
III-12 Enzyme-Linked Immunosorbent Assay (ELISA)………… 32
III-13 Expression and purification of the recombinant granulysin protein……………………………………………………... 32
III-14 Depleting granulysin and other cytotoxic proteins from SJS/TEN blister fluids…………………………………….. 34
III-15 Intradermal injections of granulysin protein into mouse skin………………………………………………………... 34
IV RESULTS
IV-1 Characteristics of carbamazepine-cADRs patients and controls……………………………………………………. 36
IV-2 Association of HLA-B*1502 and CBZ-SJS/TEN………… 36
IV-3 Fine mapping of the major histocompatibility complex region for genetic susceptibility to CBZ-SJS/TEN……….. 37
IV-4 Association screen for candidate gene SNPs with CBZ-MPE/HSS…………………………………………… 39
IV-5 Characteristics of allopurinol-cADRs patients and controls 41
IV-6 Association screen for candidate gene SNPs of allopurinol-SCAR………………………………………… 42
IV-7 Association of HLA-B*5801 and allopurinol-SCAR…….. 43
IV-8 Blister fluids and cells of SJS/TEN patients displayed cytotoxicity……………………………………………….. 44
IV-9 Up-regulated CTL/NK pathway in the blister cells of SJS/TEN patients…………………………………………. 45
IV-10 Highly expressed granulysin protein in the skin lesions of SJS/TEN patients…………………………………………. 46
IV-11 High level of granulysin protein in the blister fluids and correlation to clinical severity…………………………….. 47
IV-12 In vitro cytotoxicity of the 15 kDa granulysin protein……. 48
IV-13 In vivo injection of 15 kDa granulysin induced significant epidermal necrosis………………………………………… 49
V DISCUSSION
V-1 Strong genetic association of HLA-B*1502 and carbmazepine- induced SJS/TEN in Han Chinese………... 50
V-2 Genetic association of HLA-B*1502 and CBZ-SJS/TEN is ethnicity-specific………………………………………….. 52
V-3 HLA B*1502 allele frequency is positively correlated with the prevalence of CBZ-SJS/TEN in different populations... 52
V-4 HLA-B*1502 as a test to identify individuals at risk for CBZ-induced SJS/TEN…………………………………… 53
V-5 Association study of HLA and flanking genes and CBZ-MPE/HSS…………………………………………… 54
V-6 Strong genetic association of HLA-B*5801 and allopurinol-SCAR…………………………………………. 57
V-7 Association between HLA and other drug induced hypersensitivity…………………………………………… 58
V-8 Granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS/TEN…………….. 60
VI References 65
VII TABLES 75
VIII FIGURES 91
IX RELATED PUBLICATIONS 104
1. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 279(15), 1200-1205 (1998).
2. Pirmohamed M, Naisbitt DJ, Gordon F, Park BK: The danger hypothesis--potential role in idiosyncratic drug reactions. Toxicology. 181-182, 55-63 (2002).
3. Gomes, E.R. & Demoly, P. Epidemiology of hypersensitivity drug reactions. Curr. Opin. Allergy Clin. Immunol. 5,309-316 (2005).
4. Roujeau JC: Clinical heterogeneity of drug hypersensitivity. Toxicology. 209(2), 123-129 (2005).
5. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006;7:889-908.
6. Roujeau, J.C. Immune mechanisms in drug allergy. Allergol. Int. 55,27-33(2006).
7. Pichler WJ, Beeler A, Keller M, et al. Pharmacological interaction of drugs with immune receptors: the p-i concept. Allergol Int. 2006;55:17-25.
8. Roujeau JC, Stern RS: Severe adverse cutaneous reactions to drugs. N. Engl. J. Med. 331(19), 1272-1285 (1994).
9. Roujeau JC, Kelly JP, Naldi L et al.: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N. Engl. J. Med. 333(24), 1600-1607 (1995).
10. Roujeau JC: The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J. Invest. Dermatol. 102(6), 28S-30S (1994).
11. Paul C, Wolkenstein P, Adle H et al.: Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br. J. Dermatol. 134(4), 710-714 (1996).
12. Cheriyan S, Patterson R, Greenberger PA et al.: The outcome of Stevens-Johnson syndrome treated with corticosteroids. Allergy Proc. 16(4), 151-155 (1995).
13. Bachot N, Roujeau JC: Intravenous immunoglobulins in the treatment of severe drug eruptions. Curr. Opin. Allergy Clin. Immunol. 3(4), 269-274 (2003).
14. Di Pascuale MA, Espana EM, Liu DT et al.: Correlation of corneal complications with eyelid cicatricial pathologies in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis syndrome. Ophthalmology. 112(5), 904-912 (2005).
15. Spies M, Sanford AP, Aili Low JF, Wolf SE, Herndon DN: Treatment of extensive toxic epidermal necrolysis in children. Pediatrics. 108(5), 1162-1168 (2001).
16. Yetiv JZ, Bianchine JR, Owen JA Jr: Etiologic factors of the Stevens-Johnson syndrome. South Med. J. 73(5), 599-602 (1980).
17. Rzany B, Mockenhaupt M, Baur S et al.: Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J. Clin. Epidemiol. 49(7), 769-773 (1996).
18. Chan HL, Stern RS, Arndt KA et al.: The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch. Dermatol. 126(1), 43-47 (1990).
19. Sharma VK, Sethuraman G, Kumar B: Cutaneous adverse drug reactions: clinical pattern and causative agents--a 6 year series from Chandigarh, India. J. Postgrad. Med. 47(2), 95-99 (2001).
20. Khoo AK, Foo CL: Toxic epidermal necrolysis in a burns centre: a 6-year review. Burns. 22(4), 275-278 (1996).
21. Kamaliah MD, Zainal D, Mokhtar N, Nazmi N: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in northeastern Malaysia. Int. J. Dermatol. 37(7), 520-523 (1998).
22. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern R: Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet. 353(9171), 2190-2194 (1999).
23. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J: Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 64(7), 1134-1138 (2005).
24. Nassif, A. et al. Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J. Invest. Dermatol. 118,728-733(2002).
25. Nassif, A. et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J. Allergy Clin. Immunol. 114,1209-1215(2004).
26. Quinn, A.M. et al. Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis. Arch. Dermatol. 141,683-687(2005).
27. Viard, I. et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282,490-493(1998).
28. Pereira, F.A., Mudgil, A.V. & Rosmarin, D.M. Toxic epidermal necrolysis. J. Am. Acad. Dermatol. 56,181-200(2007).
29. Abe, R. et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am. J. Pathol. 162,1515-1520(2003).
30. Stur, K., Karlhofer, F.M. & Stingl, G. Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas. J. Invest. Dermatol. 127,802-807(2007).
31. Brönnimann, M. & Yawalkar, N. Histopathology of drug-induced exanthems: is there a role in diagnosis of drug allergy? Curr. Opin. Allergy Clin. Immunol. 5,317-321(2005).
32. Chave, T.A., Mortimer, N.J., Sladden, M.J., Hall, A.P. & Hutchinson, P.E. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br. J. Dermatol. 153,241-253(2005).
33. Zanni, M.P., von Greyerz, S., Schnyder, B., Brander, K.A., Frutig, K., Hari, Y., Valitutti, S. & Pichler, W.J. (1998) J. Clin. Invest. 102, 1591-1598.
34. Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol. 2006;24:419-466.
35. Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889-899.
36. website: www.ihwg.org [International Histocompatibility Working Group (IHWG)]
37. Fleischhauer K, Kernan NA, O'Reilly RJ, et al. Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44. N Engl J Med. 1990;323:1818-1822.
38. Fischer PR, Shigeoka AO: Familial occurrence of Stevens-Johnson syndrome. Am. J. Dis. Child. 137(9), 914-916 (1983).
39. Johnson-Reagan L, Bahna SL: Severe drug rashes in three siblings simultaneously. Allergy. 58(5), 445-447 (2003).
40. Pritchett JH, Austin AC: Stevens-Johnson syndrome occurring in identical twins with apparent response to terramycin and aureomycin. J. Med. Assoc. Ga. 40(9), 374-376 (1951).
41. Edwards SG, Hubbard V, Aylett S, Wren D. Concordance of primary generalised epilepsy and carbamazepine hypersensitivity in monozygotic twins. Postgrad Med J. 1999;75:680-681.
42. Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol. 1992;34:377-395.
43. Wolkenstein P, Carriere V, Charue D et al.: A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Pharmacogenetics. 5(4), 255-258 (1995).
44. Roujeau JC, Huynh TN, Bracq C, et al. Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol. 1987;123:1171-1173.
45. Shirato S, Kagaya F, Suzuki Y, Joukou S. Stevens-Johnson syndrome induced by methazolamide treatment. Arch Ophthalmol. 1997;115:550-553.
46. Chan SH, Tan T. HLA and allopurinol drug eruption. Dermatologica. 1989;179:32-33.
47. Lieberman JA, Yunis J, Egea E, et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990;47:945-948.
48. Vlahov V, Bacracheva N, Tontcheva D, et al. Genetic factors and risk of agranulocytosis from metamizol. Pharmacogenetics. 1996;6:67-72.
49. Diez RA. HLA-B27 and agranulocytosis by levamisole. Immunol Today. 1990;11:270.
50. Rodriguez-Perez M, Gonzalez-Dominguez J, Mataran L, et al. Association of HLA-DR5 with mucocutaneous lesions in patients with rheumatoid arthritis receiving gold sodium thiomalate. J Rheumatol. 1994;21:41-43.
51. Batchelor JR, Welsh KI, Tinoco RM, et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet. 1980;1:1107-1109.
52. Speerstra F, Reekers P, van de Putte LB, et al. HLA-DR antigens and proteinuria induced by aurothioglucose and D-penicillamine in patients with rheumatoid arthritis. J Rheumatol. 1983;10:948-953.
53. Albani F, Riva R, Baruzzi A: Carbamazepine clinical pharmacology: a review. Pharmacopsychiatry. 28(6), 235-244 (1995).
54. Ambrosio AF, Soares-Da-Silva P, Carvalho CM, Carvalho AP: Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res. 27(1-2), 121-130 (2002).
55. Leeder JS. Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 1998; 39 Suppl 7:S8-16.
56. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995; 155:2285-2290.
57. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology 1997; 49:542-546.
58. Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994; 47:1969-1979.
59. Madden S, Maggs JL, Park BK. Bioactivation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide(s). Drug Metab Dispos 1996; 24:469-479.
60. Bellucci G, Berti G, Chiappe C, Lippi A, Marioni F. The metabolism of carbamazepine in humans: steric course of the enzymatic hydrolysis of the 10,11-epoxide. J Med Chem 1987; 30:768-773.
61. Lillibridge JH, Amore BM, Slattery JT, Kalhorn TF, Nelson SD, Finnell RH, et al. Protein-reactive metabolites of carbamazepine in mouse liver microsomes. Drug Metab Dispos 1996; 24:509-514.
62. Gaedigk A, Pirmohamed M, Park BK et al.: Genetic polymorphisms of NAD(P)H:quinone reductase (NQO1) and catechol O-methyl transferase (COMT) in patients with anticonvulsant hypersensitivity reactions. Proceedings of the XIth International Symposium on Microsomes Drug Oxidations. [Abstract]-198 (1996).
63. Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics 1994; 4:142-153.
64. Green VJ, Pirmohamed M, Kitteringham NR, Gaedigk A, Grant DM, Boxer M, et al. Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. Biochem Pharmacol 1995; 50:1353-1359.
65. Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler WJ. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995; 155:462-472.
66. Naisbitt DJ, Britschgi M, Wong G et al.: Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol. Pharmacol. 63(3), 732-741 (2003).
67. Houwerzijl J, De Gast GC, Nater JP, Esselink MT, Nieweg HO: Lymphocyte-stimulation tests and patch tests to carbamazepine hypersensitivity. Clin. Exp. Immunol. 29(2), 272-277 (1977).
68. Pirmohamed M, Lin K, Chadwick D, Park BK: TNFalpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients. Neurology. 56(7), 890-896 (2001).
69. Wortmann RL.Gout and hyperuricemia. Curr Opin Rheumatol. 2002 May;14(3):281-6.
70. Terkeltaub RA.Clinical practice. Gout. N Engl J Med. 2003 Oct 23;349(17):1647-55.
71. Auböck J, Fritsch P.Asymptomatic hyperuricaemia and allopurinol induced toxic epidermal necrolysis.Br Med J (Clin Res Ed). 1985 Jun 29;290(6486):1969-70.
72. Arellano F, Sacristán JA.Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother. 1993 Mar;27(3):337-43.
73. Braden GL, Warzynski MJ, Golightly M, Ballow M.Cell-mediated immunity in allopurinol-induced hypersensitivity. Clin Immunol Immunopathol. 1994 Feb;70(2):145-51.
74. Melsom RD.Familial hypersensitivity to allopurinol with subsequent desensitization.Rheumatology (Oxford). 1999 Dec;38(12):1301.
75. Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol 2001; 137:357-364.
76. Sugden, B. & Mark, W. Clonal transformation of adult human leukocytes by Epstein-Barr virus. J. Virol. 23,503-508(1977).
77. Smigielski EM, Sirotkin K, Ward M, Sherry ST. dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res 2000; 28:352-355.
78. Walsh EC, Mather KA, Schaffner SF, Farwell L, Daly MJ, Patterson N, et al. An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 2003; 73:580-590.
79. Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 2004; 101:4180-4185.
80. Middleton D. Current and emerging technology for HLA typing. Int J Hematol 2002; 76 Suppl 2:150-151.
81. Tilanus MGJ, Hansen JA, Hurley CK. Technical manual of 13th International Histocompatibility Working Group (IHWG), genomic Analysis of the Human MHC DNA-Based Typing for HLA Alleles and Linked Polymorphisms. Seattle, USA. (ISBN number: 0-945278-02-0) 2002.
82. Chu CC, Lin M, Nakajima F, Lee HL, Chang SL, Juji T, et al. Diversity of HLA among Taiwan's indigenous tribes and the Ivatans in the Philippines. Tissue Antigens. 2001; 58:9-18.
83. Schaid DJ, Jacobsen SJ. Biased tests of association: comparisons of allele frequencies when departing from Hardy-Weinberg proportions. Am J Epidemiol 1999; 149:706-711.
84. Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956; 20:309-311.
85. Alley, M.C. et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 48,589-601(1988).
86. Kramer HM, Curhan G.The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994.Am J Kidney Dis. 2002 Jul;40(1):37-42.
87. Young JL Jr, Boswell RB, Nies AS.Severe allopurinol hypersensitivity. Association with thiazides and prior renal compromise. Arch Intern Med. 1974 Sep;134(3):553-8.
88. Hildesheim, A., Apple, R.J., Chen, C.J., Wang, S.S., Cheng, Y.J., Klitz, W., Mack, S.J., Chen, I.H., Hsu, M.M., Yang, C.S., Brinton, L.A., Levine, P.H. & Erlich, H.A. (2002) J. Natl. Cancer Inst. 94, 1780-1789.
89. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428:486.
90. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16:297-306.
91. Pichler WJ. Modes of presentation of chemical neoantigens to the immune system. Toxicology 2002; 181-182:49-54.
92. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102:4134-4139.
93. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359:727-732
94. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of an HL-A antigen, W27, with ankylosing spondylitis. N. Engl. J. Med. 288(14), 704-706 (1973).
95. Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, Graf E, Schumacher M, Hovnanian A, Mockenhaupt M, Roujeau JC; RegiSCAR Group.A marker for Stevens-Johnson syndrome ...: ethnicity matters.Pharmacogenomics J. 2006 Jul-Aug;6(4):265-8.
96. Alfirevic A, Jorgensen AL, Williamson PR, et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics. 2006;7:813-818.
97. Hughes AR, Mosteller M, Bansal AT, et al.; CNA30027 Study Team; CNA30032 Study Team. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics. 2004;5:203-211.
98. Daar AS, Singer PA: Pharmacogenetics and geographical ancestry: implications for drug development and global health. Nat. Rev. Genet. 6(3), 241-246 (2005).
99. Wilson JF, Weale ME, Smith AC et al.: Population genetic structure of variable drug response. Nat. Genet. 29(3), 265-269 (2001).
100. dbMHC Home (http://www.ncbi.nlm.nih.gov/mhc/MHC.cgi?cmd=init)
101. Allele Frequencies (http://www.allelefrequencies.net/)
102. Phillips KA, Veenstra D, Van Bebber S, Sakowski J: An introduction to cost-effectiveness and cost-benefit analysis of pharmacogenomics. Pharmacogenomics. 4(3), 231-239 (2003).
103. Nolan D, Gaudieri S, Mallal S: Pharmacogenetics: a practical role in predicting antiretroviral drug toxicity? J. HIV Ther. 8(2):36-41 (2003).
104. Alfirevic A, Mills T, Harrington P, et al. Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster. Pharmacogenet Genomics. 2006;16:287-296.
105. Hung SI, Chung WH, Chen YT. Genetics of severe drug hypersensitivity reactions in Han Chinese. In: Drug Hypersensitivity. First Edition. Edited by Pichler WJ (editor). Basel, Karger; 2007. pp.55-64.
106. Dainachi T: Common HLA allele presented in the case of Stevens-Johnson syndrome and drug-induced hypersensitivity syndrome by allopurinol. 7th International Congress on Cutaneous Adverse Drug Reactions, Paris, September 6, 2006, abstract 608.
107. Lonjou C: A European genetic study of Stevens-Johnson syndrome and toxic epidermal necrolysis: HLA-B associations with specific high-risk drugs. 7th International Congress on Cutaneous Adverse Drug Reactions, Paris, September 6, 2006, abstract 207.
108. Hande KR, Noone RM, Stone WJ.Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984 Jan;76(1):47-56.
109. Vázquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R.Relation between adverse events associated with allopurinol and renal function in patients with gout.Ann Rheum Dis. 2001 Oct;60(10):981-3.
110. Emmerson BT.The management of gout.N Engl J Med. 1996 Feb 15;334(7):445-51.
111. Suzuki Y, Inagi R, Aono T, Yamanishi K, Shiohara T.Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome.Arch Dermatol. 1998 Sep;134(9):1108-12.
112. Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC, Alnemri ES.FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.J Biol Chem. 1997 Jul 25;272(30):18542-5.
113. Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H.Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand.Am J Pathol. 2003 May;162(5):1515-20.
114. Gati A, Guerra N, Gaudin C, Da Rocha S, Escudier B, Lécluse Y, Bettaieb A, Chouaib S, Caignard A.CD158 receptor controls cytotoxic T-lymphocyte susceptibility to tumor-mediated activation-induced cell death by interfering with Fas signaling.Cancer Res. 2003 Nov 1;63(21):7475-82.
115. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359:1121-1122.
116. Phillips EJ. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis. 2006;43:103-105.
117. Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis. 2006;43:99-102.
118. Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS. 2005;19:97-99.
119. Littera R, Carcassi C, Masala A, et al. HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients. AIDS. 2006;20:1621-1626.
120. Kim SH, Choi JH, Lee KW, et al. The human leucocyte antigen-DRB1*1302-DQB1*0609-DPB1*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin Exp Allergy. 2005;35:339-344.
121. Kim SH, Ye YM, Lee SK, Park HS. Genetic mechanism of aspirin-induced urticaria/angioedema. Curr Opin Allergy Clin Immunol. 2006;6:266-270.
122. Ueta M, Sotozono C, Tokunaga K, et al. Strong association between HLA-A*0206 and Stevens-Johnson syndrome in the Japanese. Am J Ophthalmol. 2007;143:367-368.
123. Gamen, S. et al. Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways. J. Immunol. 161,1758-1764(1998).
124. Stenger, S. et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282,121-125(1998).
125. Hanson, D.A., Kaspar, A.A., Poulain, F.R. & Krensky, A.M. Biosynthesis of granulysin, a novel cytolytic molecule. Mol. Immunol. 36,413-422(1999).
126. Krensky, A.M. & Clayberger, C. Granulysin: a novel host defense molecule. Am. J. Transplant. 5,1789-1792(2005).
127. Anderson, D.H. et al. Granulysin crystal structure and a structure-derived lytic mechanism. J. Mol. Biol. 325,355-365(2003).
128. Pardo, J. et al. A role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis. J. Immunol. 167,1222-1229(2001).
129. Deng, A. et al. Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J. Immunol. 174,5243-5248(2005).
130. Peña, S.V., Hanson, D.A., Carr, B.A., Goralski, T.J. & Krensky, A.M. Processing, subcellular localization, and function of 519 (granulysin), a human late T cell activation molecule with homology to small, lytic, granule proteins. J. Immunol. 158,2680-2688(1997).
131. Ogawa, K. et al. Granulysin in human serum as a marker of cell-mediated immunity. Eur. J. Immunol. 33,1925-1933(2003).
132. Nagasawa, M. et al. Analysis of serum granulysin in patients with hematopoietic stem-cell transplantation: its usefulness as a marker of graft-versus-host reaction. Am. J. Hematol. 81,340-348(2006).
133. Balaji KN. et al. Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation. J. Exp. Med. 196,493-503(2002).
134. Correia, O. et al. CD8+ lymphocytes in the blister fluid of severe acute cutaneous graft-versus-host disease: further similarities with toxic epidermal necrolysis. Dermatology. 203,212-216(2001).
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊