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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28224完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩 | |
| dc.contributor.author | Jui Wu | en |
| dc.contributor.author | 吳睿 | zh_TW |
| dc.date.accessioned | 2021-06-13T00:03:04Z | - |
| dc.date.available | 2008-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-31 | |
| dc.identifier.citation | 1. Little, M.T. and R. Storb, History of haematopoietic stem-cell transplantation. Nat Rev Cancer, 2002. 2(3): p. 231-8.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28224 | - |
| dc.description.abstract | 造血幹細胞移植(hematopoietic stem cell transplantation, HSCT)用以治療多種良性及惡性血液疾病與先天性免疫缺乏疾病。然而在HLA相容的異體移植中，仍有20-40%病人會發生移植體抗宿主疾病(graft-versus-host disease, GVHD)，顯示非HLA基因(non-HLA)的多型性對於移植後的臨床結果有所影響。本論文從兩方面探討non-HLA基因多型性對HSCT的影響：(1)捐贈者和病人次要組織相容性抗原(minor histocompatibility antigen, mHag) HA-1及HA-2的不相容；(2)T細胞調控基因CTLA-4及ICOS的基因多型性。為排除HLA的影響，總計收集123對帶有HLA-A2及/或HLA-B60之HLA-matched sibling HSCT病人及捐贈者的DNA檢體，利用DNA定序法做HLA-A2基因型鑑定，及聚合酶連鎖反應加上限制酶片段長度多型性(polymerase chain reaction- restriction fragment length polymorphism) 方法鑑定HA-1、HA-2、CTLA-4 -318C/T、CTLA-4 +49A/G、ICOS c.602及ICOS c.1624的基因型。並將病人和捐贈者的基因型與移植後的臨床結果，包括：急性GVHD、慢性GVHD、疾病復發、無疾病存活(disease-free survival)和總存活(overall survival)，進行單變項及多變項統計分析。結果發現：HA-1不相容對於移植後急性和慢性GVHD、復發、disease-free survival和overall survival的臨床結果皆無顯著影響。另外，在HLA-A*0201+的病人與捐贈者間未發現HA-2不相容，同時在306例對照組中亦未發現非免疫性(non-immunogenic)的HA-2M/M基因型者，顯示HA-2不相容在臺灣對於評估HSCT臨床結果可能不重要。另一方面，在多變項分析中顯示：捐贈者的CTLA-4 -318T allele，會使病人發生急性GVHD的可能性增加(P=0.0133; OR=3.25; 95% CI, 1.28-8.26)，尤其捐贈者為CTLA-4 -318T/T基因型時，其病人復發率會增加(P =0.0313; HR=5.91; 95% CI, 1.17-29.79)。再者，捐贈者為ICOS c.602C/C基因型時，對於病人disease-free survival (P=0.0115; HR=5.97; 95% CI, 1.49-23.87)有顯著的不良影響。此外，病人為ICOS c.1624T/T基因型對於overall survival(P=0.0019; HR=12.98; 95% CI, 2.58-65.35)亦有顯著的不良影響。總結本論文研究結果，mHag HA-1/HA-2 不相容在臺灣對於移植後的臨床結果可能沒有影響，另一方面，帶有CTLA-4 -318T/T與ICOS c.602C/C基因型的捐贈者及帶有ICOS c.1624T/T 基因型的病人，在移植後的臨床結果較差，這顯示病人和捐贈者之T細胞調控基因的多型性會影響移植後病人的臨床結果。 | zh_TW |
| dc.description.abstract | Hematopoietic stem cell transplantation (HSCT) has evolved into an effective therapy for non-malignant and malignant hematological diseases as well as congenital immunodeficiencies. Graft-versus-host disease (GVHD) occurs in 20-40% of patients even with HLA-matched allogeneic HSCT. It indicates that non-HLA genetic polymorphisms may influence HSCT outcome. In this study, we investigated the impacts of non-HLA genetic polymorphisms on the outcome of HLA-matched sibling HSCT including: (1) minor histocompatibility antigens HA-1 and HA-2 mismatch; (2) polymorphisms of T cell regulatory genes, CTLA-4 and ICOS, in patients and donors. In order to exclude the effect of HLA, 123 pairs of DNA samples of HLA-A2- and/or HLA-B60-positive HLA-matched sibling HSCT were recruited. HLA-A2 alleles were identified by sequencing-based typing. Genotypes of single nucleotide polymorphisms at HA-1, HA-2, CTLA-4 -318C/T, CTLA-4 +49A/G, ICOS c.602A/C and ICOS c.1624C/T were analyzed by polymerase chain reaction and restriction fragment length polymorphism. The non-HLA genetic polymorphisms were examined for the association with HSCT outcome, including acute GVHD, chronic GVHD, disease relapse, disease-free survival and overall survival, by univariable and multivariable analyses. The results showed there was no significant correlation between HA-1 mismatch and the outcome of HSCT. Besides, no HA-2 mismatch was found in the cases studied and no non-immunogenic HA-2M/M genotype in control population, either. It suggestes that HA-2 mismatch may not be essential to evaluate HSCT outcome in Taiwan. In multivariable analyses, donor CTLA-4 -318T/T genotype, donor ICOS c.602C/C genotype and recipient ICOS c.1624T/T genotype had influence on HSCT outcome. Donor CTLA-4 -318T allele increased the risk of acute GVHD (P=0.0133; OR=3.25; 95% CI, 1.28-8.26). Additionally donor CTLA-4 -318T/T genotype increased the risk of disease relapse (P=0.0313; HR=5.91; 95% CI, 1.17-29.79). Patients receiving hematopoietic stem cells from a donor with ICOS c.602C/C genotype had worse disease-free survival (P=0.0115; HR=5.97; 95% CI, 1.49-23.87). On the other hand, patients with ICOS c.1624T/T genotype had worse overall survival (P=0.0019; HR=12.98; 95% CI, 2.58-65.35). According to the present study, neither HA-1 nor HA-2 mismatch was associated with the outcome of HLA-matched sibling HSCT. However, donor CTLA-4 -318T/T genotype, donor ICOS c.602C/C genotype and recipient ICOS c.1624T/T genotype were risk factors for HLA-matched sibling HSCT. These results suggest that genetic polymorphisms at T cell regulatory genes, CTLA-4 and ICOS, are associated with the HSCT outcome. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T00:03:04Z (GMT). No. of bitstreams: 1 ntu-96-R94424020-1.pdf: 783853 bytes, checksum: 6e2f346be44b263d4693fa7b900360d0 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii 英文摘要 v 第一章、緒論 1 第一節 造血幹細胞移植 1 1. 造血幹細胞 1 2. 造血幹細胞移植發展史 1 3. 造血幹細胞移植的類別----依捐贈者分類 2 3.1 異體造血幹細胞移植 2 3.2 自體造血幹細胞移植 3 3.3 異體造血幹細胞移植與自體造血幹細胞移植之比較 3 4. 造血幹細胞移植的類別----依造血幹細胞來源分類 3 4.1 骨髓移植 3 4.2 周邊血液造血幹細胞移植 4 4.3 臍帶血移植 5 5. 造血幹細胞移植前後的檢查 5 5.1 移植前檢查 5 5.2 移植後檢查 6 6. 造血幹細胞移植後的併發症 6 6.1 移植失敗 6 6.2 感染 6 6.3 肝靜脈阻塞病變 6 6.4 移植體對抗宿主疾病 7 6.4.1 致病機轉 7 6.4.2 急性GVHD 7 6.4.3 慢性GVHD 8 7. 造血幹細胞移植的臨床結果 8 7.1 疾病復發 8 7.2 無疾病存活(disease-free survival)和總存活(overall survival) 9 8. 造血幹細胞移植的適用症 9 第二節 次要組織相容性抗原 9 1. 何謂次要組織相容性抗原 9 2. 次要組織相容性抗原HA-1及HA-2 10 第三節 T細胞的調控基因 12 1. CTLA-4 (cytotoxic T-lymphocyte antigen 4) 12 2. ICOS (inducible costimulator) 13 第四節 研究目的 14 第二章、材料與方法 16 第一節 實驗材料 16 1. DNA檢體 16 2. 臨床資料 16 2.1 捐贈者年齡 16 2.2 疾病診斷 16 2.3 疾病風險 17 2.4 性別不相容 17 2.5 GVHD預防用藥 17 2.6 移植後結果的評估 17 3. 酵素 17 4. 試劑組 18 5. 化學藥品 18 6. 自配溶液 18 第二節 實驗方法 19 1. HLA-A 對偶基因型之DNA序列鑑定 19 1.1 聚合酶連鎖反應及產物純化 19 1.2 Cycle-sequencing 反應 19 1.3 酒精沉澱 20 1.4 ABI 3100-avant sequencer上機操作 20 1.5 DNA序列分析 20 2. SNP鑑定法 21 2.1 PCR之引子設計 21 2.2 聚合酶連鎖反應 21 2.3 洋菜膠電泳 22 2.4 限制酶反應 22 3. 統計分析 22 3.1 卡方檢定 22 3.2 單套體基因型(Haplotype) 22 3.3 單變項分析 23 3.4 多變項分析 23 第三章、實驗結果 24 第一節 HLA-A對偶基因型鑑定 24 第二節 病人及捐贈者和對照組之對偶基因及基因型比較 24 第三節 CTLA-4及ICOS的單套體基因型(Haplotype) 25 第四節 HA-1 不相容對移植後臨床結果的影響 26 第五節 HA-2 不相容對移植後臨床結果的影響 26 第六節 病人及捐贈者之CTLA-4及ICOS 基因多型性對移植後臨床結果 的影響 27 1. 病人及捐贈者之CTLA-4及ICOS SNP對GVHD發生率的影響 27 2. 病人及捐贈者之CTLA-4及ICOS基因多型性對惡性疾病復發率 、disease-free survival及overall survival的影響 27 第七節 HLA-matched sibling HSCT之臨床結果的多變項分析 28 1. 病人發生急性及慢性GVHD的多變項分析 28 2. 惡性疾病復發率、disease-free survival及overall survival的多變項 分析 29 第四章、討論 30 圖 34 表 39 參考文獻 66 附錄 80 附錄一 附表 80 附錄二 實驗步驟 85 圖目錄 Figure 1 RFLP patterns of HA-1 genotypes 34 Figure 2 RFLP patterns of HA-2 genotypes 35 Figure 3 RFLP patterns of CTLA-4 -318C/T and +49 A/G genotypes 36 Figure 4 RFLP patterns of ICOS c.602A/C genotypes 37 Figure 5 RFLP patterns of ICOS c.1624C/T genotypes 38 表目錄 Table 1 Characteristics of patients with HLA-matched sibling HSCT 39 Table 2 Primer Sequences of PCR and DNA sequencing for detection of genetic polymorphisms 41 Table 3 PCR conditions used for detection of genetic polymorphisms 42 Table 4 Genes and SNPs studied 43 Table 5 Restriction enzymes used for detection of genetic polymorphisms 44 Table 6 Allele frequency of HLA-A2 in 91 sibling sets with HSCT 45 Table 7 The experimental groups of genes studied 46 Table 8 Allele and genotype frequencies of HA-1 and HA-2 genes 47 Table 9 Allele and genotype frequencies of CTLA-4 single nucleotide polymorphisms(SNPs) 48 Table 10 Allele and genotype frequencies of ICOS single nucleotide polymorphisms(SNPs) 49 Table 11 Haplotype frequencies of CTLA-4 and ICOS single nucleotide polymorphisms(SNPs) in controls (n=200) 50 Table 12 HA-1 genotypes in HLA-matched sibling sets with HLA-A*0201, HLA-A*0206 and/or HLA-B60 51 Table 13 HA-1 mismatch and clinical outcome of HLA-matched sibling HSCT 52 Table 14 Univariate analyses of HA-1 mismatch on GVHD 53 Table 15 Univariate analyses of HA-1 mismatch on clinical outcome of HSCT 54 Table 16 HA-2 genotypes in HLA-matched sibling sets with HLA-A*0201 55 Table 17 Patient CTLA-4 and ICOS genetic polymorphisms on GVHD 56 Table 18 Donor CTLA-4 and ICOS genetic polymorphisms on GVHD 57 Table 19 Univariate analyses of patient CTLA-4 and ICOS genetic polymorphisms on GVHD 58 Table 20 Univariate analyses of donor CTLA-4 and ICOS genetic polymorphisms on GVHD 59 Table 21 Patient CTLA-4 and ICOS genetic polymorphisms on HSCT outcome 60 Table 22 Donor CTLA-4 and ICOS genetic polymorphisms on HSCT outcome 61 Table 23 Univariate analyses of patient CTL-4 and ICOS genetic polymorphisms on HSCT outcome 62 Table 24 Univariate analyses of donor CTLA-4 and ICOS genetic polymorphisms on HSCT outcome 63 Table 25 Logistic regression analyses of risk factors for GVHD 64 Table 26 Cox’s regression analyses of risk factors for HSCT outcome 65 | |
| dc.language.iso | zh-TW | |
| dc.subject | 移植體抗宿主疾病 | zh_TW |
| dc.subject | 造血幹細胞移植 | zh_TW |
| dc.subject | 次要組織相容性抗原 | zh_TW |
| dc.subject | T細胞調控基因 | zh_TW |
| dc.subject | 基因多型性 | zh_TW |
| dc.subject | graft-versus-host disease | en |
| dc.subject | hematopoietic stem cell transplantation | en |
| dc.subject | minor histocompatibility antigen | en |
| dc.subject | T cell regulatory gene | en |
| dc.subject | genetic polymorphisms | en |
| dc.title | 非人類白血球抗原(non-HLA)基因多型性對於
HLA相容之造血幹細胞移植的影響 | zh_TW |
| dc.title | Impacts of non-HLA genetic polymorphisms on HLA-matched hematopoietic stem cell transplantation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 唐季祿,胡忠怡,林東燦 | |
| dc.subject.keyword | 造血幹細胞移植,次要組織相容性抗原,T細胞調控基因,基因多型性,移植體抗宿主疾病, | zh_TW |
| dc.subject.keyword | hematopoietic stem cell transplantation,minor histocompatibility antigen,T cell regulatory gene,genetic polymorphisms,graft-versus-host disease, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-96-1.pdf 未授權公開取用 | 765.48 kB | Adobe PDF |
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