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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 伍安怡 | zh_TW |
| dc.contributor.advisor | Betty A. Wu-Hsieh | en |
| dc.contributor.author | 黃娟娟 | zh_TW |
| dc.contributor.author | Chuan-Chuan Huang | en |
| dc.date.accessioned | 2024-02-23T16:16:48Z | - |
| dc.date.available | 2024-02-24 | - |
| dc.date.copyright | 2024-02-23 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-02-02 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91848 | - |
| dc.description.abstract | Anti-CD3的專一性療法在治療異體器官移植及第一型糖尿病具有良好前景。藉由減低抗體之Fc 與Fc 受體結合能力減少副作用，可以因而增加anti-CD3抗體用於治療的可能性。本研究利用一段能自我形成三股螺旋結構的類膠原蛋白胜肽序列 (Gly-Pro-Pro)10，生產出不含Fc結構，以三倍體Fab形式的anti-mouse CD3 Collabody， h145CSA。我們將同質三倍體的h145CSA成功地以可溶性蛋白質的形式分泌至CHO 細胞培養上清液中，並且利用親合性及分子篩管柱層析的方式，製備出高純度且適合作為治療用的藥物。與兩價、FcR 結合力降低的免疫球蛋白h145chIgGAA相比，三價的h145CSA具有較佳和TCR/CD3 complex的結合強度、以及使T 細胞表面TCR/CD3 complex表現量下降的能力。與兩價的抗體相比，只有三價的h145CSA可以造成細胞凋亡，且使Th1細胞凋亡比例較Treg細胞高。有趣的是，以h145CSA處理的Th1細胞，其FasL 的表現量明顯高於Treg細胞，且 FasL中和性抗體可以阻斷h145CSA造成的Th1細胞凋亡。h145CSA投與正常活體小鼠，只會造成極低的T細胞活化以及低量細胞激素的產生。投與正常小鼠多次劑量h145CSA，造成脾臟中CD4+ T細胞減少的能力與兩價抗體相同，但它使CD4＋ T細胞回復到正常量的速度比兩價抗體更快速。以h145CSA治療剛發病第一型糖尿病之NOD小鼠的功效也比兩價抗體h145chIgGAA明顯更有效，此與在h145CSA治療小鼠的胰臟及腸繫膜淋巴結中，存有較低比例的CD4+IFNγ+ T 細胞以及Treg/Th1 比值較高有相關性。本研究結果顯示，三價非Fc結構的anti-CD3 Collabody具有治療第一型糖尿病之潛能。 | zh_TW |
| dc.description.abstract | Specific anti-CD3 treatment is deemed to be a promising therapy for allograft rejection and type 1 diabetes (T1D). Fc receptor (FcR) reduced-binding antibodies, by avoiding adverse effects of Fc and FcR interaction, have good therapeutic potential. We generated a trivalent, non-Fc-containing anti-mouse-CD3 Collabody, h145CSA, by using a triplex-forming collage-like peptide (Gly-Pro-Pro)10 to drive the trimerization of the Fab fragments. h145CSA was successfully produced as a soluble protein in the culture supernatant of CHO cells and could be purified as a homotrimer by affinity and size-exclusion chromatography to high purity, suitable for use as therapeutics. Trivalent h145CSA exhibited better binding strength and greater potency in downregulation of the TCR/CD3 complex compared to FcR reduced-binding format IgG, h145chIgGAA. Moreover, while h145CSA induced a significantly higher percentage of Th1 cell apoptosis than Treg cells, h145IgGAA did not. Interestingly, FasL was significantly up-regulated in h145CSA-treated Th1 cells compared to Treg cells. Neutralizing antibody to FasL blocked h145CSA-induced Th1 cell apoptosis. Administration of h145CSA invoked minimal T cell activation and cytokine production in normal mice. Multiple dosing of h145CSA depleted splenic CD4+ T cells, which was comparable to bivalent antibodies, yet it was characterized by more rapid CD4+ T cell recovery kinetics than treatment with other bivalent antibodies. Importantly, h145CSA was more potent than h145chIgGAA in inducing long-lasting remission in recent-onset diabetic NOD mice. Its therapeutic effect was accompanied by a significantly lower percentage of CD4+IFN+ T cells and a higher Treg/Th1 ratio in pancreatic and mesenteric lymph nodes. The results of our study demonstrate that trivalent non-Fc anti-CD3 Collabody has potential to be used in treatment of T1D. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-02-23T16:16:48Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-02-23T16:16:48Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
致謝 ii 中文摘要 iii Abstract iv Table of contents vi List of Table and Figures x Chapter 1: Introduction 1 1.1 Role of T cell in immune response 2 1.2 T cell subsets and their characteristics 2 1.2.1 Th1 and Th2 cells 2 1.2.2 Th17 cells 3 1.2.3 Regulatory T cells 3 1.3 The role of different subsets of T cells in T1D pathogenesis 4 1.3.1 The role of Th1 cells in T1D pathogenesis 4 1.3.2 The role of Th17 cells in T1D pathogenesis 5 1.3.3 The role of Treg cells in T1D pathogenesis 6 1.3.4 The role of CD8+ T cells in T1D pathogenesis 6 1.3.5 The roles of CD4+ and CD8+ T cells in diabetes 7 1.4 T cell-targeting therapy for T1D 7 1.4.1 Broad-spectrum immunosuppressive drugs 8 1.4.2 Anti-thymocyte globulin (ATG) 8 1.4.3 Anti-CD3 antibody 9 1.5 The effect of anti-CD3 antibody on T cells 9 1.5.1 Components and function of CD3/TCR in T cell 9 1.5.2 The effect of anti-CD3 antibody on T cells 9 1.6 Clinical application of anti-CD3 antibody 10 1.6.1 Immunogenicity 10 1.6.2 Adverse effects 11 1.6.3 Fc-modification of anti-CD3 antibody 11 1.6.4 Clinical application of anti-CD3 antibody in T1D 12 1.7 Collabody 13 1.8 Research goal 14 Chapter: 2 Materials and Methods 16 2.1 Materials 17 2.1.1 Ethics statement 17 2.1.2 Mice 17 2.1.3 Antibodies and reagents 18 2.1.4 Culture medium, Resins and Buffers 21 2.1.5 Mouse T cell isolation kits 23 2.1.6 Primer sequences used in qPCR 23 2.2 Methods 23 2.2.1 Construction of recombinant plasmids 24 2.2.2 Antibody expression and purification 24 2.2.3 Antibody characterization 25 2.2.4 T cell enrichment 25 2.2.5 Staining and flow cytometry 26 2.2.6 Direct and competitive T cell binding assays 26 2.2.7 TCR downregulation assay 27 2.2.8 CD4＋ T cell activation and differentiation 28 2.2.9 In vitro T cell apoptosis assay 28 2.2.10 Quantitative PCR 29 2.2.11 Pharmacokinetics of h145CSA 29 2.2.12 Biodistribution profile of h145CSA 30 2.2.13 Measurements of T cell counts in vivo 30 2.2.14 Serum cytokine assay 31 2.2.15 Antibody treatment of NOD mice 31 2.2.16 Statistics 31 Chapter 3: Results 33 3.1 Generation and characterization of anti-CD3 Collabody and its bivalent antibody counterparts 34 3.2 Anti-CD3 CSA is superior to bivalent antibodies in binding strength and ability to downregulate cell surface TCR 34 3.3 Naïve and activated CD4+ T cells differ in their susceptibility to trivalent anti-CD3 CSA- and bivalent anti-CD3 IgG-induced apoptosis 36 3.4 Th1 cells are more susceptible than Treg cells to anti-CD3 CSA-induced apoptosis 36 3.5 Anti-CD3 CSA induces Th1 cell apoptosis by up-regulating FasL expression 37 3.6 Pharmacokinetics and its biodistribution profile of anti-CD3 CSA 38 3.7 Multiple dosing of anti-CD3 CSA efficiently reduces splenic T cells, followed by rapid recovery kinetics in naïve mice 39 3.8 Anti-CD3 CSA induces weak mitogenic response in vivo 40 3.9 Anti-CD3 CSA is therapeutically more efficacious than anti-CD3 IgGAA in treating recent-onset diabetic NOD mice 40 3.10 The efficacy of anti-CD3 CSA correlates with reduction of CD4+IFN-+ T cells 41 Chapter 4: Discussion 43 4.1 Application of Collabody as a trivalent and non-Fc-containing antibody 44 4.2 The benefit of anti-CD3 CSA in CD3/TCR downregulation and apoptosis induction compared to bivalent antibodies 45 4.3 The characteristics of anti-CD3 CSA for in vivo use 46 4.4 Anti-CD3 therapy selectively deplete pathogenic Th1 cells is a viable approach to treat T1D 48 4.5 The role of regulatory/exhausted CD8+ T cells in diabetic patients responding to anti-CD3 antibody treatment 50 4.6 Summary 51 Chapter 5: References 53 Chapter 6: Table and Figures 71 Chapter 7: Appendix 113 | - |
| dc.language.iso | en | - |
| dc.title | Anti-CD3 Collabody特性分析與糖尿病NOD小鼠治療應用 | zh_TW |
| dc.title | Characterization of Anti-CD3 Collabody and its Therapeutic Use in Diabetic NOD Mice | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 周民元 | zh_TW |
| dc.contributor.coadvisor | Min-Yuan Chou | en |
| dc.contributor.oralexamcommittee | 孔祥智;繆希椿;李建國;顧家綺 | zh_TW |
| dc.contributor.oralexamcommittee | John T. Kung;Shi-Chuen Miaw;Chien-Kuo Lee;Chia-Chi Ku | en |
| dc.subject.keyword | CD3,Collabody,第一型糖尿病,第一型輔助Ｔ細胞,細胞凋亡, | zh_TW |
| dc.subject.keyword | CD3,Collabody,type 1 diabetes,Th1,apoptosis, | en |
| dc.relation.page | 113 | - |
| dc.identifier.doi | 10.6342/NTU202400452 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-02-02 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 免疫學研究所 | - |
| 顯示於系所單位： | 免疫學研究所 | |
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