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研究生:古瑋紅
研究生(外文):Wei Hong Khoo
論文名稱:探討B淋巴細胞誘導成熟蛋白1 (Blimp-1) 對於T細胞所調控的皮膚移植之免疫耐受性機轉
論文名稱(外文):B Lymphocyte-induced Maturation Protein 1 (Blimp-1) Enhances Alloskin Graft Take via T-cell Immunomodulation
指導教授:魏福全魏福全引用關係
指導教授(外文):F. C. Wei
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:74
中文關鍵詞:Blimp-1異體皮膚移植免疫耐受誘導T細胞免疫反應異體細胞植入
外文關鍵詞:Blimp-1skin allografttolerance inductionT-cell immune responseadoptive transfer
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在移植領域中,發展安全可靠的策略來誘導完全免疫耐受性仍是難以實現之目標。B細胞誘導成熟蛋白1 (Blimp-1) 是個調控B細胞分化成漿細胞的重要轉錄因子,而Blimp-1全身缺陷小鼠會自發性地產生結腸炎,且有較多活化T細胞的浸潤及較多的作用型T細胞,顯示 Blimp-1 對於發炎性或調節性T細胞扮演重要的調節角色。然而,Blimp-1 在異體複合組織移植中對於T細胞所調控的免疫耐受性其功能尚未清楚。而皮膚在一個複合組織中被證實抗原性最高,因此也是T細胞所調控之免疫排斥最主要的對象。此研究針對Blimp-1 專一性大量地表現在 T 細胞的基因轉殖小鼠上,研究其在異體皮膚移植中誘發免疫耐受性之機轉。初步發現在不給予任何免疫抑制劑的情況下,Blimp-1 Tg(+) 小鼠相較於Blimp-1 Tg(-) 小鼠可有效促進皮膚移植物之存活。利用細胞增生實驗證實Tg(+) 小鼠的淋巴細胞較不容易被活化增生,並呈現較低的供體免疫抗原反應。Blimp-1透過各種免疫細胞的調控,大幅降低Th1發炎細胞及其相關的細胞激素,並提升抑制型Treg細胞及其相關的免疫抑制細胞激素,以此塑造了一個抗發炎的環境,延緩異體皮膚的排斥現象。整體而言,Blimp-1高量表現的T細胞不管是全身性、在鄰近發炎部位的淋巴結、或是皮膚移植物本身均能塑造一個抗發炎的環境,產生較緩和及下降的反應,大幅降低外來抗原所造成的排斥反應。
Safe, reliable strategies for the induction of full immunologic tolerance remains an elusive goal in transplant immunology and clinical transplantation. Skin is known to be the most immunogenic component of a composite tissue, hence in allotransplantation, it is the primary target of T cell-mediated rejection. Studies in the literature have demonstrated great difficulty in obtaining allograft acceptance in skin transplantation between fully mismatched MHC animals. B lymphocyte-induced maturation protein 1 (Blimp-1) was first discovered as a transcription factor that regulates the terminal differentiation of B cells into plasma cells. It is also expressed in multiple cell lineages and in particular, T cells. Blimp-1-deficient mice develop spontaneous inflammatory colitis mediated by the infiltration of activated T cells, with more effector T cells than wild type mice. This suggests that Blimp-1 may play a critical immunomodulatory role in the development of inflammatory or regulatory T cells (Treg). However, the role of Blimp-1 in T cell-mediated allograft tolerance has never been explored. In this study, transgenic (Tg) C57BL/6 mice with Blimp-1 overexpression in T cells were used to explore their potential roles in T cells following skin allograft transplantation. Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. A lesser degree of allograft lymphocytic infiltration in Tg(+) mice and dampened donor-stimulated alloimmune response were observed. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and type 1 regulatory T cells was significantly decreased in lymphoid organs and allograft, as well as cytolytic proteins. T-cell-intrinsic alloprotective effects of transgenic Blimp-1 T cells were confirmed when they were adoptively transferred to wild-type mice with ongoing allograft rejection. The evidence presented conclusively proves that overexpression of Blimp-1 in T cells is key in the orchestration of an anti-inflammatory cell-cytokine composition, both systemically, peri-graft and locally, which in turn results in the promotion of high allogeneic graft survival through the creation of an ‘allograft protective microenvironment’.
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致謝 iii
中文摘要 iv
Abstract v
目錄 vi
圖目錄 viii
壹、研究動機與目的 1
貳、文獻回顧 3
一、 整形重建手術與異體複合組織移植 3
二、 移植免疫耐受性 (Tolerance Induction) 4
1. 免疫排斥反應 4
2. 免疫耐受性 5
3. 混合細胞嵌合 (Mixed-chimerism) 與耐受性 6
三、 B淋巴細胞誘導成熟蛋白1 (Blimp-1) 8
1. Blimp-1的發現及結構 8
2. Blimp-1於免疫系統的表現 9
2.1、 Blimp-1於B細胞的表現 9
2.2、 Blimp-1於T細胞的表現 9
2.3、 Blimp-1、CD4+T、Treg細胞 11
四、 Interleukin-35 (IL-35) 在免疫系統的功能 12
1. Treg與IL-35之關係 12
2. IL-35之功能與表現 13
3. IL-35於疾病中之抑制作用 14
4. IL-35與免疫耐受性之誘導 15
参、實驗設計與方法 17
一、 實驗架構 17
二、 材料與實驗方法 20
肆、結果 33
伍、討論與後續發展 42
陸、附錄 44
柒、參考文獻 60

圖目錄
Figure. 1 Blimp-1 基因轉殖鼠之 PCR 鑑定 44
Figure. 2 異體皮膚移植存活率 45
Figure. 3 異體免疫反應 48
Figure. 4 周邊淋巴細胞的分析 50
Figure. 5 脾臟與淋巴結之發炎型與抗發炎型細胞族群 52
Figure. 6 局部發炎型與抗發炎型細胞族群 53
Figure 7. Blimp-1 Tg(+)細胞能有效減緩正發生的排斥反應 56
Figure 8. Blimp-1 Tg(+) T 細胞於異體皮膚移植之影響示意圖 57
Figure 9. Blimp-1 高量表現對 IL-35 之表現量 59

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