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Title: | 探討以間質幹細胞應用到原發性膽管炎的治療 The therapeutic application of mesenchymal stem cells on primary biliary cholangitis |
Authors: | Si-Sim Kang 江序心 |
Advisor: | 江伯倫(Bor-Luen Chiang) |
Keyword: | 間質幹細胞,原發性膽管炎,細胞治療, Mesenchymal stem cell,primary biliary cholangitis,Cell therapy, |
Publication Year : | 2020 |
Degree: | 碩士 |
Abstract: | 原發性膽管炎(Primary biliary cholangitis)為慢性自體免疫肝炎,患者體內產生高量的自體抗體——抗粒線體抗體(anti-mitochondrial antibodies),此抗體的出現會加速膽道的破壞,導致膽管發炎、免疫細胞浸潤至肝臟門脈三角,並加速肝臟纖維化、肝硬化的發生。目前針對原發性膽管炎的療法主要是透過抑制膽汁外溢誘發的症狀來改善患者病況,本研究希望藉由間質幹細胞(Mesenchymal stem cell)療法,調節疾病上游的免疫反應,進而影響疾病進程。間質幹細胞為具有自我更新(self-renewal)與多功能分化能力(multipotency)的全能幹細胞,近年有許多研究指出間質幹細胞具有免疫調節的能力,我們透過試管內測試驗證了培養出具有正確性質的間質幹細胞。接著,利用以注射外源物質2-octynoic acid (OA)-ovalbumin (OVA) 誘發原發性膽管炎的模式小鼠,以尾靜脈注射的方式給予間質幹細胞,分析疾病晚期小鼠肝臟的免疫細胞浸潤情形、免疫細胞組成以及肝臟纖維化程度。研究結果顯示,儘管靜脈注射間質幹細胞對血清中抗粒線體抗體的濃度沒有影響,也不影響各淋巴球亞群的活化程度,但此療法能降低T細胞的浸潤,使浸潤的免疫細胞組成趨向未發病小鼠的情形。同時,為了使間質幹細胞的同源性增加、促進其免疫調節性質,我們測試了以類鐸受體-2(TLR-2)之配體(ligand)Pam3CSK4預先處理的間質幹細胞,將其應用於原發性膽管炎的疾病模式,發現處理後的間質幹細胞在in vitro實驗中,對於T細胞的抑制有更強的效果,同時可以抑制原發性膽管炎小鼠肝臟之T細胞分泌發炎性細胞激素的能力。然而,使用於小鼠疾病模式的治療並無顯著的效果。 Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by the high level of circulating anti-mitochondrial antibodies (AMA), which results in immune cell infiltration in the liver portal area and causing inflammation and damage of the bile duct. Current medicine for PBC including ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was used to ameliorate the cholestatic symptoms, however, still a large portion of the patients are unresponsive to these drugs. In this study, we proposed a therapeutic strategy via infusing mesenchymal stem cells (MSC) to modulate the inflammation caused by autoimmunity. Studies have suggested that MSCs exert anti-inflammatory and immunomodulatory functions that have been applied to various disease models and clinical trials. We followed the previously established protocol of 2-octynoic acid (OA)-ovalbumin (OVA) immunized PBC model. After culturing and characterizing MSCs, we injected the cells into the immunized mice in the early stages of the disease progression. After MSC infusion, PBC mice have decreased in the T cell population and increased in NKT cells, however, the treatment did not alter the level of anti-mitochondrial antibodies, and did not affect the number of activated lymphocyte subpopulations. Further, a previous study from our lab had demonstrated that the pre-treatment of TLR-2 ligand, Pam3CSK4, promoting homogeneity in the MSC population and enhanced the immunoregulation property of MSCs. We then applied the Pam3CSK4-treated MSCs on the PBC model and evaluated the therapeutic efficacy of the treatment. our data indicated that the proliferation of T cells within the liver leukocytes isolated from the PBC mice reduced the most in the Pam3CSK4-treated MSC group. Moreover, the Pam3CSK4-polarized MSCs reduced the activation sensitivity of CD4 and CD8 T cells and reduced the expression level of TNF-α from the liver tissue of PBC mice. However, Pam3CSK4-polarized MSCs did not have a significant effect on the PBC mice. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19054 |
DOI: | 10.6342/NTU202003846 |
Fulltext Rights: | 未授權 |
Appears in Collections: | 免疫學研究所 |
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