葡萄膜炎(Uveitis)是造成視力不良重要的原因之一。最常見的葡萄膜炎是原因不明的急性前葡萄膜炎(acute anterior uveitis of unknown etiology)，而在國內以HLA-B27 陽性急性前葡萄膜炎最常見。此類型的葡萄膜炎非常容易復發，隨著發作次數增加,病人常會造成續發性白內障(secondary cataract),續發性青光眼(secondary glaucoma),帶狀角膜病變(band keratopathy)或黃斑部水腫(cystoid macular edema,CME)等併發症而導致視力不良。
大部分的葡萄膜炎,被認為是一種自體免疫疾病。病患有時會合併其他自體免疫疾病,如風濕性關節炎,僵直性脊椎炎..等。其致病機轉目前並不清楚，在治療方面主要是以類固醇(steroid)來治療,但是效果不好,易反覆發作。類固醇本身也會壓制所有免疫反應，而產生全身性的副作用。對於類固醇敏感的病人，也會因而引發--類固醇性青光眼(steroid glaucoma)..等副作用。
chemokine是一種蛋白質。具有許多重要的生理功能，包括：白血球細胞的發育，新生血管的增生，白血球的導引…等。當身體局部遭受感染或發炎時，特定種類chemokine的濃度就會增加，而導引特定種類之發炎性白血球到發炎位置，而產生特定的發炎反應。
本研究藉由對前葡萄膜炎的動物模式--實驗性自體免疫前葡萄膜炎(experimental autoimmune anterior uveitis; EAAU)的研究，來探討chemokine及其受體在前葡萄膜炎所扮演的角色。藉由在大鼠體內注射MAA(melanin-associated antigen)，即可引發實驗性自體免疫前葡萄膜炎。臨床上與人類最常見的急性前葡萄膜炎非常類似，大約在注射抗原後第十四天開始發病，第十九天達到頂點，並在第三十天完全恢復，而且沒有視網膜，後極部(posterior pole)方面的侵犯，因此是研究人類急性前葡萄膜炎非常好的動物模式。
本實驗在不同時間點中，摘取大鼠膕部淋巴結(popliteal lymph node)、虹彩和睫狀體(iris/ciliary body)，粹取其mRNA，經由RT-PCR 以半定量的方式來觀察CC chemokine (包括: MIP-1/ CCR2, MCP-1/CCR5, RANTES/ CCR3)； CXC ELR(+) chemokine,如 IL-8；CXC ELR(-) chemokine(包括IP-10/ CXCR3, SDF-1/CXCR4)及受體在疾病過程中表現的時序性和相對的量。
在虹彩及睫狀體方面。本實驗發現大鼠在注射MAA後，尚未出現臨床發炎症狀之前，CC (包括: MIP-1/ CCR2, MCP-1/CCR5, RANTES/ CCR3)chemokine及受體之mRNA濃度已經有升高的現象。RANTES mRNA的濃度在第九天開始升高，第十四天達到頂點，是CC chemokine中最早升高者。而MIP-1 及 MCP-1 mRNA的濃度都在第十一天開始升高，並在第十四天達到頂點。在頂點中以 MCP-1 mRNA的濃度升高最多。在受體方面，本實驗發現CCR2, CCR3, CCR5 mRNA都在第十一天開始增加，並在第十四天達到頂點。其中CCR2,CCR3 mRNA只有少量的增加，而CCR5 mRNA增加的量較多；CXC ELR(+) chemokine,如 IL-8 mRNA的濃度在第三天即開始升高，並在第十一天達到頂點；然而其受體 CXCR1, CXCR2 mRNA在整個病程中並沒有增加的現象；CXC ELR(-) chemokine: 包括IP-10/ CXCR3, SDF-1/CXCR4 方面。本實驗發現SDF-1 及IP-10 mRNA，在第三天即有表現，IP-10mRNA在第九天繼續升高，並在第十一到十四天達到頂點。而SDF-1mRNA在第十一天急速增加，並達到頂點。其受體─CXCR3, CXCR4 mRNA皆在第十一天開始增加，並在第十四天達到頂點。
在淋巴組織方面，本實驗發現CC (包括: MIP-1/ CCR2, MCP-1/CCR5, RANTES/ CCR3) chemokine及受體mRNA濃度，在第九天就開始有升高的現象。在時序上，比虹彩及睫狀體chemokine的表現早兩天。
本研究發現,chemokine在實驗性自體免疫前葡萄膜炎中的確佔有重要角色,CC chemokine及CXC ELR(-)chemokine mRNA的增加，間接證明chemokine的分泌也增加，而這些chemokine會吸引單核球的聚集，而導致以單核球的浸潤為主的前葡萄膜炎。
NF-kB 是一種轉錄因子(transcription factor), 它的活化與人類很多發炎疾病有關。NF-kB藉由增加細胞中特定基因的表現來調節宿主發炎及免疫反應。這些基因包括細胞素(cytokine)、chemokine和黏合分子(adhesion molecules)..等。NF-kB平常存於細胞質中與I-kB結合。在未受刺激的情形下I-kB 會抑制NF-kB 的作用而彼此結合形成一個複合體。當受到外界刺激時會激發I-kB kinase,使I-kB被磷酸化(phosphrylation),而易被proteosome分解,如此NF-kB 就可進入細胞核中，此時NF-kB 會認目標基因上之kB motif 而與之鍵結，再透過目標基因上之啟動子(promoter)或促進子(enhancers)來調控目標基因的大量轉錄表現。
Pyrrolidine Dithiocarbamate (PDTC)是一種抗氧化劑,是一種金屬鉗合物，也是一種很強的NF-kB抑制劑。本研究發現在接受抗原曝露後，無論發病與否，注射PDTC這種NF-kB抑制劑在臨床上並沒有預防發病的效果。然而在臨床上已得病的大鼠注射PDTC後確能有效降低發炎，因此PDTC有治療實驗性自體免疫前葡萄膜炎的效果。組織病理方面, 藉由H&E 染色，發現得到前葡萄膜炎的大鼠，其虹彩及睫狀體發炎細胞的密度都增加，而且最主要是以淋巴球和巨噬球的浸潤。在分子生物學方面，藉由粹取第二十一天大鼠虹彩及睫狀體中chemokine及其受體mRNA，來比較接受PDTC治療和對照組之間的差異。本研究發現在CC chemokine中，接受PDTC治療後，MCP-1和RANTES mRNA的表現比對照組少，兩組有統計學上的差異。在受體方面，CCR2和CCR3的mRNA的濃度比對照組少，兩組有統計學上的差異。至於CCR5mRNA的濃度則無統計學上的差異。在CXC ELR(+)chemokine方面,接受過PDTC治療後，IL-8 mRNA 和其受體CXCR1, CXCR2和對照組間也沒有統計學上的差異。CXC ELR(-) chemokine方面，SDF-1mRNA在接受過PDTC治療後比對照組少，兩組達到統計學上的差異。至於IP-10 mRNA則無統計學上的差異。其受體CXCR3, CXCR4的mRNA接受過PDTC治療後比對照組少，兩組有統計學上的差異。本研究認為這些在接受PDTC 治療而減少表現的chemokine，其本身的促進子順序中都含有NF-kB 結合位置。因此PDTC就是藉由降低這些chemokine的表現，尤其以MCP-1, RANTES, SDF-1為主，來減少發炎細胞的浸潤，以減少發炎反應，而達到臨床上治療的效果。

Uveitis is a major cause of visual impairment. The most frequent form of human uveitis is acute anterior uveitis (AAU) of unknown etiology which accounts for approximately 75% of all uveitis. The exact mechanism of AAU has yet to be determined, although autoimmune origin was thought to be the causes. AAU is a highly recurrent disease. With the frequency of recurrent and disease progression, it may result in secondary complications such as cataract, cystoid macular edema or glaucoma. Steroids remain the mainstay of therapy for uveitis. However, some, particular those who receive long-term steroid therapy, develop unacceptable side effects at the dosages that need to be given to control the disease. These complications include steroid glaucoma, secondary cataract, which further contribute to visual deterioration.
The migration of leukocytes plays an essential role in the initiation and development of autoimmune disease. Migration of lymphocytes from the blood to the site of antigenic challenge is controlled by a series of steps involving adhesion molecules and chemoattracts. The process of chemoattracts is mainly controlled by chemokine.
Chemokines are divided into two major subfamilies based on the spacing of the first pair of N-terminal cysteine residues. Chemokines in which these residues are adjacent, such as MCP-1, RANTES and MIP-1a, form the CC subfamily, and those in which they are separated by a single amino acid, such as IL-8 and IP-10, comprise the CXC subfamily. Additional variants of these motifs exist. There is at least one chemokine in which the cysteines are separated by three residues (CX3C), and one that lacks the first cysteine in the pair (C). This molecular subdivision generally correlates with function. The CXC chemokines usually recruit neutrophils, where CC chemokines tend to attract monocytes. The CC chemokines such as MIP-1 and RANTES are efficient chemoattractants for Th1 lymphoctyes but not for Th2 lymphocytes. RANTES, a chemoattractant for macrophages and mast cells also attracts memory T cells and NK cells.
The chemkines mediated their activity through a large family of G-protein-coupled receptors. The receptors for chemokines also comprise two major groups: CC receptors (CCR), which bind CC chemokines, and CXC receptors (CXCR), which bind CXC chemokines.
Since chemokines play a crucial role in the pathogenesis of autoimmune disease, they may be good therapeutic targets if we know the pattern of expression during the disease process. To study AAU, we used an animal model called “ experimental autoimmune anterior uveitis (EAAU). EAAU is induced by sensitization to melanin associated antigen (MAA) derived from iris and ciliary body. The pattern of inflammation of EAAU was quite similar to human AAU because it had the characteristic latent period of at least 10 days and lasted 3 weeks longer and main feature of anterior uvietis without photoreceptor and pineal involvement.
In this study, we analyzed sequential expression of chemokines and their receptors mRNA in iris/ciliary body and popliteal lymph node of Lewis rats with EAAU. The levels of various CC chemokines including regurlated on activationof normal T-cell-expression and excreted (RANTES), monocyte chemoattracant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 and their receptors (CCR2, CCR3, CCR5) were semi-quantified by reverse-transcriptase reaction followed by PCR. mRNA for CXC chemokines (IL-8, interferon-r-inducible protein (IP)-10, stromal derived factor (SDF)-1) and their receptors (CXCR-1, CXCR-2, CXCR-3) was also analyzed with the same methods.
We found the peak expression of chemokines and their receptors has been detected 3 to 5 days prior to the onset of clinical disease and throughout acute clinical disease. The time sequence between the activation of chemokines and development of clinical disease may be due to the multi-step process in the pathogenesis of uveitis. In response to stimuli, the concentrations of chemokines and receptors in iris/ciliary body increase dramatically. These chemokines then promote recruitment and migration of selective leukocytes from peripheral blood to iris/ciliary body. These activated leukocytes may ultimately infiltrate in tissue, produce oxygen radicals, and release granule contents, which results in destruction of local tissues and presenting clinical signs of uveitis.
Our results showed that the expression of mRNA for chemokines receptors in the popiteal lymph node was two days earlier than that in the eyes. This result may be due to antigens were injected in the hind footpad of rats to induce EAAU. When foreign antigen gains entrance into the tissue, it is picked up by the lymphatic system and carried to lymph node, which trap the foreign antigen. Some of the lymphocytes and macrophages in the node may respond by proliferation, activation and release of inflammatory mediators (cytokines and chemokines). The antigens carried by lymphatic channels were ultimately converged into blood stream and into blood vessel enriched uvea, which induced another waves of inflammation.
The type of inflammatory infiltrate that characterizes a specific disease is controlled by the subgroup of chemokines expressed in the diseased tissue. In EAAU, inflammation is characterized by T lymphocytes, especially CD4+ cells, and mononuclear cells infiltration of the anterior uvea. In this study, we found that all three CC chemokine- MIP-1, RANTES, MCP-1-that have powerful chemoattractant and activator properties for monocytes and T cells were upregulated. Their receptors are also upregulated simultaneously. The early expression of those chemokines in eyes provides a mechanism for the later influx of macrophages and T lymphocytes and consequently, characterized the disease pattern.
NF-kB is a heterodimer composed of p50 and p65 (RelA) subunits, and is found in the cytoplasm associated with inhibitory molecule call I-kB. Exposure to stimuli will lead to phosphorylation, ubiquitination, and degradation of I-kB. A protasome complex degrades I-kB after it is phosphorylated and ubiquitinated. NF-kB, free of complexed with IkB, can translocate to the nucleus and induced trascription of a variety of gene that bear NF-kB binding sites, inculding pro-inflammatory cytokines, chemokines, cell adhesion molecules. Activation of the NF-kB transcription family plays a central role in inflammation through its ability to induce transcription of pro-inflammatory genes. It has been well known that activation of the NF-kB pathway is involved in the pathogenesis of chronic inflammatory diseases, such as asthma, rheumatoid arthritis and inflamatory bowel disease.
Since NF-kB may play an important role in the pathogenesis of acute anterior uveitis, pharmacological antagonists of NF-kB activation might display broad anti-inflammatory acitivites and may be a new treatment modality for anterior uveitis. Therefore, we try to use NF-kB inhibitor to treat EAAU in the following experiments. Pyrrolidine dithiocarbamate (PDTC) is a potent NF-kB inhibitor. The mechanisms of the action of PDTC remain unknown. One mechanism suggested that PDTC inhibits I-kB degradation on the signaling cascade, thus inhibiting NF-kB activation. The others suggested that PDTC suppress NF-kB activation through its antioxidant property for PDTC is a well-known antioxidant. In our study, we demonstrated that PDTC had no prophylactic effect, which showed no statistical difference in view of maximal clinical score between the treatment and control groups, on rats immunized with MAA without clinical signs of EAAU. However, we provided the evidence that PDTC attenuates 1). the degree of inflammation as presented by reduced clinical score ; 2). the infiltration of the iris and ciliary body with T-lymphocyte ; 3).the expression of chemokine mRNA. All of these findings support the view that PDTC attenuated the degree of acute inflammation in the rats with EAAU. There were statistically significant differences between PDTC treatment group and control group in the expression of mRNA for MCP-1, RANTES, SDF-1. These results support the view that the promoter regions of these genes contain binding sites for NF-kB and thus, inhibition of NF-kB may sufficient to reduce the activation of these genes. The present results suggest NF-kB activation mediates the expression of multiple inflammatory genes. Thus, blocking of NF-kB activation by NF-kB inhibitor may be an effective strategy in the treatment of acute anterior uveitis.

目錄
口試委員會審定書………………………………………….i
誌謝………………………………………………………….ii
目錄………………………………………………………….iii
縮寫…………………………………………………………..iv
中文摘要……………………………………………………..1
英文摘要……………………………………………………. 4
緒論…………………………………………………………..9
研究方法與材料…………………………………………….15
結果………………………………………………………….26
討論………………………………………………………….30
圖表與圖表說明…………………………………………….36
參考文獻…………………………………………………….62

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