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研究生：	許聖民 Hsu, Sheng-Min
論文名稱：	應用小鼠之實驗性自體免疫性葡萄膜視網膜炎動物模型開發對自體免疫葡萄膜炎的新穎免疫治療法 Development of novel immune mechanism-based therapies for autoimmune uveitis using a mouse model of experimental autoimmune uveitis
指導教授：	謝奇璋 Shieh, Chi-Chang
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	138
中文關鍵詞：	實驗性自體免疫葡萄膜炎、前房相關免疫偏移、容忍性抗原表現細胞
外文關鍵詞：	experimental autoimmune uveitis, tolerogenic antigen presenting cells, proteasome inhibitors, reactive oxygen species
相關次數：	點閱：112 下載：3
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本研究的主要目的是探討是否能利用體外產生之容忍性抗原表現細胞或其他藥物如Bortezomib或N-acetylcysteine (NAC)之治療減緩改善小鼠之實驗性自體免疫性葡萄膜炎，並探討可能之作用機轉，希望將來應用在人類上，達到治療人類自體免疫性葡萄膜炎之目的。葡萄膜炎是指眼球之葡萄膜組織的發炎，若是自體免疫所引起，目前常用類固醇治療。然而，類固醇治療並不一定會成功地抑制葡萄膜炎，且長期使用類固醇治療也會引發明顯且嚴重之副作用，例如白內障或青光眼。因此，尋找其他的治療方法成為重要的課題。在過去幾年間我們利用C57BL/6(B6)小鼠的實驗性自體免疫葡萄膜炎之動物模型模擬人類之自體免疫性葡萄膜炎，利用不同治療策略與方法達到治療人類自體免疫性葡萄膜炎之目的。本研究分成三部分：第一部分是利用體外產生之容忍性抗原表現細胞做治療。因為之前研究發現”前房相關免疫偏移”(ACAID)即眼前房內打入自體免疫抗原可抑制自體免疫疾病之發生，因此我們使用”轉化生長因子”(TGF-β2)處理過之容忍性抗原表現細胞治療發現也可以減緩小鼠實驗性自體免疫葡萄膜炎之發生。在第二部分，細胞內的Ubiquitin-Porteasome系統(UPS)是細胞用來分解蛋白質之重要工具，可維持細胞之恆定，在NF-κB路徑中，IκB分子原本和NF-κB分子結合，受外界刺激時IκB分子會被接上ubiquitin後經由UPS系統所分解，此時NF-κB分子就會活化進入細胞核內使細胞對外界刺激產生反應。由於NF-κB是產生免疫反應的重要路徑，因此如果抑制proteasome則會經由UPS系統進而抑制NF-κB與免疫反應之進行，達到治療人類自體免疫性葡萄膜炎之目的。本研究探討是否使用proteasome抑制劑bortezomib可抑制小鼠實驗性自體免疫葡萄膜炎之發生並探討其作用機制。在第三部分是有關Ncf1基因與葡萄膜炎相關之研究。Ncf1基因產生的蛋白質是NADPH氧化酶複合物的重要成份。Ncf1基因突變已知會引起慢性肉芽腫性疾病，其身上的嗜中性球與巨噬細胞將無法殺死入侵的病原菌。之前研究還發現Ncf1基因突變與關節炎、腦脊髓炎等自體免疫疾病有關，因此在本研究我們想探討Ncf1基因在小鼠之實驗性自體免疫葡萄膜炎之角色，且試著將研究結果用於治療上。
在結果方面，首先我們成功地在C57BL/6小鼠身上誘發實驗性自體免疫葡萄膜炎(EAU)，此動物模型可用於此研究探討眼睛自體免疫疾病機制與可能的治療方法之研究。接著我們發現注射容忍性抗原表現細胞的小鼠發生實驗性自體免疫葡萄膜炎的機率顯著減少，且較慢發生，嚴重程度也較小。當我們將從容忍性抗原表現細胞治療後之C57BL/6小鼠取出之脾臟T細胞注射到B6小鼠可抑制新的實驗性自體免疫葡萄膜炎之發生，且必需注射CD8+T細胞才有此效果，而非CD4+T細胞。因此，容忍性抗原表現細胞將是未來治療實驗性自體免疫葡萄膜炎的新方法。接著我們發現在proteasome抑制劑bortezomib治療的小鼠將表現出明顯減弱之實驗性自體免疫葡萄膜炎反應。接著我們在NF-κB相關的發炎介質研究結果顯示:小鼠誘發實驗性自體免疫葡萄膜炎後其NF-κB相關的發炎介質例如TNF-α, IL-1α, IL-1β, IL-12, IL-17, MCP-1與iNOS表現會上升，但是經過proteasome抑制劑bortezomib治療後其NF-κB相關的發炎介質表現會顯著下降。最後，在NF-κB與proteasome活性分析研究結果，在小鼠誘發實驗性自體免疫葡萄膜炎後其NF-κB的活化與proteasome活性會較正常B6小鼠上升，但經過proteasome抑制劑bortezomib治療後其NF-κB的活化與proteasome的活性都會顯著下降。因此proteasome抑制劑bortezomib的治療將會是未來治療自體免疫葡萄膜炎之新方法。最後我們研究發現相對於正常B6小鼠，在缺乏p47蛋白質之Ncf1突變小鼠會表現明顯減弱之實驗性自體免疫葡萄膜炎反應。我們發現將來自基因正常B6且已誘發實驗性自體免疫葡萄膜炎之小鼠身上的CD4+T細胞轉移至Ncf1基因突變小鼠身上會誘發微弱之實驗性自體免疫葡萄膜炎反應，同樣地，當我們將來自Ncf1基因突變且已誘發實驗性自體免疫葡萄膜炎之小鼠身上的CD4+T細胞轉移至基因正常之B6小鼠身上會誘發微弱之實驗性自體免疫葡萄膜炎反應。證明包括捐贈者之CD4+T細胞與接受者之B6小鼠都需表現Ncf1基因才會正常誘發實驗性自體免疫葡萄膜炎反應。而且在本研究也發現在Ncf1基因突變之C57BL/6小鼠身上誘發實驗性自體免疫葡萄膜炎時其視網膜上之TNF-α分泌會顯著減少，如果使用抑制ROS產生之藥物N-acetylcysteine (NAC) 治療則實驗性自體免疫葡萄膜炎也會明顯減弱，與Ncf1基因突變之小鼠表現很類似，因此調控小鼠ROS之表現可能將會是未來治療自體免疫葡萄膜炎之新方法。

The purpose of this study is to ameliorate experimental autoimmune uveitis (EAU) in mice as an animal model with tolerogenic antigen presenting cells (TolAPC) or other drugs including proteasome inhibitor bortezomib and N-acetylcysteine and then to investigate the mechanisms. Uveitis refers to inflammation of the uveal tissues and can cause significant ocular morbidities in individuals with protracted diseases. Clinical courses refractory to conventional treatment with corticosteroids are not uncommon, and the adverse effects associated with steroids, such as cataracts and glaucoma, preclude its chronic use. Therefore, investigating the disease mechanisms and searching for alternative treatments for uveitis remain important issues.
Experimental autoimmune uveitis (EAU) is a rodent model of human uveoretinitis. Here, we want to treat experimental autoimmune uveitis (EAU) in mice as an animal model with different novel immune mechanism-based strategies. In the first part, it is well known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces Anterior Chamber Associated Immune Deviation (ACAID), which in part is mediated by antigen specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by inoculation ( i.v.) of ex-vivo generated tolerogenic antigen presenting cells (TolAPC). Therefore, we plan to test if ex-vivo generated retinal antigen pulsed TolAPC could suppress established experimental autoimmune uveitis (EAU) or not. In the second part, bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. Therefore, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU) in mice and investigated the potential mechanisms related to NF-κB inactivation. In the third part, The Ncf1 protein is an essential component of the NADPH oxidase complex that catalyzes the transfer of a single electron from NADPH to oxygen and generates reactive oxygen species (ROS). The mutation of Ncf1 gene is related to chronic granulomatous disease (CGD), a rare genetic disorder characterized by severe recurrent infections due to the inability of neutrophils and macrophages to mount a respiratory burst and thereby kill the invading pathogens. However, enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene were reported. Therefore, we postulate that Ncf1 gene also plays an important role in experimental autoimmune uveitis in mice.
As the result, first of all, we established an experimental autoimmune uveitis (EAU) mouse model to address the mechanisms and potential methods of treatment for ocular autoimmune diseases in this study. Then, in the first part, I found that IRBP1-20-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory mediators. Moreover, extract of whole retina could replace human IRBP1-20 as antigen in the preparation of TolAPC used to induce tolerance in EAU mice. The suppression of EAU could be transferred to a new set of EAU mice with CD8+ but not with CD4+ Treg cells. In the second part, we found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, MCP-1, and iNOS were lowered in the high-dose bortezomib treated group. In the third part, we found that the EAU response became much milder in Ncf1-mutant mice. Adoptive transfer of CD4+ T cells from wild-type EAU mice induced partial EAU response in Ncf1 mutant naïve mice. Adoptively transfer of CD4+ T cells from Ncf1 mutant EAU mice also induced partial EAU response in naïve B6 mice. It meant that the Ncf1 gene expression in both donor CD4+ T cells and recipient B6 mice contributed to EAU induction. Finally, we treated the EAU B6 mice with N-acetylcysteine (NAC) i.p. every other day to suppress the ROS production as in Ncf1-mutant mice. We found the EAU response was ameliorated in NAC treated mice as in Ncf1-mutant EAU mice. Therefore, NAC treatment with ameliorated ROS production seems to be a novel immune mechanism-based therapy for autoimmune uveitis.
In conclusion, we find many potential novel immune mechanism-based treatment strategies for human uveoretinitis including tolerogenic antigen presenting cells (TolAPC) with retinal extract as antigen, proteasome inhibitor bortezomib with NF-κB inactivation, and N-acetylcysteine (NAC) for ROS suppression as in Ncf1 mutant mice. We hope these novel immune mechanism-based therapies could be applied for autoimmune uveitis treatment in human in the future.

Contents
Chapter 1. Introduction.................................. 1
1 Uveitis and tolerogenic antigen presenting cells (TolAPC) ............. 3
1.1 The immunologic privilege of the eye .............. 3
1.2 Anterior chamber associated immune deviation (ACAID) .................. 3
1.3 Ocular immunosuppressive microenvironments ................................... 4
1.4 In vitro generation of an ACAID-inducing signal and unique characteristics of the ACAID-inducing APCs ............................................... 5
1.5 Can tolerogenic APC prevent experimental autoimmune uveitis in mice as in ACAID? ............................. 6
2 Uveitis, proteasome inhibitor bortezomib, and nuclear factor kappa B ...... 9
2.1 Ubiquitin-proteasome system (UPS) and proteosome inhibitor bortezomib ............................ 9
2.2 Proteasome inhibitors in preclinical models of immune disorders ..... 11
2.3 Proteasome inhibitor (bortezomib) with uveitis .... 11
3 Uveitis, Ncf1 gene, and ROS production .............. 13
3.1 The Ncf1 protein and the NADPH complex .......... 13
3.2 A mutation in the Ncf1 gene can enhance autoimmunity and arthritis in mice with a reduced oxidative burst ........................................ 14
3.3 What is the role of Ncf1 gene in experimental autoimmune uveitis (EAU)? ...................... 16
4 Thesis Aims ........................... 17
Chapter 2. Ex-vivo tolerogenic F4/80+ antigen-presenting cells (APC) induce efferent CD8+ regulatory T cell-dependent suppression of experimental autoimmune uveitis ........ 19
1 Background and Aims ..................... 19
1.1 Background ............................ 19
1.2 Aims .................................... 21
2 Materials and Methods ......................... 23
2.1 Animals ................................. 23
2.2 Reagents ............................... 23
2.3 Flow cytometry and cell sorting .................. 24
2.4 Induction of adoptive transfer experimental autoimmune uveitis (AdEAU) ....................... 25
2.5 Scoring of adoptive transfer experimental autoimmune uveitis (AdEAU) .................................. 25
2.6 Histopathological evaluation .................... 26
2.7 Preparation of TolAPC ............................. 27
2.8 Preparation of T cells from spleens for treatment of EAU mice ........ 27
2.9 In vitro correlate for ACAID ...................... 28
2.10 Assay of in vitro Th1 and Th17 related cytokine production ........... 29
2.11 Local adoptive transfer (LAT) Assay .............. 29
2.12 Preparation of retinal extract ................. 30
2.13 Preparation of corneal extract ................... 30
2.14 Statistical analysis ............................ 31
3 Results ............................................ 32
3.1 IRBP pulsed TolAPC suppress pre-existing EAU ................ 32
3.2 TolAPC treatment down regulates the production of EAU associated inflammatory cytokines .................. 33
3.3 Ability of retinal extract- vs. IRBP- pulsed TolAPC to suppress EAU... 33
3.4 TolAPC induce Treg cells in the spleens in host EAU mice .............. 34
3.5 CD8+, but not CD4+, Treg cells transfer suppression to EAU mice ... 35
3.6 Characterization of the Treg Cell ................ 36
3.7 Local Adoptive Transfer Assay .................... 37
4 Discussion ....................................... 39
5 Figures and Tables ................................. 46
Chapter 3. Proteasome inhibitor bortezomib suppresses nuclear factor-kappa B activation and ameliorates eye inflammation in experimental autoimmune uveitis ......... 56
1 Background and Aims ........................ 56
1.1 Background .................................... 56
1.2 Aims ...................................... 58
2 Materials and Methods ........................ 60
2.1 Animals ..................................... 60
2.2 Induction and treatment of experimental autoimmune uveitis (EAU) 60
2.3 Clinical scoring of experimental autoimmune uveitis (EAU) ............ 61
2.4 Histopathological evaluation ................ 62
2.5 Analysis of inflammatory mediators in retinas by Luminex .............. 62
2.6 Immunohistochemical (IHC) studies of inflammatory mediators in retinas .................................... 63
2.7 Measurement of proteasome activity in the retina .............................. 64
2.8 Nuclear protein extract and electrophoretic mobility shift assay of NF-κB (EMSA) ..................... 64
2.9 Statistical analysis ....................... 65
3 Results ...................................... 67
3.1 EAU mice treated with high-dose bortezomib showed significantly milder posterior uveitis .................. 67
3.2 Bortezomib treatment suppressed EAU more significantly than TNF-alpha antagonist treatment ....... 68
3.3 The influence of bortezomib on the levels of inflammatory mediators in retina after experimental autoimmune uveitis induction ......................... 69
3.4 Decreased expression of TNF-α, iNOS, IL-1β, and MCP-1 in retina of bortezomib-treated EAU mice ................ 70
3.5 Proteasome activity was significantly lowered after bortezomib treatment ......................... 71
3.6 The increased NF-κB DNA binding after EAU induction was inhibited by bortezomib treatment ............ 72
4 Discussion ..................................... 73
5 Figures and Tables ............................. 77
Chapter 4. EAU is ameliorated in Ncf1 mutant mice and N-acetylcysteine suppresses EAU response in wild-type mice .......................................... 87
1 Background and Aims .......................... 87
1.1 Background ..................................... 87
1.2 Aims ....................................... 90
2 Materials and Methods ......................... 92
2.1 Animals ................................... 92
2.2 Induction of experimental autoimmune uveitis (EAU) ...................... 92
2.3 Induction of adoptive transfer experimental autoimmune uveitis ...... 93
2.4 Clinical scoring of experimental autoimmune uveitis (EAU) ............ 93
2.5 Histopathological evaluation ..................... 94
2.6 Induction of experimental autoimmune uveitis (EAU) in both wild-type and Ncf1-mutant mice ..................... 94
2.7 Adoptive transfer of immunogenic APC from wild-type mice to Ncf1-mutant mice with EAU induction ............ 95
2.8 Adoptive transfer of CD4+ T cells from wild-type EAU mice to naïve Ncf1-mutant mice .................. 96
2.9 Adoptive transfer of CD4+ T cells from Ncf1 mutant mice to naïve wild-type mice ................... 96
2.10 Detection of TNF-α expression by real time polymerase chain reaction in wild-type and Ncf1-mutant EAU mice ...................................... 97
2.11 Statistical analysis .......................... 98
3 Results ......................................... 99
3.1 EAU was ameliorated in Ncf1 mutant mice .......... 99
3.2 Adoptive transfer of immunogenic APC from wild-type mice into Ncf1-mutant mice could not recover EAU response in Ncf1-mutant mice 100
3.3 Adoptive transfer of CD4+ T cells from wild-type EAU mice to Ncf1-mutant naïve mice could only induce partial EAU response ............ 100
3.4 Adoptive transfer of CD4+ T cells from Ncf1 mutant EAU mice to naïve wild-type mice could only induce partial EAU response ................. 101
3.5 TNF-α expression was elevated in retinas of wild-type EAU mice but suppressed in those of Ncf1 mutant mice in real-time PCR and ELISA analysis ................. 102
3.6 Wild-type EAU mice treated with N-acetylcysteine (NAC) showed
significantly ameliorated uveitis as EAU in Ncf1 mutant mice ................. 103
4 Discussion ................................... 105
5 Figures and Tables ........................... 107
Chapter 5. General Discussion, Conclusion and Prospects.. 114
1 Experimental findings ............................ 114
1.1 TolAPC for AdEAU treatment ....................... 116
1.2 Proteasome inhibitor bortezomib for EAU treatment .. 117
1.3 Relationship between Ncf1 gene expression and EAU formation .... 119
2 Methodological considerations .................... 120
2.1 Substrains of C57BL/6 mice ................... 120
2.2 EAU and adoptive transfer EAU .................... 122
3 Prospects .......................................... 123
Publication lists ..................................... 125
Bibliography .......................................... 127
                                    

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