本文選題：CD40 + 潰瘍性結(jié)腸炎�。� 參考：《蘇州大學(xué)》2014年博士論文

【摘要】：第一部分CD40在潰瘍性結(jié)腸炎組織中的表達(dá)及意義 目的：研究CD40分子在潰瘍性結(jié)腸炎組織中的表達(dá)，及其與潰瘍性結(jié)腸炎嚴(yán)重度之間的相關(guān)性。 方法：應(yīng)用免疫組化技術(shù)檢測(cè)56例潰瘍性結(jié)腸炎組織和10例正常組織中CD40分子表達(dá)。 結(jié)果：CD40分子在潰瘍性結(jié)腸炎組織中的陽(yáng)性表達(dá)率為62.5%，明顯高于對(duì)照組（P＜0.05）。與輕度潰瘍性結(jié)腸炎相比，CD40陽(yáng)性表達(dá)率在中度潰瘍性結(jié)腸炎中明顯升高（P＜0.05）。 結(jié)論：潰瘍性結(jié)腸炎患者結(jié)腸組織中CD40表達(dá)異常。 第二部分抗CD40單克隆抗體在潰瘍性結(jié)腸炎中治療效應(yīng)及作用機(jī)制的 實(shí)驗(yàn)研究 目的初步探討抗CD40單克隆抗體在葡聚糖硫酸鈉(dextran sulfate sodium, DSS)誘導(dǎo)的小鼠潰瘍性結(jié)腸炎(ulcerative colitis, UC)中的治療效應(yīng)及作用機(jī)制。方法24只BALB/c小鼠按隨機(jī)數(shù)字表分為：A組(對(duì)照組，n=6)、B組(模型組，n=6)、C組(奧沙拉秦干預(yù)組，n=6)、D組(抗CD40單克隆抗體干預(yù)組，n=6)。A組小鼠自由飲用蒸餾水7天；B、C、D組小鼠自由飲用5%DSS溶液7天以制成UC小鼠模型；造模的同時(shí)于第1、3、5及7天分別給以A、B組腹腔注射無(wú)菌蒸餾水。C組小鼠每天灌服奧沙拉秦(60mg/kg)、D組小鼠于造模第1、3、5、7天腹腔注射抗CD40單克隆抗體（20ug/次），，于造模第8天，處死所有各組小鼠。大體觀察各組小鼠疾病活動(dòng)指數(shù)(disease activity index, DAI)，常規(guī)病理切片評(píng)估結(jié)腸組織病理學(xué)評(píng)分(histopathological score, HPS)。RT-PCR測(cè)定各組小鼠遠(yuǎn)端結(jié)腸中IFN-γmRNA、TNF-αmRNA的表達(dá)，ELISA法測(cè)定各組小鼠血清中IFN-γ、TNF-α含量的變化。 結(jié)果(1)與對(duì)照組DAI(0.29±0.48)和HPS(0.16±0.32)相比，模型組小鼠DAI(6.21±1.25)和HPS(7.00±0.58)明顯增高(p0.05)；與模型組相比，奧沙拉秦干預(yù)組C組DAI(4.58±2.36)和HPS(4.35±0.76)均有不同程度的下降(p0.05)；抗CD40單克隆抗體干預(yù)組D組DAI(3.98±1.86)和HPS(3.25±0.66)亦有不同程度的下降(p0.05)(2)模型組IFN-γ mRNA、TNF-mRNA表達(dá)量（分別為3.21±0.26、1.23±0.36）明顯高于對(duì)照組(分別為1.35±0.18、0.21±0.13)(p0.05)，奧沙拉秦干預(yù)后，IFN-γ mRNA、TNF-mRNA表達(dá)在C組(2.58±0.24、0.72±0.15)、抗CD40單克隆抗體干預(yù)組D組(2.34±0.25、0.59±0.18)均顯著下降(p0.05)。（3）對(duì)照組小鼠血清中IFN-γ、TNF-α的水平分別為(215.18±32.51)、(20.06±5.20)，模型組小鼠血清中IFN-γ、TNF-α的表達(dá)比例分別為(953.32±40.96)、(42.97±8.76)，模型組小鼠血清中IFN-γ、TNF-α的表達(dá)比例與對(duì)照組相比明顯升高(P0.05)，奧沙拉秦干預(yù)后C組、抗CD40抗體干預(yù)組D組小鼠血清中IFN-γ、TNF-α的表達(dá)比例分別為C組(768.73±31.86)、(37.75±6.75)、D組(693.47±51.38)、(30.93±3.18)，與模型組相比干預(yù)組均有明顯降低(P0.05)； 結(jié)論(1)抗CD40抗體干預(yù)組干預(yù)的UC小鼠模型大體癥狀可明顯好轉(zhuǎn)，結(jié)腸炎癥程度亦得到明顯減輕；(2)奧沙拉秦干預(yù)后C組、抗CD40抗體干預(yù)組D組的UC小鼠遠(yuǎn)端結(jié)腸中IFN-γ mRNA、TNF-αmRNA明顯下降，提示促炎性細(xì)胞因子在UC發(fā)病中可能發(fā)揮重要作用；(3)抗CD40抗體干預(yù)的UC小鼠血清中IFN-γ和TNF-α的表達(dá)水平均明顯下降；提示抗CD40單克隆抗體可下調(diào)效應(yīng)細(xì)胞因子，減輕UC炎癥。
[Abstract]:Expression and significance of first part CD40 in ulcerative colitis

Objective : To study the expression of CD40 molecule in ulcerative colitis and its correlation with the severity of ulcerative colitis .

Methods : Immunohistochemical technique was used to detect the expression of CD40 in 56 ulcerative colitis and 10 normal tissues .

Results : The positive expression rate of CD40 molecule in ulcerative colitis was 62.5 % , which was significantly higher than that in control group ( P < 0.05 ) .

Conclusion : The expression of CD40 in colonic tissues of patients with ulcerative colitis is abnormal .

Effect of the second part of anti - CD40 monoclonal antibody on ulcerative colitis and its mechanism of action

experimental study

Objective To investigate the therapeutic effect and mechanism of anti - CD40 monoclonal antibody in ulcerative colitis ( UC ) induced by dextran sulfate sodium ( DSS ) . Methods Twenty - four BALB / c mice were randomly divided into group A ( control group , n = 6 ) , group B ( model group , n = 6 ) , group C ( group C , n = 6 ) and D group ( anti - CD40 monoclonal antibody intervention group , n = 6 ) . Group A mice were free to drink distilled water for 7 days ;
B , C and D groups were free to drink 5 % DSS solution for 7 days to prepare UC mice model ;
All groups of mice were sacrificed on Days 1 , 3 , 5 and 7 , respectively , and the mice were given intraperitoneal injection of the anti - CD40 monoclonal antibody ( 20ug / kg ) on day 1 , 3 , 5 and 7 . All the groups of mice were sacrificed on the 8th day of the molding . The disease activity index ( DAI ) and the pathological score of colonic tissues were assessed by routine pathological sections . The expression of IFN - 緯 mRNA and TNF - 偽 mRNA in the distal colon of each group were determined by RT - PCR . The changes of IFN - 緯 and TNF - 偽 in serum of each group were determined by ELISA .

Results ( 1 ) Compared with control group DAI ( 0.29 鹵 0.48 ) and hps ( 0.16 鹵 0.32 ) , DAI ( 6.21 鹵 1.25 ) and hps ( 7.00 鹵 0.58 ) in model group were significantly higher ( p < 0.05 ) .
Compared with model group , DAI ( 4.58 鹵 2.36 ) and HPs ( 4.35 鹵 0.76 ) decreased in group C ( p < 0.05 ) .
The levels of IFN - 緯 and TNF - 偽 in the serum of the model group were significantly higher than those in the control group ( 2.58 鹵 0 . 24 , 0 . 21 鹵 0 . 13 ) ( P < 0 . 05 ) . The levels of IFN - 緯 and TNF - 偽 in the serum of the model group were significantly higher than those in the control group ( 2.58 鹵 0 . 24 , 0 . 21 鹵 0 . 15 ) , and the levels of IFN - 緯 and TNF - 偽 in the serum of the model group were significantly lower than those in the control group ( P < 0 . 05 ) .


Conclusion ( 1 ) The general symptoms of UC mice with anti - CD40 antibody intervention group can be improved obviously , and the degree of colonic inflammation is obviously reduced .
( 2 ) There was a significant decrease in IFN - 緯 mRNA and TNF - 偽 mRNA in the distal colon of UC mice in group D of anti - CD40 antibody , suggesting that pro - inflammatory cytokines might play an important role in the pathogenesis of UC .
( 3 ) The levels of IFN - 緯 and TNF - 偽 in serum of UC mice with anti - CD40 antibody were significantly decreased .
It is suggested that anti - CD40 monoclonal antibody can down - regulate effector cytokines and reduce UC inflammation .

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R574.62

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