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  本文關(guān)鍵詞：維生素D缺乏動物模型的建立及其應(yīng)對結(jié)核抗原的免疫變化　出處：《第三軍醫(yī)大學(xué)》2011年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： VD缺乏 VD生理作用 動物模型 免疫反應(yīng) 變態(tài)反應(yīng)

【摘要】：背景及目的: 中國是結(jié)核高疫情國家,是世界上22個結(jié)核病高負擔(dān)國家之一,并且為耐藥結(jié)核病疫情最嚴重的國家之一[1]。第四次全國結(jié)核病流行病學(xué)抽樣調(diào)查顯示全國結(jié)核發(fā)病率平均為367/10萬人,而重慶地區(qū)為549/10萬人,是結(jié)核病的高發(fā)地區(qū),每年新發(fā)現(xiàn)4萬結(jié)核病患者,是京津滬的10余倍,其原因目前尚不清楚。重慶是著名的山城,地理氣候比較獨特,其年日照量全國最低,紫外線照射嚴重不足。前期調(diào)查發(fā)現(xiàn)重慶地區(qū)63.16%的健康獻血者與66.67%的骨關(guān)節(jié)結(jié)核患者存在維生素D缺乏。VD對免疫細胞的功能有著多方面的作用,體外研究表明VD既可增強巨噬細胞的吞噬能力,又可抑制DC細胞成熟,并影響T細胞的分化及功能[2]。 (一)1 ,25 (OH) 2 D3及其衍生物具有增強天然免疫作用,研究表明VD缺乏與結(jié)核易感性密切相關(guān),隨著25(OH)D水平的升高,感染危險降低,潛伏感染發(fā)展為結(jié)核病的危險也降低[3]。在結(jié)核化療前時代,光照療法和營養(yǎng)療法是治療結(jié)核病的主要措施,經(jīng)皮膚合成和飲食攝入增加了體內(nèi)25 (OH) D和1 ,25 (OH) 2 D3水平,結(jié)核治愈率提高至約25%,抗結(jié)核藥物發(fā)明后VD在結(jié)核病治療中逐漸被淡忘。近年來,VD免疫調(diào)節(jié)作用研究的興起、結(jié)核耐藥與抗結(jié)核藥物研發(fā)滯后的矛盾促使學(xué)者們重新重視VD在防治結(jié)核病中的應(yīng)用[4]。重慶地區(qū)獨特的地理和氣候特點導(dǎo)致年日照量全國最低,紫外線照射不足而皮膚合成的VD較少,因貧困經(jīng)飲食攝取VD不足,冬季VD缺乏較為普遍。VD與免疫系統(tǒng)的關(guān)系近年來受到廣泛關(guān)注,通過黃光照射、去VD合成營養(yǎng)素飼料喂養(yǎng)建立的小鼠VD缺乏模型,免疫機制嚴重紊亂,表現(xiàn)為T細胞亞群分布失調(diào)、免疫耐受減弱而自體免疫損傷加重,T淋巴細胞亞群分布紊亂、功能下降(Th2抑制),提示1 ,25 (OH) 2 D3在單核/巨噬細胞分化成熟中的重要意義,補充VD 8周后可恢復(fù)正常;因建立條件嚴格、耗時長,佝僂病研究中未被廣泛采用,但該模型為研究環(huán)境因素導(dǎo)致VD缺乏對免疫系統(tǒng)影響的最理想模型。 (二)1 ,25 (OH) 2 D3及其衍生物具有誘導(dǎo)免疫耐受減輕免疫自體損傷作用。1 ,25 (OH) 2 D3能夠影響DCs生命周期中所有的主要階段:阻礙單核細胞分化成DCs;阻止幼稚DCs向成熟DCs分化, MHC-Ⅱ類分子和共刺激分子CD40、CD80、CD86表達下調(diào),IL-12分泌減少,IL-10顯著增加,從而誘導(dǎo)出具有致耐受性表型和功能的未成熟DCs,未成熟DCs與T淋巴細胞的耐受性相關(guān)。 然而VD缺乏是否是結(jié)核的易感因素尚需要體內(nèi)實驗進一步證明。為研究VD缺乏在結(jié)核感染發(fā)病中的作用,我們首先建立了VD缺乏小鼠模型,然后用卡介菌刺激,觀察體內(nèi)的免疫變化與正常小鼠刺激后的差別。 方法: 1.維生素缺乏純合成小鼠飼料的配制 將雙蒸水50L平均分裝到容量為50L的金屬桶裝容器中,分別加入625g瓊脂,在105℃加熱40分鐘,然后放入到60℃的保溫箱中備用。將比例[3]稱量的各種原料放入混合機中混合30min,后加入到無塵粉碎機中粉碎,全部一次性通過200鉬篩。將其平均分成兩份分別加入到瓊脂溶液中,并加入脂溶性維生素溶液各250ml(一份含VD,一份未含),充分攪拌30min,室溫下冷卻1h,然后放入到-20℃冰箱中凍存。 2.維生素缺乏動物模型的建立及評價 36只懷孕2周的BALB/C小鼠,分為三組。正常組喂正常飼料、VD+組喂VD+飼料、VD-組喂VD-飼料。VD-組遮光黃光燈照射。剔除雄性子鼠,入組的子鼠正常組18只、VD+組15只、VD-組13只,出生3周斷奶,飼養(yǎng)環(huán)境及飲食同母鼠。測4-10周、12周子鼠體重,8、12周時測每天子鼠飲食消耗量,同時觀察子鼠運動習(xí)性。12周時將上述三組子鼠剪尾取血100ul離心取血清測VD水平,每組隨機取三只子鼠摘眼球取血,測白蛋白水平;將VD缺乏子鼠10只隨機分為組I繼續(xù)遮光+正常飲食,組II正常環(huán)境+正常飲食,6周后摘眼球取血測VD水平。 3.VD缺乏子鼠體內(nèi)免疫機能變化的檢測 尾靜脈取血測VD后將上述三組子鼠每組取5只分別在其尾根部注射BCG(0.1mlBCG含卡介苗0.05mg)0.1ml,再飼養(yǎng)六周,飼養(yǎng)環(huán)境同前。刺激6周后分離血清,-70℃凍存待檢;無菌分離脾淋巴細胞,調(diào)整濃度為5×10~6 cell/ml。取200μl脾淋巴細胞懸液,流式細胞儀檢測CD4 +和CD8 +T細胞百分比。間接ELISA方法測定特異性IFN-γ和IL-10水平,及血清特異性抗體滴度。CCK-8檢測脾淋巴細胞增殖情況,結(jié)果用刺激指數(shù)(Stimulation index,SI)表示,SI=A實驗孔/A對照孔。如刺激指數(shù)1,則用Annexin V-PI試劑盒檢測是否凋亡。 結(jié)果: 1.正常組與VD+組體重?zé)o統(tǒng)計學(xué)差異(P0.05);VD+組、VD-組8周、12周日平均消耗飼料,經(jīng)統(tǒng)計學(xué)分析8周時有差異,12周時無差異。 2.正常組、VD+組、VD-組血漿白蛋白分別為33.2±1.04、32.4±0.53、32.8±0.67(g/L),無統(tǒng)計學(xué)差異。 3.正常組與VD+組血漿VD水平無顯著差異,但VD-組血漿VD含量下降到正常的20%以下,提示小鼠VD缺乏模型建立成功;六周后,組I、組II VD水平分別為18.46±1.53、58.46±5.53(nmol/L)(P0.001)。 4.測子鼠血漿鈣水平分別為2.32±0.087、2.49±0.144、1.73±0.091(mmol/L),血漿磷水平分別為2.20±0.071、2.41±0.042、1.77±0.091(mmol/L),經(jīng)統(tǒng)計學(xué)分析三組之間血漿鈣磷含量均有統(tǒng)計學(xué)差異(P0.05),正常組與VD+組無顯著差異(P0.05),VD-組與另外兩組均有顯著差異(P0.05)。 5.BCG刺激正常組、VD+組及VD-組6周后,脾淋巴細胞中CD4+細胞亞群百分率分別為28.64±0.59、24.86±0.49、30.1±0.8, CD8+為10.9±0.72、9.42±0.55、14.14±0.83, CD4+/CD8+的比值分別為2.64±0.19、2.66±0.23、2.13±0.09,VD-組CD4+及CD8+淋巴細胞百分比均顯著上升尤其以CD8+上升幅度更大。 6.血漿IFN-γ分別為375.40±13.11、301.96±23.60、478.43±17.50(pg/ml),血漿IL-10分別為27.35±2.81、28.55±0.72、21.47±1.34(pg/ml),VD-組較其他兩組血漿IFN-γ顯著上調(diào)而IL-10顯著下調(diào)。 7.VD-組血清特異性抗TB-PPD抗體顯著高于正常組及VD+組。 8.三組脾淋巴細胞增值刺激指數(shù)分別為1.47±0.12、1.15±0.11、0.65±0.16,VD-抑制了脾臟T淋巴細胞在TB-PPD刺激下的增殖能力,其中VD-組淋巴細胞出現(xiàn)顯著凋亡。 結(jié)論: 1.通過控制食物和光照,成功建立VD缺乏BALB/c小鼠動物模型。 2.在VD的天然來源中,紫外線的作用較飲食作用重要,但直接補充VD效果顯著。 3.VD缺乏可引起一系列疾病,在本實驗中出現(xiàn)佝僂病癥狀。 4.VD缺乏顯著改變了機體免疫系統(tǒng)對BCG刺激的應(yīng)答特征,提示可能與VD缺乏容易引起結(jié)核病相關(guān)。 5.VD在天然免疫中發(fā)揮重要病因?qū)W作用,同時增加免疫耐受,減輕自身免疫性損傷。這為臨床治療結(jié)核感染及自身免疫性疾病提供一條嶄新的思路。
[Abstract]:Background and purpose:
China is high tuberculosis epidemic state, is one of the world's 22 TB high burden countries, and is one of the most serious drug-resistant TB epidemic in the country [1]. fourth national epidemiological sampling survey of tuberculosis showed the incidence of TB was 367/10 million, while the Chongqing area 549/10 million people, is a high incidence of tuberculosis, 40 thousand were new TB patients each year, Beijing Tianjin and Shanghai is more than 10 times, the reason is unclear. Chongqing is the famous mountain, unique geography and climate, the annual sunshine with the lowest amount of ultraviolet radiation is seriously insufficient. The investigation found that Chongqing area of 63.16% healthy blood donors in patients with osteoarticular tuberculosis and 66.67% in the presence of vitamin D a number of roles of.VD lack of immune cell function in vitro studies showed that VD can enhance the phagocytosis of macrophage, but also inhibit the maturation of DC cells, and the influence of T fine Cell differentiation and function [2].
(a) 1, 25 (OH) 2 D3 and its derivatives with enhanced natural immunity, lack of research shows that VD is closely related with the susceptibility to tuberculosis, 25 (OH) with elevated levels of D, reduce the risk of infection, latent infection development risk of TB also decreased [3]. in tuberculosis chemotherapy era, light therapy and nutrition therapy is the main measures for treatment of tuberculosis, the skin synthesis and dietary intake increased in 25 and 1 D (OH), 25 (OH) 2 D3, tuberculosis cure rate increased to about 25%, anti tuberculosis drugs invented after VD in the treatment of tuberculosis was gradually forgotten. In recent years, the rise of VD immunoregulation the contradiction between tuberculosis and anti TB drug research lag makes scholars attach great importance to the unique geographical and climate characteristics in the application of [4]. VD in prevention and treatment of tuberculosis in Chongqing area resulted in the lowest amount of annual sunshine and ultraviolet irradiation skin synthesis of V D less, due to poor dietary intake by VD is insufficient, lack of common relationship between winter VD.VD and immune system attracted widespread attention in recent years. Through the yellow light irradiation to mouse VD VD synthetic diet to establish the lack of model, serious disorder of immune mechanism for T cell subsets disorders, immune tolerance weakened and autoimmune injury, T lymphocyte subsets distribution disorder, functional decline (Th2 inhibitor), suggesting that the 1, 25 (OH) 2 important D3 in monocyte / macrophage differentiation, VD 8 weeks after the return to normal; because of the establishment of strict conditions, time-consuming, rickets is not on widely used, but the model for the study of environmental factors cause the ideal model of VD lack of effect on the immune system.
(two) 1, 25 (OH) 2 D3 and its derivatives with immune tolerance induced by autologous immune reduce the damage effect of.1, 25 (OH) 2 D3 to all the main stages in the life cycle of DCs block the differentiation of monocytes into DCs; prevent the differentiation of naive DCs DCs, MHC- class II and costimulatory molecules CD40, CD80, CD86 expression, IL-12 secretion decreased, IL-10 increased significantly, which is caused by DCs induced immature phenotype and function of tolerance, tolerance of immature DCs and T lymphocytes.
However, the lack of VD is a susceptibility factor for tuberculosis in vivo still need further proof. For the study of VD deficiency in the pathogenesis of tuberculosis infection, we first establish a VD deficient mouse model, and then stimulated with BCG immune changes observed in vivo and in normal mice after stimulation.
Method:
Preparation of 1. vitamin lack of pure synthetic mice feed
The double distilled water 50L the average capacity of metal packaging to bottled container 50L, were added to the 625g agar, heated at 105 DEG C for 40 minutes, then add to the spare box 60 degrees. The proportion of raw materials weighing [3] into mixing 30min, adding to clean and crushing, through all the time 200 Mo sieve. The average is divided into two parts were added to the agar solution, and add fat soluble vitamin 250ml solution (including a VD, a not included), fully mixing 30min, 1H cooling at room temperature, and then put into the refrigerator to -20 DEG C and frozen.
Establishment and evaluation of an animal model of 2. vitamin deficiency
36 only 2 weeks pregnant BALB/C mice were divided into three groups. The control group fed with normal diet, group VD+ fed VD+ diet, VD- group fed VD- diet group.VD- shading yellow light irradiation. Excluding male mice, the group were 18 rats in the normal group, 15 rats in group VD+, 13 rats in group VD-, born 3 week of weaning, feeding environment and diet were measured. The same 4-10 weeks, weighing 12 weeks in sub 8,12 weeks were measured every day, food consumption, and exercise characteristic was observed at.12 weeks of the three group were cut the tail blood serum were measured 100ul VD levels of each group were randomly selected three offspring mice eyeballs. Blood test, albumin level; VD lack of offspring 10 were randomly divided into group I to group II shading + normal diet, normal environment + normal diet, 6 weeks after the eyeball blood VD level.
3.VD lack of detection of changes in immune function in rats
The tail vein blood were measured after VD of the three group were 5 rats in each group were only in the root of the tail injection of BCG (0.1mlBCG 0.05mg 0.1ml, including BCG) and then fed for six weeks. Before stimulation feeding environment 6 weeks after separation of serum, -70 C frozen for inspection; aseptic splenic lymphocytes, adjust the concentration of 5 * 10~6 cell/ml. 200 L spleen lymphocyte suspension, flow cytometry and CD8 CD4 + +T cell percentage. Determination of specific IFN- and IL-10 levels of indirect ELISA method, and serum specific antibody titer.CCK-8 detection of splenic lymphocyte proliferation, the stimulation index (Stimulation index SI) said, SI=A experimental hole /A control holes. Such as the stimulation index of 1, using the Annexin V-PI kit to detect whether apoptosis.
Result:
1., there was no significant difference in body weight between normal group and VD+ group (P0.05). In group VD+, group VD- consumed 8 weeks, 12 weeks on average, and consumed 8 times a week. There was no difference between 8 weeks and 12 weeks.
The plasma albumin of 2. normal group, VD+ group and VD- group was 33.2 + 1.04,32.4 + 0.53,32.8 + 0.67 (g/L), and there was no statistical difference.
3. there was no significant difference in plasma VD level between normal group and VD+ group, but plasma VD content in group VD- dropped to less than 20% of normal level, suggesting that the VD deficient model of mice was established successfully. After six weeks, the II VD level of group I was 18.46 + 1.53,58.46 + 5.53 (nmol/L) (P0.001).
4. measurements of plasma calcium levels were respectively 2.32 + 0.087,2.49 + 0.144,1.73 + 0.091 (mmol/L), serum phosphorus levels were 2.20 + 0.071,2.41 + 0.042,1.77 + 0.091 (mmol/L), there was statistical plasma calcium and phosphorus content difference between the three groups (P0.05), there was no significant difference between the normal group and VD+ group (P0.05). The VD- group and the other two groups had significant difference (P0.05).
The stimulation of 5.BCG normal group, VD+ group and VD- group after 6 weeks, spleen lymphocyte CD4+ cell subsets was 28.64 + 0.59,24.86 + 0.49,30.1 + 0.8, CD8+ = 10.9 + 0.72,9.42 + 0.55,14.14 + 0.83, CD4+/CD8+ ratio were 2.64 + 0.19,2.66 + 0.23,2.13 + 0.09, VD- group CD4+ and CD8+ lymphocyte percentage were significantly the CD8+ Rose Rose more steeply.
6., plasma IFN- gamma was 375.40 + 13.11301.96 + 23.60478.43 + 17.50 (pg/ml), plasma IL-10 was 27.35 + 2.81,28.55 + 0.72,21.47 + 1.34 (pg/ml), VD- group was significantly higher than other two groups, and IL-10 significantly decreased.
The serum specific anti TB-PPD antibody in 7.VD- group was significantly higher than that of the normal group and the VD+ group.
8., the three groups of spleen lymphocyte proliferation stimulation index were 1.47 + 0.12,1.15 + 0.11,0.65 + 0.16, VD- inhibited the proliferation of spleen T lymphocytes stimulated by TB-PPD, and VD- group had significant apoptosis.
Conclusion:
1. the animal model of VD deficient BALB/c mice was successfully established by controlling the food and light.
2. in the natural source of VD, the effect of ultraviolet light is more important than diet, but the effect of direct supplement of VD is significant.
The deficiency of 3.VD can cause a series of diseases and the symptoms of rickets in this experiment.
4.VD deficiency significantly changes the response characteristics of the immune system to BCG stimulation, suggesting that it may be associated with the lack of VD to cause tuberculosis.
5.VD plays an important role in the etiology of innate immunity, and at the same time, increases immune tolerance and reduces autoimmune injury. This provides a new way for clinical treatment of tuberculosis infection and autoimmune diseases.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R392

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6 謝電;陳耀星;王子旭;李俊英;曹靜;賈六軍;;單色光對肉雞脾淋巴細胞免疫功能的影響[A];中國畜牧獸醫(yī)學(xué)會動物解剖學(xué)及組織胚胎學(xué)分會第十四次學(xué)術(shù)研討會論文集[C];2006年

7 徐艷娟;黃光照;;雷公藤甲素的誘導(dǎo)凋亡作用及其機制初步探討[A];全國第六次法醫(yī)學(xué)術(shù)交流會論文摘要集[C];2000年

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10 李朝虹;徐開林;潘秀英;;體外阻斷CD137-CD137L途徑控制小鼠移植物抗宿主病研究[A];2005年華東六省一市血液病學(xué)學(xué)術(shù)會議暨浙江省血液病學(xué)學(xué)術(shù)年會論文匯編[C];2005年

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6 劉_

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