本文關(guān)鍵詞：人源化CD52單克隆抗體對食蟹猴淋巴細(xì)胞作用的研究　出處：《南京大學(xué)》2011年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 人源化CD52單克隆抗體 食蟹猴 上皮內(nèi)淋巴細(xì)胞 固有層淋巴細(xì)胞 粘膜地址素細(xì)胞粘附分子 淋巴細(xì)胞歸巢

【摘要】：人源化CD52單克隆抗體(Campath-1H)對表達(dá)CD52抗原的T、B淋巴細(xì)胞、單核細(xì)胞、NK細(xì)胞等具有強(qiáng)大的清除作用,最初用于治療慢性淋巴細(xì)胞白血病、多發(fā)性硬化等疾病,近年來常用于腎移植、肝移植、小腸移植等實(shí)體器官移植中誘導(dǎo)產(chǎn)生免疫耐受。雖然Campath-1H應(yīng)用于器官移植已十余年,但缺少適宜的動物模型評價(jià)其在器官移植中的安全性和有效性,因此限制了其在器官移植中的進(jìn)一步應(yīng)用。Campath-1H只與非人靈長類動物中的某些種屬具有交叉反應(yīng),而不能識別嚙齒類動物細(xì)胞上的抗原。非人靈長類動物在親緣關(guān)系上與人最接近,是研究人類疾病的理想動物模型。在臨床移植中應(yīng)用Campath-1H誘導(dǎo)方案后,可清除移植病人外周血中99%以上的淋巴細(xì)胞,并維持很長一段時(shí)間低淋巴細(xì)胞水平狀態(tài)。腸道中的淋巴細(xì)胞數(shù)量比外周組織中的多,腸道是全身最大的免疫器官。目前國內(nèi)外對Campath-1H的研究多集中于對外周血淋巴細(xì)胞的清除作用,尚缺乏對腸道淋巴細(xì)胞作用的研究。本研究中,我們采用食蟹猴作為動物模型,給予Campath-1H處理后,觀察給藥后不同時(shí)間食蟹猴外周血、脾臟、淋巴結(jié)淋巴細(xì)胞的變化,腸道上皮內(nèi)及固有層淋巴細(xì)胞數(shù)量及亞群的變化,以及腸道粘膜地址素細(xì)胞粘附分子與淋巴細(xì)胞歸巢受體的相互關(guān)系。研究Campath-1H對淋巴細(xì)胞的清除作用及歸巢機(jī)制,為臨床小腸移植中更好的應(yīng)用Campath-1H提供實(shí)驗(yàn)依據(jù)。第一部分動物模型的建立及人源化CD52單克隆抗體對食蟹猴外周血、脾臟、淋巴結(jié)淋巴細(xì)胞的作用目的:人源化CD52單克隆抗體運(yùn)用于器官移植已十余年,但缺少適宜的動物模型評價(jià)其在器官移植中的安全性和有效性,限制了其在器官移植中的進(jìn)一步應(yīng)用。本實(shí)驗(yàn)首先建立人源化CD52單克隆抗體誘導(dǎo)食蟹猴動物模型,并觀察其對食蟹猴外周血、脾臟、淋巴結(jié)淋巴細(xì)胞的作用。方法:雄性食蟹猴,3-5歲齡,體重3-5.5 kg,使用流式細(xì)胞儀篩選紅細(xì)胞表面不表達(dá)CD52抗原的食蟹猴,將篩選出的食蟹猴隨機(jī)分為實(shí)驗(yàn)組和對照組,實(shí)驗(yàn)組按3 mg/kg給予靜脈滴注Campath-1H,對照組給予等量生理鹽水。分別于給藥后9、14、35、56天處死實(shí)驗(yàn)組動物取材,給藥組中的第56天處死的3只食蟹猴分別于第3、6、9、14、21、35、56天取外周血進(jìn)行淋巴細(xì)胞計(jì)數(shù)及流式細(xì)胞儀分析淋巴細(xì)胞亞群,觀察給藥前后不同時(shí)間血中淋巴細(xì)胞數(shù)量變化情況。數(shù)據(jù)采用SPSS 13.0統(tǒng)計(jì)軟件作單因素方差分析(ANOVA,LSD),兩組間比較采用t檢驗(yàn),P0.05為差異有顯著性統(tǒng)計(jì)學(xué)意義。結(jié)果:從40只食蟹猴中篩選出15只紅細(xì)胞表面不表達(dá)CD52抗原的食蟹猴,篩選出的與未被篩選出的食蟹猴在血液生理和生化指標(biāo)方面無顯著性差異。給藥后食蟹猴血中單核細(xì)胞、淋巴細(xì)胞呈現(xiàn)出快速被清除及恢復(fù)的過程,單核細(xì)胞在給藥后第6天降至最低點(diǎn),T、B淋巴細(xì)胞在給藥后第9天降至最低點(diǎn)。單核細(xì)胞在給藥后第14天恢復(fù)至給藥前水平,CD20+B淋巴細(xì)胞、CD8+T淋巴細(xì)胞、CD4+T淋巴細(xì)胞分別在給藥后21、35、56天恢復(fù)至給藥前水平。給藥后第9天,脾臟淋巴細(xì)胞、淋巴結(jié)淋巴細(xì)胞減少,給藥后第35天,淋巴細(xì)胞數(shù)量逐漸增多,給藥后第56天,脾臟、淋巴結(jié)組織形態(tài)恢復(fù)至給藥前水平。結(jié)論:成功建立人源化CD52單克隆抗體誘導(dǎo)食蟹猴動物模型。應(yīng)用Campath-1H后食蟹猴外周血中淋巴細(xì)胞清除效果強(qiáng)大,并逐漸恢復(fù),脾臟、淋巴結(jié)淋巴細(xì)胞均呈現(xiàn)清除與恢復(fù)的過程。本實(shí)驗(yàn)?zāi)Ｐ涂捎糜谌嗽椿疌D52單克隆抗體臨床前移植模型的研究。第二部分人源化CD52單克隆抗體對食蟹猴腸道淋巴細(xì)胞的作用目的:觀察應(yīng)用人源化CD52單克隆抗體后,食蟹猴腸道上皮內(nèi)及固有層淋巴細(xì)胞的變化,評價(jià)該抗體對食蟹猴腸道淋巴細(xì)胞的作用,以及食蟹猴腸道粘膜地址素細(xì)胞粘附分子與淋巴細(xì)胞歸巢受體的變化,研究兩者相互關(guān)系。方法:雄性食蟹猴,3-5歲齡,體重3-5.5 kg,紅細(xì)胞表面不表達(dá)CD52抗原15只,隨機(jī)分為實(shí)驗(yàn)組和對照組,實(shí)驗(yàn)組按3mg/kg給予靜脈滴注Campath-1H,對照組給予等量生理鹽水。分別于給藥后9、14、35、56天處死實(shí)驗(yàn)組動物取材,切取長約10 cm小腸,分離上皮內(nèi)及固有層淋巴細(xì)胞,進(jìn)行計(jì)數(shù)、流式細(xì)胞儀分析淋巴細(xì)胞亞群。取近回盲部回腸組織,進(jìn)行病理、免疫熒光染色檢查。采用RIPA法提取腸粘膜總蛋白,進(jìn)行Western Blot檢測腸粘膜MAdCAM-1蛋白的表達(dá)變化。流式細(xì)胞儀檢測外周血T淋巴細(xì)胞β7整合素變化情況。數(shù)據(jù)采用SPSS 13.0統(tǒng)計(jì)軟件作單因素方差分析(ANOVA,LSD),P0.05為差異有顯著性統(tǒng)計(jì)學(xué)意義。結(jié)果:給藥后第9天腸道IEL、LPL數(shù)量降至最低點(diǎn),給藥后14天仍處于低水平,給藥后第35天數(shù)量逐漸增加,至給藥后第56天恢復(fù)至給藥前水平。免疫熒光染色證實(shí)了上述變化。給藥后第14天,腸道IEL、LPL亞群發(fā)生改變,IEL中CD4-CD8+、TCRαβ+T淋巴細(xì)胞比例顯著降低,而CD4+CD8+T淋巴細(xì)胞比例顯著升高;LPL中CD3-CD20+B淋巴細(xì)胞、TCRyδ+T淋巴細(xì)胞比例顯著降低,而CD4+CD8-、CD4-CD8+、CD4+CD8+T淋巴細(xì)胞比例顯著升高。給藥后第56天,腸道IEL、LPL各亞群比例恢復(fù)至給藥前水平。病理結(jié)果顯示對照組回腸粘膜完整,絨毛呈柱狀,高度正常,給藥后第9天回腸絨毛萎縮,高度變短,上皮細(xì)胞形態(tài)紊亂,有脫落,至給藥后第56天回腸絨毛高度恢復(fù)正常,粘膜完整,上皮細(xì)胞排列整齊。Western Blot檢測表明給藥后第9天腸粘膜MAdCAM-1蛋白減少,給藥后14天仍處于低水平,給藥后第35天恢復(fù)至給藥前水平。免疫熒光染色證實(shí)了上述變化。給藥后第9天外周血T淋巴細(xì)胞β7整合素表達(dá)比例增高,給藥后14天仍處于較高水平,給藥后第35天恢復(fù)至給藥前水平。結(jié)論:Campath-1H對腸道IEL、LPL具有清除作用,同時(shí)對其亞群也產(chǎn)生影響。腸道MAdCAM-1表達(dá)的變化與外周血T淋巴細(xì)胞α4β7整合素表達(dá)的變化趨勢有相關(guān)性。在食蟹猴模型上,α4β7整合素與MAdCAM-1的特異性結(jié)合,可能是腸道淋巴細(xì)胞歸巢的機(jī)制之一。
[Abstract]:Humanized CD52 monoclonal antibody (Campath-1H) on the expression of CD52 antigen T, B lymphocytes, monocytes, NK cells have strong scavenging effect, originally used for the treatment of chronic lymphocytic leukemia, multiple sclerosis and other diseases, in recent years, commonly used in kidney transplantation, liver transplantation, immune tolerance induced by intestinal transplantation in solid organ transplantation. Although the application of Campath-1H in organ transplantation has been more than ten years, but the lack of a suitable animal model for the evaluation in organ transplantation is safe and effective, thus limiting its in organ transplantation should be further used.Campath-1H only with nonhuman primates in some animal species has cross reaction, but not identification of rodent animal cells. The antigen in non-human primate animal genetic relationship with people most close, is an ideal animal model for the study of human disease. Application of Campath-1H induction in clinical transplantation After the program can be more than 99% of the lymphocytes in peripheral blood of patients with clearance of transplantation, and maintained for a long period of time. Low lymphocyte levels in the intestinal tract lymphocytes than in peripheral tissues, intestinal tract is the body's largest immune organ. The scavenging effect of Campath-1H at home and abroad research focused on peripheral blood, is a lack of research on intestinal lymphocytes. In this study, we used cynomolgus monkeys as animal model, given after the Campath-1H treatment, were observed at different time after administration of cynomolgus monkey peripheral blood, spleen, lymph node lymphocytes changes, intestinal intraepithelial and lamina propria lymphocytes subsets the changes, as well as the relationship between intestinal mucosal addressin cell adhesion molecules and lymphocyte homing receptors. Campath-1H on lymphocyte clearance and homing mechanism for clinical small bowel transplantation Provide the experimental basis for the application of Campath-1H in the better. Establishment and humanized CD52 monoclonal antibody partithe animal model on the cynomolgus monkey peripheral blood, spleen, lymph node lymphocytes. Objective: using humanized CD52 monoclonal antibody in organ transplantation has been more than ten years, but the lack of suitable animal model to evaluate the organ in less in the transplantation of safety and effectiveness, limiting its further application in organ transplantation. The humanized CD52 monoclonal antibody induced animal model in cynomolgus monkeys, and observe the effect on cynomolgus monkey peripheral blood, spleen, lymph node lymphocytes. Methods: male cynomolgus monkeys, 3-5 age, weight 3-5.5 kg, using the screening of red blood cell surface expression of CD52 antigen in cynomolgus monkeys by flow cytometry, the selected cynomolgus monkeys were randomly divided into experimental group and control group, the experimental group received intravenous injection of Campath-1H at 3 mg/kg, The control group received normal saline respectively. Based on the experimental animal group were sacrificed at 9,14,35,56 days after administration, the drug group in fifty-sixth days were only 3 cynomolgus monkeys were in the 3,6,9,14,21,35,56 days from the peripheral blood lymphocyte count and analysis of lymphocyte subsets by flow cytometry, observed before and after administration of blood lymphocytes at different time the number of changes. The data using SPSS 13 statistical software for single factor analysis of variance (ANOVA, LSD), between the two groups using t test, P0.05 difference was statistically significant. Results: We screened out 15 red cell surface expression of CD52 antigen in cynomolgus monkeys from 40 cynomolgus monkeys. There was no significant difference between the screened and was not screened in cynomolgus monkeys in the blood physiological and biochemical indexes. After administration of fresh monocytes in blood lymphocytes of cynomolgus monkeys, showing a rapid removal process and recovery of mononuclear cells in Sixth days after the administration of the lowest, T, B lymphocytes fell to the lowest level in ninth days after administration. The mononuclear cells in Fourteenth days after administration and returned to the level before administration, CD20+B lymphocytes, CD8+T lymphocytes, CD4+T lymphocytes in 21,35,56 days after administration to recover before administration level to ninth. Days after administration of spleen lymphocytes, lymph node lymphocytes decreased thirty-fifth days after dosing, the number of lymphocytes gradually increased to fifty-sixth days after the administration of spleen, lymph node morphology restored to the level before administration. Conclusion: the successful establishment of humanized CD52 monoclonal antibody induced animal model in cynomolgus monkeys after application of Campath-1H food. Fascicularis in peripheral blood lymphocyte clearance effect is strong, and gradually restored, spleen, lymph node lymphocytes showed the process of removal and recovery. This model can be used to study the transplantation model of humanized CD52 monoclonal antibody before clinic. Second Division of humanized CD52 monoclonal antibody on cynomolgus monkey intestinal lymphocyte function objective: To observe the application of humanized CD52 monoclonal antibody, changes in cynomolgus monkey intestinal intraepithelial and lamina propria lymphocytes, evaluation of the role of the antibody on the cynomolgus monkey intestinal lymphocytes, as well as changes in cynomolgus monkey intestinal mucosal addressin cell adhesion molecule with the lymphocyte homing receptor, studies the relationship between the two. Methods: male cynomolgus monkeys, aged 3-5 years old, weighing 3-5.5 kg, red cell surface expression of CD52 antigen in 15, were randomly divided into experimental group and control group, the experimental group received intravenous infusion of Campath-1H by 3mg /kg, the control group received normal saline respectively. Based on the experimental animal group were sacrificed at 9,14,35,56 days after dosing, cut a length of about 10 cm small intestine intraepithelial and lamina propria lymphocytes separation, counting, analysis of lymphocyte subsets by flow cytometry. From ileocecal junction back Intestinal tissue, pathology, immunofluorescence staining. The intestinal mucosa extract total protein by RIPA method, the expression of Western Blot of intestinal mucosa and the detection of MAdCAM-1 protein. T lymphocyte beta peripheral blood flow cytometry 7 integrin changes. Data using SPSS 13 statistical software for single factor analysis of variance (ANOVA, LSD P0.05), there was significant difference statistically significant. Results: ninth days after administration of intestinal IEL, LPL number dropped to the lowest point, 14 days after administration is still at a low level, thirty-fifth days after administration, the number gradually increased to fifty-sixth days after administration, restored to the level before administration. Immunofluorescence staining confirmed the above changes. For fourteenth days, after the administration of intestinal IEL subgroup LPL change, IEL CD4-CD8+, TCR alpha and beta +T lymphocyte ratio decreased significantly, and the percentage of CD4+CD8+T cells was significantly increased; CD3-CD20+B lymphocyte LPL, TCRy lymphocyte ratio was significantly +T. Reduce, and CD4+CD8-, CD4-CD8+, CD4+CD8+T lymphocyte ratio increased significantly. For fifty-sixth days, after the administration of intestinal IEL, LPL subsets restored to the level before administration. The pathological results showed that the control group of ileal mucosa integrity, villous columnar, normal height, Ninth days after administration of ileal villous atrophy, height shorter that epithelial cells form disorder, dropped to fifty-sixth days after administration of ileum mucosa intact, normal epithelial cells arranged in.Western Blot assay showed that MAdCAM-1 protein of intestinal mucosa decreased ninth days after administration, 14 days after administration is still at a low level, thirty-fifth days after the administration restored to the level before administration. Immunofluorescence staining confirmed the changes. After administration of T lymphocytes in peripheral blood of 7 day beta ninth integrin expression ratio increased after administration of 14 days is still at a high level, thirty-fifth days after the administration restored to the level before administration. Conclusion: Campath-1H on intestinal IEL, L PL has a scavenging effect, but also affect the subsets. There is correlation between the changes of expression of 4 integrin beta 7 trends on expression of intestinal MAdCAM-1 alpha and T lymphocytes in peripheral blood. In the cynomolgus monkey model, specific binding of alpha 4 beta 7 integrin and MAdCAM-1, may be one of the mechanisms of intestinal lymph cells homing.

【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R392

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