發(fā)布時(shí)間：2018-06-15 15:10

  本文選題：程序性死亡因子-1 + T細(xì)胞非霍奇金淋巴瘤　； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：背景T細(xì)胞非霍奇金淋巴瘤(T cell non-Hodgkin lymphoma,T-NHL)是一組異質(zhì)性疾病,其惡性程度高,5年總生存率僅為20-40%。目前常規(guī)治療方案都易復(fù)發(fā),并且一旦復(fù)發(fā)缺乏有效的挽救治療方案。因此積極推動(dòng)T-NHL臨床研究,探究其發(fā)病機(jī)制及藥物靶點(diǎn)應(yīng)當(dāng)成為淋巴瘤研究的重點(diǎn)。腫瘤微環(huán)境和腫瘤相關(guān)免疫是近年的研究和治療熱點(diǎn),外周血循環(huán)淋巴細(xì)胞是腫瘤患者機(jī)體免疫系統(tǒng)的重要組成部分,已有研究證實(shí)淋巴瘤患者外周血T細(xì)胞表面的共刺激分子中常存在異常表達(dá),與腫瘤的免疫逃逸相關(guān)。其中程序性死亡因子-1(programmed death-1,PD-1)與腫瘤免疫關(guān)系最為密切,然而循環(huán)淋巴細(xì)胞表面PD-1在T-NHL中的研究相對(duì)較少,本文對(duì)PD-1對(duì)于T-NHL患者的機(jī)體免疫的影響及作用進(jìn)行初步探討。目的1.明確PD-1及相關(guān)共刺激分子在初治T-NHL外周血Treg細(xì)胞表面的表達(dá)及其治療后變化。2.探究T-NHL患者與健康人外周血PD-1(+)淋巴細(xì)胞功能的差異性。3.初步揭示T-NHL患者外周血PD-1(+)淋巴細(xì)胞功能差異性的分子基礎(chǔ)。方法本研究共納入2015年9月至2017年4月在北京協(xié)和醫(yī)院診治的60例T-NHL患者,和在健康體檢中心查體的65名健康志愿者。采用流式細(xì)胞技術(shù)分析外周血Treg細(xì)胞表面PD-1及相關(guān)共刺激分子的表達(dá)水平,分析表達(dá)與患者預(yù)后間的關(guān)系。并在患者治療第2-6療程后,再次測(cè)定患者外周血T淋巴細(xì)胞表面PD-1及相關(guān)共刺激分子的表達(dá)情況,探究表達(dá)與患者療效的關(guān)系。利用磁珠分選10例初治T-NHL及10例健康受試者的外周血PD-1(+)淋巴細(xì)胞,進(jìn)行體外培養(yǎng),采用MTT試驗(yàn)對(duì)比患者及健康受試者外周血PD-1(+)淋巴細(xì)胞功能,此外利用數(shù)字化基因表達(dá)譜測(cè)序技術(shù)分析患者及健康受試者外周血PD-1(+)淋巴細(xì)胞基因表達(dá)譜差異,探究功能差異的分子基礎(chǔ)。結(jié)果1.1)初治T-NHL患者外周血Treg細(xì)胞表面CD279及CD152平均熒光強(qiáng)度較健康對(duì)照組明顯升高(P0.001);CD152及CD28表達(dá)比例較健康對(duì)照明顯降低(P0.001);2)中/高危患者外周血Treg細(xì)胞表面CD279及CD152平均熒光強(qiáng)度較低�；颊呓M明顯升高(P0.05),CD28表達(dá)比例較低危患者組明顯降低(P0.05);3)血管免疫母細(xì)胞性T細(xì)胞淋巴瘤患者外周血Treg細(xì)胞表面CD279及CD28表達(dá)平均熒光強(qiáng)度較結(jié)外NK/T細(xì)胞淋巴瘤(鼻型)患者明顯降低(PP0.05);4)T-NHL患者治療后外周血Treg細(xì)胞表面CD279及CD152平均熒光強(qiáng)度較治療前明顯降低(P0.05),CD28平均熒光強(qiáng)度較治療前明顯升高(P0.05)。5)T-NHL患者外周血Treg細(xì)胞表面PD-1及CD152表達(dá)與患者無(wú)事件生存時(shí)間相關(guān)(P0.05)。2.T-NHL患者外周血PD-1(+)淋巴細(xì)胞轉(zhuǎn)化率低于健康受試者(P0.001)。3.與健康對(duì)照相比,T-NHL患者外周血PD-1(+)淋巴細(xì)胞具有明顯不同的基因表達(dá)譜,與差異基因相關(guān)的生物學(xué)過(guò)程包括細(xì)胞增殖/凋亡、免疫反應(yīng)、信號(hào)傳導(dǎo)、物質(zhì)代謝及細(xì)胞粘附等,主要涉及IFN、MYD88以及Toll樣受體相關(guān)通路。結(jié)論1、初治T-NHL患者外周血Treg表面PD-1及相關(guān)共刺激分子表達(dá)較健康人具有明顯差異,與疾病分層及預(yù)后相關(guān);經(jīng)過(guò)治療后,T-NHL患者外周血Treg細(xì)胞表面PD-1及相關(guān)共刺激分子表達(dá)向健康人水平轉(zhuǎn)變。2、T-NHL患者外周血PD-1(+)淋巴細(xì)胞功能較健康人明顯減弱。3、T-NHL患者外周血PD-1(+)淋巴細(xì)胞較健康人基因表達(dá)譜具有明顯差異,差異表達(dá)的基因可能與T-NHL的發(fā)生及腫瘤免疫相關(guān)。
[Abstract]:Background T cell non Hodgkin lymphoma (T cell non-Hodgkin lymphoma, T-NHL) is a heterogeneous group of heterogeneous diseases with a high degree of malignancy. The 5 year total survival rate is only 20-40%. and the conventional therapy is easy to relapse, and once a relapse lacks effective salvage therapy, T-NHL clinical research is actively promoted to explore its pathogenesis and drug. The target point should be the focus of lymphoma research. Tumor microenvironment and tumor related immunity are the focus of research and treatment in recent years. Peripheral blood circulating lymphocytes are an important part of the immune system of the tumor patients. The abnormal expression of the co stimulators in the T cell surface of the peripheral blood of the lymphoma patients has been proved to be abnormal. The immune escape of the tumor is related. The procedural death factor -1 (programmed death-1, PD-1) is most closely related to the tumor immunity. However, the study of PD-1 in the circulating lymphocyte surface is relatively less in T-NHL. The effect and effect of PD-1 on the immunity of T-NHL patients were preliminarily discussed in this paper. Objective 1. PD-1 and associated co stimulation were clearly defined. The expression of molecules on the surface of Treg cells in the primary T-NHL peripheral blood and the change of.2. to explore the differential.3. of PD-1 (+) lymphocyte function in peripheral blood of T-NHL patients and healthy people preliminarily reveal the molecular basis of the functional difference of PD-1 (+) lymphocyte in peripheral blood of T-NHL patients. Methods this study was included in the Beijing association from September 2015 to April 2017. 60 patients with T-NHL, and 65 healthy volunteers who were examined in a health check-up center, were used to analyze the expression level of PD-1 and related co stimulators on the surface of peripheral blood Treg cells by flow cytometry, and to analyze the relationship between the expression and the prognosis of the patients. After the treatment of the 2-6 course of treatment, the T lymph nodes were again measured in the peripheral blood of the patients. The expression of PD-1 and related costimulatory molecules on the cell surface was used to explore the relationship between the expression and the curative effect of the patients. Using magnetic beads, the peripheral blood PD-1 (+) lymphocytes of 10 patients with T-NHL and 10 healthy subjects were selected and cultured in vitro. The function of PD-1 (+) lymphocyte in peripheral blood of the patients and healthy subjects was compared with those of the healthy subjects, and the digitalization was also used. The gene expression spectrum sequencing technique was used to analyze the difference of PD-1 (+) lymphocyte gene expression profiles in patients and healthy subjects and to explore the molecular basis of functional differences. Results 1.1) the average fluorescence intensity of CD279 and CD152 on the surface of peripheral blood Treg cells in the early treatment of T-NHL patients was more than that of the healthy control group of Xian Shenggao (P0.001); the expression ratio of CD152 and CD28 was healthier than that of healthy controls. The average fluorescence intensity of CD279 and CD152 on the surface of peripheral blood Treg cells in the middle / high risk patients was significantly higher than that in the low risk group (P0.05), and the proportion of CD28 expression was significantly lower than that of the low risk group (P0.05), and the average fluorescence intensity of CD279 and CD28 expression of the Treg cell surface of peripheral blood on the peripheral blood of the patients with angioimmunocyte T cell lymphoma was significantly increased (P0.05) in the middle / high risk patients. (2) the average fluorescence intensity of CD279 and CD152 in the peripheral blood of the middle / high risk patients was significantly higher than that in the low risk group (P0.05) The patients with NK/T cell lymphoma (nasal type) were significantly lower (PP0.05); 4) the average fluorescence intensity of CD279 and CD152 on the Treg cell surface of the peripheral blood of T-NHL patients was significantly lower than that before treatment (P0.05), and the average fluorescence intensity of CD28 was significantly higher than that before treatment (P0.05).5). The transformation rate of PD-1 (+) lymphocyte in peripheral blood of patients with P0.05.2.T-NHL was lower than that of healthy subjects (P0.001).3. and healthy controls. The PD-1 (+) lymphocyte in peripheral blood of T-NHL patients had distinct gene expression profiles. The biological processes related to differential genes included cell proliferation / apoptosis, immune response, and signal transduction IFN, MYD88 and Toll like receptor related pathways are mainly involved in material metabolism and cell adhesion. Conclusion 1, the expression of PD-1 and related co stimulators on the Treg surface of the peripheral blood of T-NHL patients is significantly different from that of the healthy people, and is related to the stratification and prognosis of the disease. After treatment, the PD-1 and associated co stimulation of the peripheral Treg cells on the peripheral blood of the patients with T-NHL are stimulated. The expression of PD-1 (+) lymphocyte function in peripheral blood of T-NHL patients was significantly lower than that of healthy people. The expression of PD-1 (+) lymphocyte in peripheral blood of T-NHL patients was significantly different from that of healthy people. The differentially expressed genes may be related to the occurrence of T-NHL and tumor immunity in patients with T-NHL.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.1

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4 陳聰;IL-12不同亞基在經(jīng)典型霍奇金淋巴瘤及彌漫性大B細(xì)胞淋巴瘤中的表達(dá)及意義[D];安徽醫(yī)科大學(xué);2015年

5 劉申婷;自體外周血造血干細(xì)胞移植治療外周T細(xì)胞淋巴瘤1例報(bào)道并文獻(xiàn)復(fù)習(xí)[D];昆明醫(yī)科大學(xué);2015年

6 王宏;淋巴瘤中EB病毒潛伏膜蛋白1基因多態(tài)性研究[D];青島大學(xué);2015年

7 何延輝;~(18)F-FDG PET/CT顯像在不同病理亞型淋巴瘤療效評(píng)價(jià)方面的價(jià)值[D];安徽醫(yī)科大學(xué);2015年

8 王芳;EBER、PTEN和VEGF在血管免疫母T細(xì)胞淋巴瘤中的表達(dá)及其臨床病理學(xué)意義[D];安徽醫(yī)科大學(xué);2015年

9 石源源;青島地區(qū)淋巴瘤中EB病毒編碼基因EBNA1多態(tài)性研究[D];青島大學(xué);2015年

10 張?jiān)?~(18)F-FDG PET/CT在彌漫大B細(xì)胞淋巴瘤化療中期診斷及療效評(píng)價(jià)的研究[D];新疆醫(yī)科大學(xué);2015年

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