【摘要】： 移植物抗宿主病(GVHD)仍然是臨床骨髓移植治愈血液系統(tǒng)惡性疾病的主要障礙之一。供者異基因淋巴細胞的異常活化是GVHD發(fā)生、發(fā)展的重要因素,誘導受者產(chǎn)生針對供者異基因主要組織相容性抗原(MHC)特異性耐受是預防GVHD、保存GVL的最佳途徑。配對免疫球蛋白樣受體(Paired immunoglobin-like receptor,PIR)是近年發(fā)現(xiàn)的主要表達在小鼠樹突狀細胞(DCs)上的免疫抑制性調(diào)節(jié)受體,包括免疫抑制性受體(PIR-B)及免疫活化性受體(PIR-A),其配體均是MHC-Ⅰ,二者與其配體的結合的水平是決定DCs免疫活化程度的重要分子標志之一。由于DC不僅是調(diào)控體內(nèi)T細胞活化的關鍵,也是誘導免疫耐受的理想的靶細胞,可以直接或間接通過誘導供者抗原特異性調(diào)節(jié)性T細胞的生成、在體內(nèi)形成T細胞階聯(lián)效應而抑制異基因T淋巴細胞的活化,因此研究PIR在樹突狀細胞的表達、T細胞階聯(lián)的關系及與免疫耐受的關系,可能為誘導供者MHC特異性耐受,實現(xiàn)GVHD及GVL的分離提供新的途徑。 第一部分免疫球蛋白樣受體在小鼠樹突狀細胞上的表達及與免疫耐受關系的研究 目的配對的免疫球蛋白樣受體A、B(paired immunoglobulin-like receptor A、B, PIR-A、PIR-B)屬于小鼠免疫球蛋白超家族成員。研究配對免疫球蛋白樣受體PIR-A、B在小鼠DCs上的表達及與表面共刺激分子變化的關系,探討PIR與免疫耐受的關系,探索誘導耐受性DCs的有效途徑。 方法以C57BL/6小鼠來源DC系DC2.4細胞為研究對象,分別以重組小鼠白介素-10(recombinant mouse interleukin-10,rmIL-10)、重組人轉化生長因子β1 (recombinant human transforming growth factorβ1,rhTGF -β1)誘導DC2.4細胞為耐受性DC(tolerogenic DC,T-DC),脂多糖(LPS)刺激48h為成熟DC2.4細胞(LPS-DC),體外化學合成特異PIR-B小RNA干擾片段(small interfering RNA,siRNA),以Lip2000轉染DC2.4細胞(Si-DC)。分別應用半定量RT-PCR、流式細胞儀(Flow cytometry, FCM)及Western blot檢測IL-10、TGF-β1、LPS及小干擾RNA對DC2.4細胞上PIR-A/B表達的影響;檢測LPS刺激Si-DCs后表面共刺激分子CD80、CD86、MHC-Ⅱ及PIR-A的變化;以2-△△Ct表示各目的基因cDNA轉錄的相對表達量。分別以上述各組DCs細胞為刺激細胞,以異基因BALB/c小鼠脾淋巴細胞為反應細胞,應用3H-TdR標記法檢測同種異體淋巴細胞的增殖能力(MLR),ELISA方法測MLR上清中IFN-γ的分泌水平變化。 結果FCM檢測DC2.4細胞上PIR-A、PIR-B的共同的胞外區(qū)PIR表達的陽性率為(28.65±8.12)%,IL-10、TGF-β1及LPS誘導后PIR表達均上調(diào)(P0.05),分別為(54.21±6.34)%,(58.78±4.70)%,(48.24±6.75)%,但IL-10、TGF-β1及LPS各組間無顯著性差別(P0.05)。半定量RT-PCR及Western blot顯示,IL-10、TGF-β1誘導DC2.4細胞后PIR-B的mRNA及蛋白表達升高,而PIR-A表達則降低,而LPS刺激時則相反,PIR-A的mRNA及蛋白表達升高、PIR-B的表達則降低。流式細胞儀檢測SiRNA陽性對照組的轉染率為93.12%,SYBR greenⅠRealtime-PCR檢測,LPS刺激后Si-DCs CD80、CD86、MHC-Ⅱ及PIR-A的表達高于正常DCs組。LPS-DCs組CD80、CD86、MHC-Ⅱ及PIR-A的2-△△Ct分別為5.02±1.09、4.69±1.75、5.46±1.79、6.02±2.13;LPS刺激后Si-DC組TAI分別為8.79±2.2、11.03±1.96、10.26±2.55、12.10±2.83,同LPS刺激的正常組相比,Si-DC組分別增加了3.72、6.34、4.8、6.08倍(P0.05)。混合淋巴細胞反應顯示:正常DC2.4細胞可刺激異基因淋巴細胞反應,IL-10、TGFβ1誘導的T-DC組MLR明顯受抑(P0.05),MLR上清中IFN-γ水平也相應降低(P0.05)。LPS-DC及Si-DCs組MLR明顯增強(P0.05),MLR上清中IFN-γ水平明顯增高(P0.05); 結論上調(diào)免疫抑制性受體PIR-B、下調(diào)活化性受體PIR-A是小鼠DCs獲得耐受的普遍表型特征及分子生物學機制,沉默PIR-B的表達可使PIR-A及CD80、CD86、MHC--Ⅱ及PIR-A過表達,使DCs活化的機制,PIR-A和PIR-B構成了小鼠樹突狀細胞耐受的新靶點。 第二部分高度表達免疫球蛋白樣受體B耐受性樹突狀細胞可誘導CD4+CD25+調(diào)節(jié)性T細胞生成 目的研究配對免疫球蛋白樣受體B在樹突狀細胞上表達與調(diào)節(jié)性T細胞的生成的關系,探討耐受性DCs誘導耐受的詳細機制,為體內(nèi)誘導耐受性DCs及調(diào)節(jié)性T細胞(Treg)生成提供實驗依據(jù)。 方法免疫磁珠分選BALB/c小鼠CD4+T脾淋巴細胞。以rmIL-10(50ng/ml)、rhTGF-β1(50ng/ml)聯(lián)合誘導C57BL/6小鼠來源的DC2.4細胞3天生成耐受性DCs(T-DC),同時設正常DC2.4細胞(DC)及LPS刺激48h后成熟的DC2.4細胞(mDC)干擾PIR-B組(Si-DCs)為對照組,各組DCs分別與BALB/c小鼠CD4+T脾淋巴細胞混合培養(yǎng)48h,檢測Treg生成。RT-PCR檢測轉錄因子Foxp3mRNA的表達變化,流式細胞儀檢測CD4+CD25+Treg細胞的比例,PI檢測CD4+T細胞的凋亡。磁珠分選的CD4+CD25+Treg與CD4+T細胞按照不同的比例加入MLR體系中,3H檢測Treg對異基因DCs刺激的同基因淋巴細胞的增殖能力影響。 結果磁珠分選BALB/c小鼠脾CD4+T及CD4+CD25+T淋巴細胞純度95%,正常DCs、T-DCs、Si-DC及mDCs各組細胞同BALB/c小鼠脾細胞CD4+T細胞混合培養(yǎng)3天,RT-PCR檢測表明,T-DCs組誘導后CD4+T細胞Foxp3mRNA表達明顯高于正常DCs、LPS-DC及Si-DC組。而Si-DC及LPS-DC刺激的CD4+T細胞Foxp3mRNA的表達明顯降低(P0.05)。流式細胞儀檢測表明,正常DCs、T-DCs、Si-DC及mDCs誘導的CD4+CD25+Treg細胞比例分別為(5.19±1.2)%、(28.29±2.36)%、(1.06±0.55) %,(2.01±0.66) %,以T-DC組誘導的Treg細胞比例明顯增高(P0.01)。PI檢測正常DCs、T-DCs、mDCs及Si-DC組誘導48h后CD4+T細胞的的凋亡率分別為(8.3±0.7)%、(21.56±2.32)%、(2.5±0.8)%、(1.9±0.7)%。3H檢測異基因混合淋巴細胞增殖反應細胞刺激的增殖效應,且呈劑量依賴性。 結論誘導Treg細胞生成、促進異基因淋巴細胞凋亡是PIR-B介導性DCs耐受的分子機制,為臨床應用耐受性DCs誘導免疫耐受提供理論依據(jù),也為Treg的誘導提供新的途徑。 第三部分CD8+CD28-T細胞對小鼠樹突狀細胞上配對免疫球蛋白樣受體A和B表達的影響及與耐受的關系 目的誘導宿主產(chǎn)生供者主要組織相容性抗原的特異性耐受是臨床骨髓移植的最終目標,CD8 + CD28-T(Ts)細胞是具有免疫抑制作用的調(diào)節(jié)性T細胞亞群之一,體外誘導異基因抗原特異性Ts生成,以研究Ts細胞與小鼠樹突狀細胞(DCs)上配對免疫球蛋白樣受體A和B表達的關系,探討其誘導免疫耐受的分子機制及特點,為臨床抗原特異性免疫治療的誘導提供理論基礎。 方法體外誘導Ⅰ類主要組織相容性抗原(H-2b)抗原特異性Ts細胞群,以C57BL/6小鼠(H-2b)骨髓來源的樹突狀細胞系DC2.4細胞為刺激細胞,同BALB/c小鼠(H-2d)脾淋巴細胞混合培養(yǎng),連續(xù)兩次,每次培養(yǎng)7天,第10天于培養(yǎng)體系中加入IL-2(10u/ml),第14天結束培養(yǎng)。以生物素標記的CD28、CD8標記上述細胞群,以鏈親和素標記的免疫磁珠分兩步分選Ts細胞,首先負選CD8+T細胞,再正選CD28+T細胞,陰選細胞懸液為Ts細胞群。Ts同C57BL/6小鼠DC2.4(H-2b)細胞混合培養(yǎng)48h,RT-PCR檢測DCs細胞PIR-A、PIR-BmRNA的表達,Westernblot檢測DCs細胞PIR-A、B的表達。3H標記檢測混合淋巴細胞增殖反應(MLR),體外誘導培養(yǎng)KM鼠骨髓來源的樹突狀細胞,分別以DC2.4(H-2b)及第三者主要組織相容性抗原無關的KM供鼠DCs細胞為刺激細胞,以BALB/c小鼠來源的脾CD4+T淋巴細胞為反應細胞,加入Ts細胞,以CPM檢測異基因淋巴細胞增殖反應能力。 結果體外以C57BL/6小鼠DCs誘導并在體外應用免疫磁珠分選的CD8+、CD8+CD28-Ts 90%,以BALB/c小鼠Ts細胞(H-2d)與異基因C57BL/6小鼠DCs細胞(H-2b)混合培養(yǎng)48h后,RT-PCR及Western blot檢測PIR-BmRNA及蛋白表達上調(diào)、PIR-A的mRNA及蛋白表達則下調(diào)。3H摻入標記檢測顯示,DC2.4細胞及KM鼠DCs細胞均可刺激BALB/c小鼠(H-2d)脾CD4+T淋巴細胞增殖,加入Ts細胞后,可以明顯抑制DC2.4細胞刺激的BALB/c小鼠脾CD4+T淋巴細胞(H-2d)的增殖,而并不抑制KM鼠DCs細胞刺激的CD4+T脾淋巴細胞(H-2k)的增殖反應。 結論體外誘導的Ts呈現(xiàn)Ⅰ類主要組織相容性抗原特異性抑制異基因反應性淋巴細胞的增殖。其機制與Ts細胞上調(diào)PIR-B mRNA、下調(diào)PIR-A mRNA的表達有關。升高供體移植物中抗原特異性Ts細胞比例或受體樹突狀細胞表面免疫抑制性受體的表達可能成為誘導受者產(chǎn)生針對供體抗原特異性免疫耐受的有效途徑。
[Abstract]:Graft-versus-host disease (GVHD) is still one of the major obstacles in the treatment of malignant diseases of the blood system in clinical bone marrow transplantation. Abnormal activation of allogeneic lymphocytes in donors is an important factor in the development of GVHD. It is the most important factor to induce the recipient to produce MHC specific tolerance against donor allogeneic major histocompatibility (MHC), which is the most important factor to prevent GVHD and to preserve GVL Paired immunoglobin-like receptor (PIR) is an immunosuppressive receptor that is mainly expressed in mouse dendritic cells (DCs), including immunosuppressive receptor (PIR-B) and immune activation receptor (PIR-A). The ligand of the ligand are MHC- I, the level of the binding of two to its ligand. It is one of the important molecular markers to determine the degree of immune activation of DCs. Because DC is not only the key to regulate the activation of T cells in the body, it is also an ideal target cell for inducing immune tolerance. It can directly or indirectly induce the generation of donor antigen specific regulatory T cells and form the order of T cells in the body to inhibit T lymphatic fining of the allogenic T. Therefore, the study of the expression of PIR in dendritic cells, the relationship of T cell order and the relationship with immune tolerance may provide a new way for inducing MHC specific tolerance and the separation of GVHD and GVL.
The first part is the expression of immunoglobulin like receptor on mouse dendritic cells and its relationship with immune tolerance.
Objective the paired immunoglobulin like receptor A, B (paired immunoglobulin-like receptor A, B, PIR-A, PIR-B) belong to the members of the mouse immunoglobulin superfamily. The relationship between the expression of paired immunoglobulin like receptor PIR-A, B on mice DCs and the changes in the surface costimulatory molecules, and the relationship between the immune tolerance and the immune tolerance are explored to explore the induction of tolerance. An effective way of being subjected to sexual DCs.
Methods the DC DC2.4 cells from C57BL/6 mice were used as the research object, and the recombinant human interleukin -10 (recombinant mouse interleukin-10, rmIL-10) and recombinant human transforming growth factor beta 1 (recombinant human transforming growth) were induced. 48h is a mature DC2.4 cell (LPS-DC), and the specific PIR-B small RNA interference fragment (small interfering RNA, siRNA) is synthesized in vitro (small interfering RNA, siRNA), and Lip2000 transfected to DC2.4 cells (Si-DC). The changes in the surface CO stimulatory molecules CD80, CD86, MHC- II and PIR-A were detected after LPS stimulation of Si-DCs, and the relative expression of cDNA transcript of each target gene was expressed with 2- Delta Delta Ct. The DCs cells in all of the above-mentioned groups were stimulated cells and the spleen lymphocytes of heterologous BALB/c mice were used as reactive cells, and the lymphatic allograft was detected by 3H-TdR labeling method. Cell proliferation ability (MLR), ELISA method was used to measure the secretion level of IFN- IFN- in supernatant.
Results FCM detected PIR-A on DC2.4 cells and the positive rate of PIR expression in the common extracellular domain of PIR-B was (28.65 + 8.12)%, IL-10, TGF- beta 1 and LPS induced PIR expression up up (P0.05), respectively (54.21 + 6.34)%, (58.78 + 4.70)%, (48.24 + 6.75)%, but IL-10, TGF- beta 1 and each group showed no significant difference. The expression of mRNA and protein in PIR-B was increased after DC2.4 cells were induced by IL-10 and TGF- beta 1, but the expression of PIR-A decreased, while LPS stimulation was the opposite, the mRNA and protein expression of PIR-A were increased and the expression of PIR-B decreased. The transfection rate of SiRNA positive control group was 93.12%. 86, the expression of MHC- II and PIR-A is higher than that of the normal DCs group.LPS-DCs group CD80, CD86, MHC- II and PIR-A's 2- Delta Delta Ct are 5.02 + 1.09,4.69 + + + 2.13 respectively. P0.05. The mixed lymphocyte reaction showed that normal DC2.4 cells could stimulate the reaction of allogeneic lymphocytes. The MLR in T-DC group induced by IL-10, TGF beta 1 was obviously inhibited (P0.05), and the level of IFN- gamma in MLR supernatant was also decreased (P0.05).LPS-DC and Si-DCs group increased significantly.
Conclusion up regulation of immunosuppressive receptor PIR-B and down-regulation of activated receptor PIR-A are the universal phenotypic characteristics and molecular biological mechanism of DCs tolerance in mice. The expression of silent PIR-B can make PIR-A and CD80, CD86, MHC-- II and PIR-A overexpressed. The mechanism of DCs activation, PIR-A and PIR-B are the new targets of mouse dendritic cell tolerance.
The second part of the highly expressed immunoglobulin like receptor B tolerant dendritic cells can induce the formation of CD4+CD25+ regulatory T cells.
Objective to study the relationship between the expression of paired immunoglobulin like receptor B and the production of regulatory T cells in dendritic cells, and to explore the detailed mechanism of tolerance induced tolerance of DCs, and to provide experimental basis for inducing tolerance DCs and regulatory T cells (Treg) in vivo.
The CD4+T splenic lymphocyte of BALB/c mice was selected by immunomagnetic beads. The DC2.4 cells derived from C57BL/6 mice were combined with rmIL-10 (50ng/ml) and rhTGF- beta 1 (50ng/ml) to induce the tolerance DCs (T-DC). The CD4+T splenic lymphocyte of /c mice was mixed with 48h, and the expression of Foxp3mRNA was detected by Treg generation.RT-PCR. The proportion of CD4+CD25+Treg cells was detected by flow cytometry. PI was used to detect the apoptosis of CD4+T cells. The CD4+CD25+Treg of magnetic beads and CD4+T cells were added to the MLR system according to the different specific cases. Stimulation of the proliferation ability of syngeneic lymphocytes.
Results the purity of CD4+T and CD4+CD25+T lymphocytes in the spleen of BALB/c mice was 95%. The cells of normal DCs, T-DCs, Si-DC and mDCs were mixed with the CD4+T cells of the spleen cells of BALB/c mice for 3 days. The RT-PCR detection showed that the expression of CD4+T cells was obviously higher than that of the normal group after the T-DCs group. The expression of Foxp3mRNA was significantly reduced (P0.05). Flow cytometry showed that the proportion of normal DCs, T-DCs, Si-DC and mDCs induced CD4+CD25+Treg cells was (5.19 + 1.2)%, (28.29 + 2.36)%, (1.06 + 0.55)%, (2.01 + 0.66)%, and the proportion of Treg cells induced by T-DC group was significantly higher (P0.01).PI detection of normal DCs. The apoptosis rate of CD4+T cells was (8.3 + 0.7)%, (21.56 + 2.32)%, (2.5 + 0.8)%, (1.9 + 0.7)%.3H, respectively, and (1.9 + 0.7)%.3H to detect the proliferation effect of allogeneic mixed lymphocyte proliferation reaction, and it was dose-dependent.
Conclusion induction of Treg cell production and promoting the apoptosis of allogeneic lymphocytes is the molecular mechanism of PIR-B mediated DCs tolerance, providing a theoretical basis for the clinical application of tolerance DCs to induce immune tolerance, and also provides a new way for the induction of Treg.
The third part is the effect of CD8+CD28-T cells on the expression of paired immunoglobulin like receptors A and B in mouse dendritic cells and their relationship with tolerance.
CD8 + CD28-T (Ts) cells are one of the regulatory T cell subsets with immunosuppressive effects, and the specific Ts generation of allogenic antigen in vitro can be induced in vitro, in order to study the paired immunity of Ts cells and mouse dendritic cells (DCs). The relationship between the expression of globulin like receptor A and B and the molecular mechanism and characteristics of its induced immune tolerance provide a theoretical basis for the induction of clinical antigen specific immunotherapy.
Methods the primary histocompatibility antigen (H-2b) antigen specific Ts cell group was induced in vitro. The dendritic cell line DC2.4 cells derived from C57BL/6 mice (H-2b) were used as stimulating cells and mixed culture with BALB/c mice (H-2d) splenic lymphocytes for two consecutive times, each time was 7 days, and IL-2 (10u/ml) was added to the culture system for tenth days and fourteenth days. At the end of the culture, CD28, CD8 labeled with biotin, were labeled with the above cell group, and the Ts cells were divided into two steps with the immunomagnetic beads labeled by streptavidin. First, the CD8+T cells were selected, and then the CD28+T cells were selected, the Ts cell group.Ts was mixed with the DC2.4 (H-2b) cells of the C57BL/6 mice, and the RT-PCR detected the expression of the cells. Westernblot detection of DCs cells PIR-A, B expression.3H markers to detect mixed lymphocyte proliferation response (MLR), and in vitro induction and culture of dendritic cells from the bone marrow of KM mice. DC2.4 (H-2b) and KM of the three main histocompatibility antigen independent KM mouse DCs cells are prickly cells. Ts cells were added into the cells, and the ability of allogeneic lymphocyte proliferation was detected by CPM.
Results in vitro, CD8+, CD8+CD28-Ts 90%, was induced by DCs in C57BL/6 mice and used in vitro by immunomagnetic beads. BALB/c mice Ts cells (H-2d) were mixed with DCs cells (H-2b) in C57BL/6 mice. The results showed that DC2.4 cells and KM mouse DCs cells stimulated the proliferation of CD4+T lymphocytes in the spleen of BALB/c mice (H-2d). After adding Ts cells, the proliferation of the spleen CD4+T lymphocyte (H-2d) of BALB/c mice stimulated by DC2.4 cells was obviously inhibited, but the proliferation reaction of spleen lymphocyte stimulated by KM mouse cells was not inhibited.
Conclusion Ts in vitro induced the proliferation of the main histocompatibility antigen specific inhibition of allogeneic reactive lymphocytes. The mechanism is related to the up regulation of PIR-B mRNA, down regulation of the expression of PIR-A mRNA, the increase of the proportion of antigen specific Ts cells in donor grafts or the expression of immunosuppressive receptors on the surface of the receptor tree process cells. It may be an effective way to induce recipient to produce donor specific antigen tolerance.
【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2007
【分類號】：R392

【共引文獻】

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