本文關(guān)鍵詞：免疫抑制劑及凋亡細胞誘導(dǎo)移植免疫耐受的實驗研究　出處：《南方醫(yī)科大學(xué)》2010年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 凋亡細胞 地塞米松 紫外線 誘導(dǎo) 小鼠 皮膚移植 凋亡細胞 動物模型 免疫抑制劑 MCP-1 細胞因子

【摘要】： 研究背景： 器官移植是目前治療器官終末期疾病的最有效的治療措施,但是移植術(shù)后的排斥反應(yīng)仍是阻礙患者和移植物長期存活的主要原因,傳統(tǒng)免疫抑制劑的應(yīng)用雖然能夠有效地抑制急性排斥反應(yīng),但是在移植物的慢性排斥方面仍是不能解決其根本原因,并且長期服用免疫抑制劑會增加患者感染、中毒、腫瘤等疾病的發(fā)生率,且費用昂貴。因此,解決器官移植術(shù)后排斥反應(yīng)的關(guān)鍵在于誘導(dǎo)受者對供者移植物的免疫耐受,免疫耐受是機體免疫系統(tǒng)在接觸某種抗原后所產(chǎn)生的對該抗原的特異性免疫無應(yīng)答狀態(tài),一旦此種免疫無應(yīng)答狀態(tài)形成后便無需任何免疫抑制劑維持,從而從更本上解決移植后的排斥反應(yīng),達到移植物與宿主能夠長期共存的目的。但是,目前擺在移植免疫學(xué)界的難題就是如何才能夠誘導(dǎo)受者的移植免疫耐受?據(jù)此孫爾維等人提出了利用供體凋亡細胞誘導(dǎo)受者免疫耐受的假說。該假說認(rèn)為凋亡細胞能主動性地調(diào)節(jié)機體的免疫功能,凋亡細胞通過給其APC主動性地傳遞吞噬信號"eat me signal"使得吞噬細胞能夠快速攝取凋亡細胞并將其所攜帶的供者抗原被特異性地濃集與受者APC內(nèi),從而短時間內(nèi)提供大量供者MHC抗原,有效地被受者APC提呈給T細胞,最終促進調(diào)節(jié)性T細胞(Treg)的產(chǎn)生,抑制輔助性T細胞的產(chǎn)生來誘導(dǎo)機體的免疫耐受。國外Fsdok等人也發(fā)現(xiàn)巨噬細胞大量吞噬凋亡細胞時,可以抑制一些炎性因子的分泌,促進了TGF-β、IL-10等一些免疫調(diào)節(jié)因子的產(chǎn)生。Voll等人發(fā)現(xiàn)在細菌脂多糖刺激外周血淋巴細胞的反應(yīng)中加入凋亡細胞不僅能夠抑制IL-2、IL-1B、TNF-α等炎性因子的分泌,而且能夠促進免疫抑制因子IL-10的產(chǎn)生。本課題組已經(jīng)成功建立了供者凋亡細胞預(yù)輸注誘導(dǎo)小動物心臟、肝臟移植免疫耐受模型,但是單純輸注凋亡細胞對大動物的移植模型誘導(dǎo)免疫耐受的作用并不明顯,同樣,國內(nèi)外眾多學(xué)者對誘導(dǎo)成年大動物移植免疫耐受進行了多次嘗試,均沒有理想的結(jié)果,但是凋亡細胞聯(lián)合免疫抑制劑對大動物移植免疫耐受的誘導(dǎo)實驗尚未見報道。 目前就如何建立成年大動物和臨床誘導(dǎo)免疫耐受已經(jīng)成為了移植免疫學(xué)界的主攻方向和目標(biāo)。因為大動物免疫系統(tǒng)比較復(fù)雜,排斥反應(yīng)強烈,且購買及飼養(yǎng)價格都比較昂貴,故本課題欲先采用小鼠建立皮膚移植模型,小鼠皮膚移植模型排斥反應(yīng)較為強烈,并且小鼠免疫系統(tǒng)簡單,易操作,費用較為低廉,給受者小鼠預(yù)輸注凋亡細胞并聯(lián)合低劑量的免疫抑制劑誘導(dǎo)其免疫耐受,并通過檢測其在不同免疫抑制劑作用下的全血中細胞因子的變化來探討其機制和原理,為下一步大動物和臨床誘導(dǎo)免疫耐受做一個探索性研究。 本課題為國家自然科學(xué)基金(供者凋亡細胞誘導(dǎo)移植免疫耐受的機制)資助項目。本實驗利用同種異基因小鼠皮膚移植作為移植模型,皮膚移植是目前可行的器官移植中排斥反應(yīng)最為強烈的模型,因觀察周期短,操作簡便,手術(shù)成功率高,可控性強等諸多優(yōu)點而被廣泛應(yīng)用于移植模型的建立；凋亡細胞的制備有多種方法,目前一般采用紫外線照射、抗體誘導(dǎo)、化療藥物誘導(dǎo)、射線誘導(dǎo)、激素誘導(dǎo)等方法,本實驗采取地塞米松藥物誘導(dǎo)法。地塞米松作為糖皮質(zhì)激素類藥物具有調(diào)節(jié)細胞生長、發(fā)育、死亡以達到維持機體組織細胞平衡穩(wěn)定的作用。地塞米松誘導(dǎo)淋巴細胞及其它免疫細胞的凋亡較其它方法穩(wěn)定、易操作已有較多文獻報道。 第一部分地塞米松誘導(dǎo)供體胸腺細胞的凋亡的初步研究 目的：摸索使用地塞米松作為誘導(dǎo)劑對小鼠胸腺細胞凋亡的誘導(dǎo)作用,為下一步實驗找到一種穩(wěn)定性高、可控性強、凋亡率高的誘導(dǎo)方法。 方法：將健康成年小鼠胸腺研磨制成細胞懸液,用血球計數(shù)板計數(shù)后用RPMI-1640完全培養(yǎng)基(含10%胎牛血清)調(diào)整細胞濃度為1×106／ml,將所獲細胞分裝進4個培養(yǎng)皿中進行不同處理：一組置于紫外線燈下20cm處直接照射15分鐘后5%C02孵箱37℃恒溫培養(yǎng)4小時。另外三組分別加入濃度為1×10-7M、2×10-5M、2×10-3M的地塞米松后置于5%CO2孵箱37℃恒溫培養(yǎng)6小時；將處理后的四組胸腺細胞懸液用Annexin V-PI試劑雙染后,用流式細胞儀檢測胸腺細胞的凋亡和壞死。 結(jié)果：1、不同濃度地塞米松處理后的小鼠胸腺細胞凋亡率略有不同,經(jīng)1×10-7M濃度的DEX處理BALB/C小鼠胸腺細胞后,用流式細胞儀檢測其凋亡率為53.72%；經(jīng)2×10-SM濃度的DEX處理BALB/C小鼠胸腺細胞后,檢測其凋亡率為58.46%；經(jīng)2×10-3M濃度的DEX處理BALB/C小鼠胸腺細胞后,測得其凋亡率為55.72%。 2、在紫外線燈下20cm處直接照射15分鐘后用5%CO2孵箱37℃恒溫培養(yǎng)4小時后的小鼠胸腺細胞,測得其凋亡率為50.29%,； 結(jié)論：用地塞米松誘導(dǎo)小鼠胸腺細胞凋亡過程復(fù)雜、耗時較長,而紫外線照射法操作簡便、耗時短。但是用地塞米松誘導(dǎo)的小鼠胸腺細胞凋亡率要高于紫外線照射法,且壞死細胞較少,結(jié)果穩(wěn)定,容易控制,因2×10-5M濃度的DEX處理BALB/C小鼠胸腺細胞凋亡率最高,故下一步實驗給受者小鼠注射凋亡細胞采取2×10-5M濃度的地塞米松誘導(dǎo)。 第二部分免疫抑制劑及凋亡細胞對誘導(dǎo)小鼠皮膚移植免疫耐受的試驗研究 目的：探索供體凋亡細胞與免疫抑制劑對小鼠皮膚移植免疫耐受的作用 方法：1、制備供體小鼠的胸腺凋亡細胞：采用研磨法獲得供者小鼠的胸腺淋巴細胞懸液,經(jīng)2×10-5M DEX處理后放入5%C02孵箱37℃恒溫培養(yǎng)6小時后,獲取供體小鼠的胸腺凋亡細胞用Annexin V-PI試劑雙染后,流式細胞儀檢測胸腺細胞的凋亡率； 2、實驗分組：將受者小鼠隨機分為四組：PBS對照組、凋亡細胞組、雷帕霉素(RAPA)組、RAPA+凋亡細胞聯(lián)合組。輸注供體胸腺凋亡細胞組別的受者小鼠分別在術(shù)前7、3、1天經(jīng)陰莖背靜脈輸注供體小鼠的凋亡細胞懸液；接受藥物處理的受者小鼠在術(shù)前3天開始灌胃給予RAPA藥物,1次／d,直到所有移植皮片完全壞死時停藥； 3、建立小鼠背對背皮膚移植模型：將修好的供者小鼠背部皮片采用6-8針間斷垂直褥式外翻縫合固定在受者小鼠背部,蓋上無菌敷料后創(chuàng)可貼加壓包扎； 4、術(shù)后觀察：在行皮膚移植術(shù)后第5天打開包扎觀察移植皮片存活情況,若植皮與宿主的背底部愈合,色澤一致,無炎癥和充血,有毛的皮膚毛發(fā)生長良好,則認(rèn)為未發(fā)生排斥反應(yīng).50%以上皮片結(jié)痂、變硬、壞死、脫落作為排斥標(biāo)準(zhǔn)。 結(jié)果：1、自體皮膚移植(手術(shù)控制組)45例,皮片存活時間1月的存活率為95%(43／45)； 2、受者小鼠術(shù)前分別預(yù)輸注一次、兩次、三次凋亡細胞比較移植皮片存活時間沒有統(tǒng)計學(xué)差異P0.05,但是輸注三次凋亡細胞的受者小鼠移植皮片存活時間呈明顯延長趨勢； 3、C57—Babl/C小鼠背—背皮膚移植手術(shù)82例,其中PBS組18例,平均存活時間6.8天；凋亡組共20例平均存活時間7.4天；RAPA組共行手術(shù)22例,平均存活時間10.36天；RAPA聯(lián)合凋亡細胞組共行22例,平均存活時間10.68天。用Kaplan-Meier統(tǒng)計方法分析后PBS對照組與凋亡細胞組移植皮片存活時間比較無統(tǒng)計學(xué)差異(P0.05); RAPA組與PBS組比較有顯著性統(tǒng)計學(xué)差異(P0.01);RAPA+凋亡細胞聯(lián)用與單純使用RAPA組比較無統(tǒng)計學(xué)差異(P0.05); 4、Babl/C— C57小鼠小鼠背—背皮膚移植手術(shù)78例,其中PBS組共18例,平均存活時間6.5天；凋亡組共20例,平均存活時間7.3天；RAPA組共行手術(shù)19例,平均存活時間10.42天；RAPA聯(lián)合凋亡細胞組共行21例,平均存活時間10.52天。用Kaplan-Meier統(tǒng)計方法分析后PBS組與凋亡細胞組移植皮片存活時間比較無統(tǒng)計學(xué)差異(P0.05),但是凋亡組較PBS組移植皮片呈延長趨勢；RAPA+凋亡細胞聯(lián)用與單純使用RAPA組比較無統(tǒng)計學(xué)差異(P0.05)。 結(jié)論：1、分別輸注1次、2次、凋亡細胞均對小鼠皮膚移植存活時間無明顯延長,但是輸注3次凋亡細胞對移植物存活時間有著明顯的延長趨勢； 2、凋亡細胞對誘導(dǎo)同種異基因小鼠皮膚移植免疫耐受作用不明顯。 3、低劑量免疫抑制劑能夠延長同種異基因小鼠的皮膚移植存活時間； 4、免疫抑制劑聯(lián)合凋亡細胞的協(xié)同作用在小鼠皮膚移植模型上效果不明顯。 第三部分：不同免疫抑制劑對全血中細胞因子分泌的機制研究 目的：研究不同免疫抑制劑對全血細胞中不同細胞因子分泌的影響。 方法：1.取樣：取健康成人外周血加入不同濃度的免疫抑制劑培養(yǎng)6 h后加入10μl濃度為0.15μg／ml的佛波酯(PMA)和10μl濃度為2.5 gg／ml的離子霉素(IONO),再培養(yǎng)6 h(37℃,5% CO2)后離心(300 G,5 min),收集上清待測; 2.利用用Bio-Plex懸浮蛋白芯片系統(tǒng)檢測細胞因子的變化,比較不同免疫抑制劑組細胞因子的水平。 3.統(tǒng)計：采用SPSS10.0統(tǒng)計分析軟件對數(shù)據(jù)進行統(tǒng)計分析。采用單向方差分析和LSD檢驗比較實驗組與對照組之間的差異,P0.05有統(tǒng)計學(xué)意義 結(jié)果：高濃度,中濃度的地塞米松(DEX)及環(huán)孢素A (CsA)都能有效抑制MCP-1的分泌,而他克莫司(FK506)和麥考酚酸(MPA)不能有效抑制細胞因子的分泌。 結(jié)論：DEX和CsA可有效抑制MCP-1的分泌,而FK506和MPA對MCP-1的分泌沒有影響。
[Abstract]:Research background:
Organ transplantation is the treatment of end-stage organ disease the most effective treatment measures, but the main reason for graft rejection is still hinder the long-term graft survival, the application of traditional immunosuppressants can effectively inhibit acute rejection, but in terms of the chronic graft rejection is still not solve the fundamental reason and long-term use of immunosuppressive patients will increase the incidence of infection, poisoning, cancer and other diseases, and expensive. Therefore, the key to solve the rejection after organ transplantation is induced by graft immune tolerance to donor immune tolerance, immune system is generated in contact with certain antigens to the antigen the specific immune unresponsiveness, once the formation of immunological unresponsiveness after without any immunosuppressive maintenance, so as to solve the shift from the Rejection after transplantation, graft and host can achieve the purpose of the long-term coexistence. However, the current problem placed in transplantation immunology circles that how to induce immune tolerance of transplant recipient? The sun Erwei proposed by immune tolerance induced by donor apoptotic cells of the hypothesis. The hypothesis that immune cells apoptosis can take the initiative to regulate the body's cell apoptosis through the APC initiative to transfer signal "eat me signal" phagocytosis of phagocytes can make rapid uptake of apoptotic cells and the donor antigen was carried by specific concentration by APC, so a short period of time to provide a large number of donor MHC antigen. Effectively by recipient APC presenting to T cells and eventually promote regulatory T cells (Treg) generation, inhibition of T helper cells to induce immune tolerance. Fsdok et al also found macrophages A large number of cell phagocytosis of apoptotic cells, can inhibit the secretion of inflammatory cytokines, promote TGF- beta, IL-10 and some other immunomodulatory cytokines produced.Voll et al found that adding apoptosis in lipopolysaccharide stimulated peripheral blood lymphocyte responses can not only inhibit IL-2 secretion of TNF-, IL-1B, and other inflammatory factors, but also can promote the immunosuppressive factor IL-10. The research group has successfully established donor apoptotic cells induced by pre infusion of small animal heart, liver transplantation immune tolerance model, but simply note the apoptotic cells transplantation model on large animal immune tolerance induced by the effect is not obvious, also, many domestic and foreign scholars have made many attempts to the adult animal induced immune tolerance, are not ideal results, but apoptotic cells combined with immunosuppressive agents on immune tolerance induced by transplantation of animal experiments have not yet See the report.
At present, how to set up the adult animal and clinical induction of immune tolerance has become the main direction and goal of transplant immunology circles. Because the immune system of large animal more complex, strong rejection, and the purchase price is relatively expensive and feeding, so this research will first established by skin transplantation model of small rat model of skin allograft rejection in mice more strongly, and the immune system is simple, easy operation, relatively low cost, to recipients immunosuppressive mice pre infusion of apoptotic cells and combined with low doses of induced immune tolerance, and through the inspection of the cells in the effects of different immunosuppressive agents of the blood factor to explore the mechanism and principle for a large animal and clinical immune tolerance induced by doing an exploratory study.
This subject is the National Natural Science Fund (the mechanism of donor apoptotic cells induce immune tolerance) projects. This experiment using murine skin allografts as transplantation model, skin transplantation is the organ transplant rejection is the most feasible in the strong model, because of the short observation period, simple operation, high success rate the establishment of the advantages of strong controllability, and is widely used in transplantation model; apoptotic cell preparation of a variety of methods, the current commonly used ultraviolet irradiation induced antibody induced by chemotherapeutic drugs, radiation, induction, hormone induction and other methods, this experiment take dexamethasone induced by dexamethasone. As glucocorticoids regulate cell growth, development, death in order to achieve the maintenance of body tissue stability. The apoptosis of lymphocytes and other immune cells induced by dexamethasone It is more stable and easier to operate than other methods.
Primary study on the apoptosis of donor thymus cells induced by dexamethasone in the first part
Objective: To explore the induction effect of dexamethasone as an inducer on thymocyte apoptosis in mice, and find a high stability, high controllability and high apoptosis inducing method for next experiment.
Methods: healthy adult mouse thymus and grinded into cell suspension by blood cell counting plate count with RPMI-1640 complete medium (containing 10% fetal bovine serum) the cell concentration was adjusted to 1 * 106 / ml, will be divided into 4 different cell culture processing dish: culture 5%C02 incubator a constant temperature of 37 DEG C group under ultraviolet lamp 20cm under direct irradiation 15 minutes after 4 hours. The other three groups were added at the concentration of 1 * 10-7M, 2 * 10-5M, 2 * 10-3M of dexamethasone after 5%CO2 incubation box at 37 C for 6 hours; the four groups after the treatment of thymus cell suspension with double Annexin V-PI kit after staining, flow cytometry was used to detect the thymocyte apoptosis and necrosis.
Results: 1, thymus cell apoptosis rate after different concentrations of dexamethasone treatment is slightly different, with 1 * 10-7M concentration of DEX BALB/C in mouse thymocytes, detected their apoptotic rate by flow cytometry was 53.72%; with 2 * 10-SM concentration of DEX BALB/C in mouse thymocytes, detected the apoptosis rate was 58.46% with 2 * 10-3M; the concentration of DEX BALB/C in mouse thymocytes, measured the apoptosis rate of 55.72%.
2, after 15 minutes of direct irradiation at 20cm under ultraviolet light, the murine thymocytes were incubated at 37 C at 37 C in 5%CO2 incubator for 4 hours, and the rate of apoptosis was 50.29%.
Conclusion: Dexamethasone induced mouse thymocyte apoptosis is complex, time-consuming, and ultraviolet irradiation method is simple, time is short. But the use of dexamethasone induced mouse thymocyte apoptosis rate is higher than that of ultraviolet irradiation, and the necrotic cells less, stable, easy to control, because the DEX BALB/C in mouse thymocytes apoptosis rate up to 2 * 10-5M concentration, so the next step of the experiment to the recipient mice with apoptotic cells induced by taking 2 * 10-5M concentration of dexamethasone.
Experimental study on immune tolerance of second parts of immunosuppressant and apoptotic cells in inducing skin transplantation in mice
Objective: To explore the effect of donor apoptotic cells and immunosuppressive agents on the immune tolerance of skin transplantation in mice
Methods: 1 cell apoptosis of thymus, preparation of donor mice: donor mice by the method of grinding the thymus lymphocyte suspension, with 2 * 10-5M after DEX treatment in the 5%C02 incubator at 37 C after 6 hours of incubation, cell apoptosis of donor mice thymus acquisition by Annexin V-PI double staining reagent, thymocyte apoptosis the rate of flow cytometry;
2, experiment group: recipient mice were randomly divided into four groups: PBS control group, apoptotic cells group, rapamycin (RAPA) group, RAPA+ group. Apoptotic cells combined with infusion of donor apoptotic cells in thymus groups of recipient mice suspension of apoptotic cells in the preoperative 7,3,1: dorsal penile vein infusion of donor mice respectively.; the treatment operation in recipient mice 3 days before intragastric administration of RAPA drugs, 1 / D, until all the skin graft necrosis completely discontinued when;
3, establish a mouse model of skin transplantation: fixed back-to-back donor mice back skin using 6-8 needle interrupted vertical mattress suture fixation in recipient mice back, covered with sterile dressing after compression bandage bandage;
4, postoperative observation: at fifth days after skin transplantation open dressing grafts survival situation, if the back bottom of skin grafting and host healing, consistent color, no inflammation and hyperemia, hairy skin and hair growth is good, is that no rejection of more than.50% skin knot scab, harden, necrosis and off as the rejection criteria.
Results: 1, 45 cases of autologous skin graft (operation control group), the survival time of skin graft survival time in January was 95% (43 / 45).
2, the recipient mice were pre injected once, two times, and three times before the operation. Compared with the three apoptotic cells, the survival time of grafted skin was not statistically different. P0.05, however, the survival time of the mice who had been transfused for three times was significantly prolonged.
3, C57 - Babl/C - mouse dorsal dorsal skin transplantation in 82 cases, including 18 cases of PBS group, the average survival time of 6.8 days; the apoptosis of 20 cases of the average survival time of 7.4 days; group RAPA underwent surgery in 22 cases, the average survival time of 10.36 days; RAPA group apoptosis were performed in 22 cases, the average survival time for 10.68 days. Using Kaplan-Meier statistical analysis method of PBS control group and group apoptosis skin graft survival time had no significant difference (P0.05); RAPA group and PBS group, there was significant difference (P0.01); and the simple use of RAPA group compared with no significant difference in apoptotic cells in combination with RAPA+ (P0.05);
4, Babl/C - C57 mouse dorsal dorsal skin graft in 78 cases, PBS group 18 cases, the average survival time of 6.5 days; apoptosis were 20 cases, the average survival time of 7.3 days; group RAPA underwent surgery in 19 cases, the average survival time of 10.42 days; RAPA group included 21 cases of apoptosis and the average survival time of 10.52 days. Using Kaplan-Meier statistical analysis method after the PBS group and the group apoptosis skin graft survival time had no significant difference (P0.05), but the apoptosis group than in PBS group of skin grafts increased; the apoptosis of RAPA+ cells associated with the use of RAPA compared with the control group showed no significant difference (P0.05).
Conclusion: 1, 1 times and 2 times of infusion 1 times, the survival time of the skin cells was not prolonged, but the survival time of the apoptotic cells was prolonged obviously after 3 times of infusion.
2, the immunological tolerance of the apoptotic cells to the allogeneic mouse skin transplantation was not obvious.
3, low dose immunosuppressant can prolong the survival time of skin allograft in allogeneic mice.
4, the synergistic effect of immunosuppressive agents combined with apoptotic cells was not effective in the mouse skin transplantation model.
The third part: the study of the mechanism of different immunosuppressive agents on the secretion of cytokines in the whole blood
Objective: To study the effect of different immunosuppressants on the secretion of different cytokines in the whole blood cells.
Methods: 1. samples: healthy adult peripheral blood with different concentrations of immunosuppressant culture phorbol ester 6 h after adding 10 L concentration of 0.15 g / ml (PMA) and 10 L concentration was 2.5 GG / ionomycin ml hormone (IONO), and then cultured for 6 h (37 DEG C, 5% CO2) after centrifugation (300 G, 5 min), the supernatant was collected to be measured;
2. the level of cytokines in different immunosuppressant groups was compared by using Bio-Plex suspension protein chip system to detect the changes of cytokines.
3. statistics: SPSS10.0 statistical analysis software was used to analyze the data. Unidirectional variance analysis and LSD test were used to compare the difference between the experimental group and the control group, P0.05 was statistically significant.
Results: high concentration, moderate concentration of dexamethasone (DEX) and cyclosporine A (CsA) can effectively inhibit MCP-1 secretion, while tacrolimus (FK506) and mycophenolic acid (MPA) can not effectively inhibit cytokine secretion.
Conclusion: DEX and CsA can effectively inhibit the secretion of MCP-1, while FK506 and MPA have no effect on the secretion of MCP-1.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2010
【分類號】：R392

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