【摘要】：免疫性血小板減少癥(immune thrombocytopenia,ITP)是一種獲得性的自身免疫異常綜合征,約占臨床出血性疾病的1/3。經(jīng)典的ITP發(fā)病機(jī)制主要是血小板特異性自身抗體介導(dǎo)的血小板破壞增多。近年來(lái)研究發(fā)現(xiàn)細(xì)胞毒性T細(xì)胞直接殺傷血小板以及血小板去唾液酸化并在肝內(nèi)清除也是ITP血小板減少的重要途徑。此外,血小板特異性自身抗體和細(xì)胞毒性T細(xì)胞都能夠抑制ITP患者骨髓巨核細(xì)胞的成熟和凋亡,導(dǎo)致血小板生成減少。ITP的發(fā)病涉及極其復(fù)雜的上游自身免疫失調(diào),基本機(jī)制是自身免疫的失耐受,糖皮質(zhì)激素對(duì)ITP的自身免疫紊亂狀態(tài)具有廣泛的調(diào)節(jié)作用。ITP患者存在自身反應(yīng)性T、B淋巴細(xì)胞凋亡障礙,導(dǎo)致異常長(zhǎng)生存,體外實(shí)驗(yàn)中地塞米松可通過(guò)抑制BAFF逆轉(zhuǎn)這種異常。ITP中還存在自身反應(yīng)性免疫細(xì)胞亞群和保護(hù)性亞群之間的失平衡,包括Th1/Th2失衡、Th1/Th17/Treg失衡等。研究發(fā)現(xiàn)地塞米松能夠恢復(fù)Th1/Th2平衡以及Th17和Treg細(xì)胞的正常數(shù)量和功能,還能促進(jìn)保護(hù)性亞群CD8+ Treg以及CD5+ Breg細(xì)胞的功能。此外,地塞米松能夠調(diào)節(jié)ITP患者抗原呈遞細(xì)胞表面功能性分子基團(tuán)間的失平衡,有助于重建患者自身免疫耐受。糖皮質(zhì)激素是國(guó)內(nèi)外ITP診療指南一致推薦的成人ITP一線治療方案,包括常規(guī)劑量潑尼松治療和大劑量地塞米松沖擊治療。潑尼松治療的早期有效率在2/3左右,但長(zhǎng)期有效率較低,且由于多數(shù)患者進(jìn)行長(zhǎng)期的持續(xù)用藥,易產(chǎn)生激素相關(guān)的不良反應(yīng)。單臂研究顯示大劑量地塞米松治療新診斷的ITP早期有效率能達(dá)到80%以上,起效迅速且不良反應(yīng)輕微,有望在改善療效的同時(shí)縮短用藥周期并降低不良反應(yīng)。然而此前研究均未直接對(duì)比兩種治療方案的療效和安全性,因此目前仍然需要前瞻性、隨機(jī)對(duì)照研究來(lái)提供可靠的循證醫(yī)學(xué)證據(jù),以闡明哪種方案應(yīng)作為ITP一線治療的首選。部分患者對(duì)糖皮質(zhì)激素治療反應(yīng)不佳或短期內(nèi)復(fù)發(fā),這種現(xiàn)象稱(chēng)為激素抵抗�？朔に氐挚宫F(xiàn)象,進(jìn)一步提高糖皮質(zhì)激素用于ITP一線治療的療效,具有重要的臨床價(jià)值。P-糖蛋白由多藥耐藥基因MDR-1編碼,具有ATP依賴的藥物轉(zhuǎn)運(yùn)泵活性,其過(guò)表達(dá)或功能上調(diào)是導(dǎo)致多種自身免疫性疾病激素抵抗發(fā)生的重要機(jī)制。研究發(fā)現(xiàn)在系統(tǒng)性紅斑狼瘡和類(lèi)風(fēng)濕性關(guān)節(jié)炎患者外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cell, PBMC) P-gp表達(dá)顯著上調(diào),尤其是糖皮質(zhì)激素療效不佳的患者,且PBMC對(duì)地塞米松的攝取能力顯著降低,環(huán)孢素、他克莫司等能夠抑制P-gp功能,恢復(fù)對(duì)地塞米松的攝取能力。因此,P-gp在ITP激素抵抗中的作用和機(jī)制值得探索。本研究應(yīng)用前瞻性、多中心、隨機(jī)對(duì)照研究的方法,通過(guò)對(duì)比大劑量地塞米松和常規(guī)劑量潑尼松兩種治療方案的療效和安全性,為ITP一線治療策略的優(yōu)化提供了高等級(jí)的循證醫(yī)學(xué)證據(jù)。同時(shí)檢測(cè)并分析了患者大劑量地塞米松療效和PBMC細(xì)胞P-gp表達(dá)以及細(xì)胞對(duì)地塞米松攝取能力之間的關(guān)系,并嘗試應(yīng)用環(huán)孢素調(diào)節(jié)P-gp功能,揭示了ITP中激素抵抗的機(jī)制和潛在的干預(yù)途徑。第一部分：大劑量地塞米松對(duì)比常規(guī)劑量潑尼松用于成人原發(fā)免疫性血小板減少癥一線治療的前瞻性、多中心、隨機(jī)對(duì)照研究研究目的：對(duì)比大劑量地塞米松和常規(guī)劑量潑尼松治療成人原發(fā)性ITP的早期療效,包括有效率和起效時(shí)間；對(duì)比兩種藥物的遠(yuǎn)期療效,包括隨訪半年的持續(xù)緩解率及評(píng)價(jià)生存曲線；評(píng)價(jià)兩種藥物治療中患者的不良反應(yīng)和耐受性,對(duì)比其安全性；評(píng)價(jià)出血癥狀的轉(zhuǎn)歸和對(duì)早期療效的預(yù)后價(jià)值；評(píng)價(jià)血小板特異性自身抗體對(duì)療效的預(yù)后價(jià)值。從而為ITP一線治療策略的優(yōu)化提供循證醫(yī)學(xué)證據(jù),并探索糖皮質(zhì)激素治療的預(yù)后因素。研究方法：1.將未接受過(guò)正規(guī)治療的新診斷的ITP患者按照1：1的比例隨機(jī)分配至大劑量地塞米松組和常規(guī)劑量潑尼松組。2.地塞米松組給予地塞米松口服40mg/d,連用4天為1個(gè)周期,第1個(gè)周期治療無(wú)效的患者于第10d后加用1個(gè)周期；潑尼松組給予潑尼松1.Omg/kg·d口服,連用28天,其后有效患者快速減量至最小維持劑量(15mg/d)或停藥,無(wú)效患者則快速減量至停用。3.主要研究終點(diǎn)是早期有效率和持續(xù)有效率。早期有效率的評(píng)價(jià)依據(jù)最新國(guó)內(nèi)外ITP診療指南,持續(xù)有效率定義為獲得早期有效后,外周血小板計(jì)數(shù)連續(xù)六個(gè)月維持在30×109/L以上,且沒(méi)有出血癥狀或者ITP特異性附加治療需求。次要研究終點(diǎn)包括出血評(píng)分、起效時(shí)間、療效維持時(shí)間和不良反應(yīng)等。4.采用改良MAIPA技術(shù)檢測(cè)患者治療前外周血小板特異性自身抗體GPIIb/Ⅲa和GPIb/IX。結(jié)果：1.地塞米松組早期總有效率和完全反應(yīng)(complete response, CR)率均顯著高于潑尼松組,且起效時(shí)間較潑尼松組更為迅速。在地塞米松組,對(duì)第1個(gè)周期無(wú)效的患者加用第2個(gè)周期治療能夠顯著提高有效率,但是在第2個(gè)周期起效的患者獲得CR的可能性低于在第1個(gè)周期就起效的患者。2.治療前外周血小板計(jì)數(shù)低于10×109/L的患者出血癥狀明顯較嚴(yán)重,治療后地塞米松組出血例數(shù)顯著低于潑尼松組。治療前出血評(píng)分8分是早期療效的不良預(yù)后因素。3.兩組患者隨訪半年的持續(xù)有效率無(wú)統(tǒng)計(jì)學(xué)差異,早期獲得CR是進(jìn)而獲得持續(xù)有效的陽(yáng)性預(yù)后因素。生存分析顯示兩組遠(yuǎn)期結(jié)局相當(dāng),早期獲得CR的患者復(fù)發(fā)率顯著較低。4.血小板特異性自身抗體GPIIb/III日性的患者基線血小板數(shù)更低,治療前出血癥狀更嚴(yán)重。兩種抗體陽(yáng)性均提示患者獲得持續(xù)有效的可能性降低。5.地塞米松組不良反應(yīng)的發(fā)生少于潑尼松組。結(jié)論：1.1或2個(gè)周期的大劑量地塞米松治療成人新診斷的ITP具有起效迅速,早期有效率高的優(yōu)點(diǎn),長(zhǎng)期有效率與傳統(tǒng)潑尼松治療相當(dāng)。2.大劑量地塞米松治療患者耐受性優(yōu)于傳統(tǒng)潑尼松治療,患者能夠在保證長(zhǎng)期有效率的前提下規(guī)避長(zhǎng)期的激素負(fù)荷及相關(guān)不良反應(yīng)風(fēng)險(xiǎn)。3.大劑量地塞米松有望成為ITP一線治療的首選方案。第二部分：P-gp介導(dǎo)免疫性血小板減少癥中激素抵抗的作用和機(jī)制研究研究目的：分別檢測(cè)P-gp在ITP患者PBMC細(xì)胞以及外周CD4+T淋巴細(xì)胞和CD19+B淋巴細(xì)胞表面的表達(dá)水平,并根據(jù)大劑量地塞米松療效分層分析；建立超高效液相色譜法(ultra performance liquid chromatography, UPLC)檢測(cè)細(xì)胞培養(yǎng)液中地塞米松濃度的方法學(xué)體系,評(píng)價(jià)PBMC細(xì)胞對(duì)培養(yǎng)液中地塞米松的攝取能力；研究環(huán)孢素對(duì)體外培養(yǎng)的PBMC細(xì)胞P-gp的抑制作用。從而明確P-gp數(shù)量和功能在ITP激素抵抗中的作用和機(jī)制,并探索逆轉(zhuǎn)激素抵抗作用的途徑。研究方法：1.采集擬進(jìn)行大劑量地塞米松治療的新診斷的ITP患者及健康志愿者的外周血,并分離PBMC細(xì)胞。2.以PE-CD4、APC-CD19和FITC-P-gp單克隆抗體標(biāo)記PBMC細(xì)胞,流式細(xì)胞術(shù)檢測(cè)ITP患者和健康志愿者PBMC細(xì)胞、CD4+T淋巴細(xì)胞和CD19+B淋巴細(xì)胞表面的P-gp表達(dá)水平。3.將ITP患者和健康志愿者PBMC細(xì)胞分別與地塞米松或地塞米松+環(huán)孢素進(jìn)行體外共培養(yǎng),收集細(xì)胞和培養(yǎng)液上清。4.建立UPLC法檢測(cè)細(xì)胞培養(yǎng)液地塞米松殘余濃度的方法學(xué)體系,使用系列稀釋的標(biāo)準(zhǔn)溶液進(jìn)行線性檢驗(yàn)以及回收率、精密度和穩(wěn)定性考察。5.流式細(xì)胞學(xué)檢測(cè)培養(yǎng)后的PBMC細(xì)胞、CD4+T淋巴細(xì)胞和CD19+B淋巴細(xì)胞表面的P-gp表達(dá)水平。UPLC檢測(cè)細(xì)胞培養(yǎng)液中地塞米松殘余濃度。結(jié)果：1.ITP患者PBMC細(xì)胞、CD4+T淋巴細(xì)胞和CD19+B淋巴細(xì)胞表面的P-gp表達(dá)水平均顯著高于健康志愿者,大劑量地塞米松治療無(wú)效的患者P-gp表達(dá)水平高于有效患者。2. PBMC細(xì)胞和地塞米松或環(huán)孢素共培養(yǎng)后,表面P-gp表達(dá)水平較培養(yǎng)前無(wú)明顯變化。3.ITP患者PBMC細(xì)胞培養(yǎng)后培養(yǎng)液中地塞米松殘余濃度明顯高于健康對(duì)照,大劑量地塞米松治療無(wú)效患者的PBMC細(xì)胞培養(yǎng)后地塞米松殘余濃度顯著高于有效患者。4.環(huán)孢素明顯降低ITP患者PBMC細(xì)胞培養(yǎng)后培養(yǎng)液中地塞米松的殘留濃度,培養(yǎng)中加入環(huán)孢素后,地塞米松殘余濃度下降至健康對(duì)照水平。結(jié)論：1.大劑量地塞米松治療無(wú)效的患者PBMC細(xì)胞表達(dá)P-gp增加,對(duì)地塞米松的攝取減少,表明P-gp的數(shù)量和功能上調(diào)是ITP患者激素抵抗的重要機(jī)制。2.環(huán)孢素能夠抑制ITP患者PBMC細(xì)胞P-gp功能,增加對(duì)地塞米松的攝取,可能成為逆轉(zhuǎn)ITP激素抵抗的干預(yù)途徑。
[Abstract]:Immune thrombocytopenia (ITP) is an acquired autoimmune disorder syndrome, accounting for about one third of clinical hemorrhagic diseases. The classical pathogenesis of ITP is increased platelet destruction mediated by platelet-specific autoantibodies. In addition, platelet-specific autoantibodies and cytotoxic T cells can inhibit the maturation and apoptosis of bone marrow megakaryocytes in ITP patients, leading to thrombocytopenia. The mechanism is autoimmune intolerance. Glucocorticoids have a wide range of regulatory effects on ITP autoimmune disorders. ITP patients have autoreactive T and B lymphocyte apoptosis disorders, leading to abnormal long-term survival. Dexamethasone can reverse this abnormality by inhibiting BAFF in vitro. There are also autoreactive immune cells in ITP. Studies have shown that dexamethasone can restore the balance of Th1/Th2 and the normal number and function of Th17 and Treg cells. It also promotes the function of CD8+Treg and CD5+Breg cells. In addition, dexamethasone can regulate antigen presentation in ITP patients. Glucocorticoid is the first-line treatment for adult ITP recommended by the ITP guidelines at home and abroad, including conventional dose prednisone therapy and high dose dexamethasone pulse therapy. Single-arm studies have shown that high-dose dexamethasone is effective in the treatment of newly diagnosed ITP at an early stage of more than 80%, with rapid onset and mild adverse reactions. It is expected to shorten the medication cycle and reduce adverse reactions while improving the efficacy. However, previous studies have not directly compared the efficacy and safety of the two regimens, so prospective, randomized controlled studies are still needed to provide reliable evidence-based medical evidence to clarify which regimen should be the first choice for ITP treatment. Some patients have poor response to glucocorticoid therapy or relapse in the short term. Phenomenon is called hormone resistance. Overcoming hormone resistance and further improving the efficacy of glucocorticoids in the first-line treatment of ITP have important clinical value. The study found that the expression of P-gp in peripheral blood mononuclear cells (PBMC) was significantly up-regulated in SLE and RA patients, especially in patients with poor glucocorticoid therapy, and the uptake of dexamethasone by PBMC was significantly decreased, cyclosporine, tacrolimus and so on. It can inhibit the function of P-gp and restore the ability of dexamethasone uptake. Therefore, the role and mechanism of P-gp in ITP hormone resistance is worth exploring. This study applied a prospective, multicenter, randomized controlled study to compare the efficacy and safety of high-dose dexamethasone and routine-dose prednisone in the first-line treatment of ITP. The relationship between the efficacy of high-dose dexamethasone and the expression of P-gp in P BMC cells and the ability of cells to uptake dexamethasone was examined and analyzed. Cyclosporin was used to regulate the function of P-gp, revealing the mechanism of hormone resistance in ITP and potential intervention pathways. Part I: Prospective, multicenter, randomized controlled trial of high-dose dexamethasone versus conventional-dose prednisone in the first-line treatment of adult idiopathic immune thrombocytopenia Objective: To compare the early efficacy of high-dose dexamethasone with conventional-dose prednisone in the treatment of adult idiopathic ITP, including efficacy and onset time. To compare the long-term efficacy of the two drugs, including six-month follow-up continuous remission rate and survival curve; to evaluate the adverse reactions and tolerability of the two drugs, and to compare their safety; to evaluate the prognostic value of hemorrhagic symptoms and early curative effect; and to evaluate the prognostic value of platelet-specific autoantibodies for therapeutic effect Methods: 1. Patients with newly diagnosed ITP who had not received regular treatment were randomly assigned to high dose dexamethasone group and routine dose prednisone group at a ratio of 1:1. Dexamethasone group was given dexamethasone. Patients in the prednisone group were given prednisone orally at a dose of 1.Omg/kg/d for 28 days, and then the effective patients were quickly reduced to the minimum maintenance dose (15mg/d) or discontinued, while those in the ineffective group were rapidly reduced to discontinuation. Effectiveness and persistent efficacy. According to the latest ITP guidelines at home and abroad, persistent efficiency was defined as a peripheral platelet count that remained above 30 *109/L for six months without bleeding symptoms or ITP-specific additional treatment requirements. Secondary endpoints included bleeding scores and effectiveness. Results: 1. The total effective rate and complete response (CR) rate in dexamethasone group were significantly higher than those in prednisone group, and the effective time was faster than that in prednisone group. In the dexamethasone group, patients who had no response to the first cycle were significantly more likely to receive CR in the second cycle than in the first cycle. 2. Patients with peripheral platelet counts below 10 *109/L had significantly worse bleeding symptoms before treatment and after treatment. The number of bleeding cases in the dexamethasone group was significantly lower than that in the prednisone group. Before treatment, 8 points of bleeding score was a poor prognostic factor for early curative effect. 3. There was no significant difference in the sustained effective rate between the two groups after six months of follow-up. Early CR was a positive prognostic factor for achieving sustained and effective prognosis. Patients with platelet-specific autoantibodies GPIIb/III had lower baseline platelet counts and worse bleeding symptoms before treatment. Positive antibodies suggested a lower likelihood of sustained efficacy. 5. Adverse reactions in dexamethasone group were less than those in prednisone group. Conclusion: 1.1 or 2 cycles High-dose dexamethasone for newly diagnosed adult ITP has the advantages of rapid onset and high early response rate. The long-term response rate is comparable to that of traditional prednisone therapy. 2. High-dose dexamethasone is more tolerable than traditional prednisone therapy. Patients can avoid long-term hormone load and related factors on the premise of long-term efficacy. Risk of adverse reactions. 3. High-dose dexamethasone is expected to be the preferred first-line treatment for ITP. Part II: Role and mechanism of hormone resistance in immune thrombocytopenia mediated by P-gp. Objective: To detect the expression of P-gp on PBMC cells, peripheral CD4 + T cells and CD19 + B lymphocytes in patients with ITP, respectively. The methodological system of ultra performance liquid chromatography (UPLC) was established to determine the concentration of dexamethasone in cell culture medium, and the uptake of dexamethasone by PBMC cells in culture medium was evaluated. Methods: 1. PBMC cells were isolated from peripheral blood of newly diagnosed ITP patients and healthy volunteers to be treated with high-dose dexamethasone. 2. PBMC cells were isolated by PE-CD4, APC-CD19 and FITC-P-gp. PBMC cells were labeled with monoclonal antibodies, and the expression of P-gp on the surface of PBMC cells, CD4+T lymphocytes and CD19+B lymphocytes in ITP patients and healthy volunteers were detected by flow cytometry. A methodological system for the determination of residual concentration of dexamethasone in cell culture medium by UPLC was established. Linear test, recovery, precision and stability were performed using a series of diluted standard solutions. 5. The expression of P-gp on the surface of cultured PBMC cells, CD4+T lymphocytes and CD19+B lymphocytes was detected by flow cytometry. Results: 1. The expression of P-gp on PBMC, CD4 + T lymphocyte and CD19 + B lymphocyte in ITP patients was significantly higher than that in healthy volunteers. The expression of P-gp in patients with high dose of dexamethasone treatment ineffective was higher than that in effective patients. 2. After co-culture of PBMC cells with dexamethasone or cyclosporine, the expression of P-gp on the surface of PBMC cells was significantly higher than that in healthy volunteers. The residual concentration of dexamethasone in PBMC culture medium of patients with ITP was significantly higher than that of healthy controls. The residual concentration of dexamethasone in PBMC cells of patients with high dose of dexamethasone treatment ineffective was significantly higher than that of effective patients. 4. Cyclosporin significantly reduced the residual concentration of PBMC cells of patients with ITP after culture. The residual concentration of dexamethasone in nutrient solution decreased to the level of healthy control after adding cyclosporine in culture. Conclusion: 1. The expression of P-gp in PBMC cells increased and the uptake of dexamethasone decreased in patients with high dose of dexamethasone ineffective treatment, indicating that the up-regulation of P-gp quantity and function is an important mechanism of hormone resistance in ITP patients. Cyclosporin can inhibit the P-gp function of PBMC cells in ITP patients and increase the uptake of dexamethasone, which may be an intervention way to reverse ITP hormone resistance.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R558.2

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