本文選題：急性腦卒中 + 免疫炎癥反應(yīng)��； 參考：《天津醫(yī)科大學(xué)》2016年博士論文

【摘要】：(第一部分)急性腦卒中的免疫干預(yù)(Clinical trial NCT02002390)研究目的與內(nèi)容:大量的動物實驗研究和臨床觀察證明急性腦卒中后的免疫炎性反應(yīng)與患者的臨床表現(xiàn)和預(yù)后緊密相關(guān)。目前腦卒中治療手段是非常有限,許多腦保護(hù)治療措施都是失敗的。那么干預(yù)免疫和炎癥反應(yīng)是否能為治療腦卒中提供了新的手段呢,這對腦卒中的臨床治療提出了新的挑戰(zhàn)及機遇。芬戈莫德是鞘氨醇1-磷酸受體(S1PR)調(diào)節(jié)劑,第一個通過了FDA的治療多發(fā)性硬化的口服藥物。它通過作用于淋巴細(xì)胞亞群S1P受體從而抑制淋巴細(xì)胞從次級淋巴器官釋放而抑制淋巴細(xì)胞浸潤腦組織,同時該藥物具有降低血腦屏障通透性以及對神經(jīng)元的直接保護(hù)作用,能夠減小病灶體積并促進(jìn)細(xì)胞再生�；谝陨侠碚�,我們在臨床開始一系列腦卒中的免疫干預(yù)試驗來驗證免疫干預(yù)治療的臨床效果及臨床實踐的可行性,本臨床實驗屬于前瞻性探究性實驗,包括出血性腦卒中的和缺血性腦卒中的研究兩項。研究方法:芬戈莫德治療腦出血的臨床概念性研究:共納入符合入選標(biāo)準(zhǔn)定的腦出血患者23例,匹配臨床和CT特點后把患者分成對照組,和芬戈莫德組。首次服藥前和服藥后對外周循環(huán)淋巴細(xì)胞亞群檢測,判斷藥物對細(xì)胞亞群的作用。對患者進(jìn)行GCS、NIHSS、m BI和m RS評分。同時在7、14天時復(fù)查患者的頭部MRI,利用FLAIR序列評估水腫體積。并且記錄患者服藥后的不良反應(yīng)和并發(fā)癥。芬戈莫德治療腦梗死臨床概念性研究:納入了符合入選標(biāo)準(zhǔn)22名急性期前循環(huán)腦梗死患者。匹配臨床和MRI特點后把患者分成對照組和芬戈莫德組。首次服藥前和服藥后對外周循環(huán)淋巴細(xì)胞亞群檢測,判斷藥物對細(xì)胞亞群的作用。并對患者進(jìn)行NIHSS、m BI和m RS評分。同時在7天時復(fù)查患者的頭部MRI,利用FLAIR序列評估病灶體積的擴大和利用T1對比增強序列計算出r T1%來評價病灶部位的血管滲出,并且記錄患者服藥后的不良反應(yīng)和并發(fā)癥。研究結(jié)果和結(jié)論:芬戈莫德治療腦出血的臨床概念性研究:服用芬戈莫德的患者與對照組比較,明顯的降低外周血液中的CD4~+、CD8~+、CD19~+淋巴細(xì)胞亞群的數(shù)量并顯示出有效治療作用。在發(fā)病7天時,服用芬戈莫德的全部患者的GCS都為15分,而對照組只有50%的患者為15分(p=0.01),以及7天時芬戈莫德的患者與對照組比較NIHSS評分明顯降低。在90天時芬戈莫德治療組病人神經(jīng)功能幾乎完全恢復(fù)。芬戈莫德治療組的7天水腫體積明顯低于對照組(47ml vs 108ml,p=0.04),7天和14天水腫體積指數(shù)明顯低于對照組。在不良反應(yīng)事件方面,兩組并無統(tǒng)計學(xué)差異芬戈莫德治療腦梗死臨床概念性研究:芬戈莫德組患者在服藥72小時后,CD4~+、CD8~+、CD19~+細(xì)胞總數(shù)分別下降了67%、70%、76%,在7天的核磁掃描發(fā)現(xiàn)芬戈莫德組病灶體積擴增明顯受到抑制(9 vs 27 cm3,p=0.05),微血管的滲出明顯受到抑制(r T1%,11.5 vs 20,p=0.005)。伴隨著急性期7天內(nèi)的病理損害減輕,臨床的神經(jīng)功能也明顯改善。在對11個藥物組患者安全性方面的觀察,未發(fā)現(xiàn)藥物的不良反應(yīng),未增加感染的幾率及腦梗死的并發(fā)癥。(第二部分)自體間充質(zhì)干細(xì)胞對視神經(jīng)脊髓炎譜系疾病的探究性治療(Clinical trial NCT02249676)研究目的與內(nèi)容:視神經(jīng)脊髓炎是一種中樞神經(jīng)系統(tǒng)的炎性自身免疫性疾病,病變多局限于視神經(jīng)和脊髓.這個病發(fā)病率較低,但它是毀滅性的,導(dǎo)致積累殘疾,5年死亡率約為30%。幸存者通常留下嚴(yán)重后遺癥,包括失明,四肢癱瘓和呼吸衰竭。目前臨床無有效治療藥物。骨髓間充質(zhì)干細(xì)胞具有免疫調(diào)節(jié)及促進(jìn)組織修復(fù)的作用,因此我們首次利用了自體骨髓間充質(zhì)干細(xì)胞對視神經(jīng)脊髓炎患者進(jìn)行治療。向15例難治性視神經(jīng)脊髓炎譜系疾病(neuromyelitis optica spectrum disorders,NMOSDs)患者回輸實驗室處理后的自體骨髓間充質(zhì)干細(xì)胞(bone mesenchymal stem cell,BMSC),初步探討B(tài)MSC對視神經(jīng)脊髓炎譜系疾病的療效及可行性。研究方法:招募符合入選標(biāo)準(zhǔn)的視神經(jīng)脊髓炎譜系疾病的患者15人,取骨髓20ml,在GMP實驗室進(jìn)行體外培養(yǎng)間充質(zhì)干細(xì)胞(mesenchymal stem cells,MSC),在培養(yǎng)至3-4代,干細(xì)胞總數(shù)已經(jīng)達(dá)到1.0×108個,經(jīng)過細(xì)胞表型的鑒定為合格的MSC,并經(jīng)過毒、微生物、細(xì)胞核的畸變率檢測,達(dá)到臨床應(yīng)用的標(biāo)準(zhǔn)后,給與患者一次性靜脈輸入,輸入后從疾病的發(fā)作及殘疾的修復(fù)兩方面從功能到結(jié)構(gòu)對視神經(jīng)、腦和脊髓3個部位進(jìn)性1年的隨訪,并且記錄患者治療的不良反應(yīng)和并發(fā)癥。采用SPSS17.0統(tǒng)計軟件包對數(shù)據(jù)進(jìn)行統(tǒng)計分析。檢驗水準(zhǔn)取α=0.05,P0.05為有統(tǒng)計學(xué)意義。研究結(jié)果:15名患者都培養(yǎng)出來合格的MSC細(xì)胞,并且順利的完成了靜脈的輸入,經(jīng)過一年的隨訪,我們發(fā)現(xiàn)患者于治療前相比:平均復(fù)發(fā)率下降了(1.1 vs 0.3,p=0.002),并且在脊髓和視神經(jīng)上的T2高信號和強化病灶的數(shù)量也減少了;伴隨患者的殘疾程度改善(Expanded Disability Status Scale,EDSS:4.3 vs 4.9,p=0.021;Visual acuity:0.4 vs 0.5,p=0.007),患者的視網(wǎng)膜纖維層厚度增加了(73 vs81μm,p0.001)、視神經(jīng)的直徑增粗了(69 vs 73 mm,p0.001)和脊髓的上經(jīng)段的橫截面積擴大了(2.3 vs 2.6 mm2,p0.001)。在整個治療及隨訪過程中我們沒有發(fā)現(xiàn)與MSC治療想過的嚴(yán)重不良反應(yīng)。研究結(jié)論:自體間充質(zhì)干細(xì)胞治療視神經(jīng)脊髓炎譜系疾病患者是安全的,可行的,該治療明顯的抑制了疾病的活動,促進(jìn)了神經(jīng)功能的恢復(fù)。對于這種臨床治療困難,殘疾程度重、生活治療低的疾病提出了新的治療策略。
[Abstract]:(Part one) the purpose and content of the Clinical trial NCT02002390 study of acute stroke: a large number of animal experiments and clinical observations have proved that the inflammatory response after acute stroke is closely related to the clinical manifestation and prognosis of the patients. At present, the treatment of stroke is very limited, and many measures of brain protection are used. It is all a failure. Then the intervention of immunization and inflammation can provide new means for the treatment of stroke, which poses new challenges and opportunities for the clinical treatment of stroke. It is a sphingosine 1- phosphate receptor (S1PR) regulator, the first oral drug for the treatment of multiple sclerosis by FDA. The S1P receptor of the cell subgroup inhibits the release of lymphocyte from secondary lymphoid organs and inhibits lymphocytic infiltration of the brain tissue. At the same time, the drug can reduce the permeability of the blood-brain barrier and direct protective effect on the neurons, which can reduce the volume of the lesion and promote the cell regeneration. The clinical effects of immunotherapy and the feasibility of clinical practice are verified by the immune intervention test of stroke. This clinical trial is a prospective exploratory experiment, including two studies of hemorrhagic stroke and cerebral apoplexy. 23 patients with intracerebral hemorrhage were divided into the control group, and the CT group. The patients were divided into the control group and the fin group. The effect of the drugs on the cell subsets was judged before and after the first medicine. The patients were evaluated with GCS, NIHSS, m BI and m RS. At the same time, the patients' head MRI was reviewed at 7,14 days and FLAIR was used for FLAIR. The sequence assessed the edema volume and recorded adverse reactions and complications after the patient took the drug. A clinical conceptual study of cerebral infarction by feingmod was included in 22 patients with acute anterior circulating cerebral infarction conforming to the criteria of admission. The patients were divided into the control group and the fingmod group after the matching of clinical and MRI characteristics. Peripheral lymphocyte subsets were detected to determine the effect of drugs on cell subsets. The patients were evaluated with NIHSS, m BI, and m RS. At the same time, the patients' head MRI was reviewed at 7 days. The enlargement of the lesion volume was evaluated by FLAIR sequence and R T1% was used to evaluate the vascular exudation of the lesion at the focus of the lesion, and the patient's clothes were recorded. Adverse reactions and complications after the drug. Results and conclusions: a clinical conceptual study of Finn Gomo De's treatment of cerebral hemorrhage: the patients taken in the patients with the control group compared with the control group significantly reduced the number of CD4~+, CD8~+, CD19~+ lymphocyte subsets in the peripheral blood and showed effective therapeutic effect. In the 7 day of the onset of the disease, the use of fine Ge mod. The GCS of all patients was 15 points, while only 50% of the patients in the control group were 15 (p=0.01), and the patients with the control group were significantly lower than the control group at 7 days. On the 90 day, the neurologic function of the group was almost completely restored. The 7 day edema volume of the group was significantly lower than that of the control group (47ml vs 108m. L, p=0.04), the edema volume index of 7 days and 14 days was significantly lower than that in the control group. In the adverse event, the two groups had no statistical difference in the clinical conceptual study of cerebral infarction. The total number of CD4~+, CD8~+, and CD19~+ cells decreased by 67%, 70%, 76% after 72 hours of medication. The volume amplification of the lesion in the mod group was significantly inhibited (9 vs 27 cm3, p=0.05), and the exudation of the microvessels was obviously inhibited (R T1%, 11.5 vs 20, p=0.005). The clinical neurological function was obviously improved with the reduction of pathological damage within 7 days in the acute period, and the safety of the patients in the 11 drug groups was not detected, and the adverse reactions were not found. Increasing the risk of infection and complications of cerebral infarction. (second) the purpose and content of the study of Clinical trial NCT02249676 with autogenous mesenchymal stem cells (MSCs) for optic neuromyelitis pedigree disease: optic neuromyelitis is an inflammatory autoimmune disease of the central nervous system, and the lesions are mostly limited to the optic nerve and spinal cord. The incidence of this disease is low, but it is devastating, resulting in the accumulation of disability. The death rate of about 5 years is about 30%. survivors, which usually leave serious sequelae, including blindness, paralysis, and respiratory failure. Autologous bone marrow mesenchymal stem cells were treated for the patients with optic neuromyelitis. Autologous bone marrow mesenchymal stem cells (bone mesenchymal stem cell, BMSC) were treated in 15 cases of refractory neuromyelitis optica spectrum disorders (NMOSDs) patients after the retransfusion laboratory, and the BMSC on the optic spinal cord was discussed. The efficacy and feasibility of inflammatory pedigree disease. Research methods: 15 patients who were recruited to the standard optic neuromyelitis lineage disease were recruited, bone marrow 20ml was taken and mesenchymal stem cells (MSC) was cultured in GMP laboratory. The total number of stem cells in the 3-4 generation had reached 1 * 108. As a qualified MSC, and after the detection of toxic, microbiological, nuclear aberration, and the standard of the clinical application, the patient was given a one-time intravenous input from the two aspects of the disease attack and the rehabilitation of the disabled from functional to the structure of the optic nerve, the brain and the spinal cord for 1 years, and to record the adverse reactions of the patients. The data were statistically analyzed with the SPSS17.0 software package. The test level was taken for alpha =0.05 and P0.05 was statistically significant. The results of the study: 15 patients were trained to pass the qualified MSC cells and successfully completed the input of the veins. After a year of follow-up, we found that the patients were compared to the average rate of recurrence before treatment: the average rate of recurrence. Decreased (1.1 vs 0.3, p=0.002), and the number of T2 high signals and enhanced lesions on the spinal cord and optic nerve also decreased; with the improvement of the degree of disability in the patients (Expanded Disability Status Scale, EDSS:4.3 vs 4.9, p=0.021; Visual acuity:0.4 0.5), the thickness of the retinal fibrous layer increased (73 The diameter of the nerve thickened (69 vs 73 mm, p0.001) and the transverse section of the superior segment of the spinal cord expanded (2.3 vs 2.6 mm2, p0.001). We did not find serious adverse reactions to the MSC treatment throughout the treatment and follow-up. Conclusions autogenous mesenchymal stem cells are safe for patients with optic neuromyelitis spectrum disease. Yes, the treatment obviously inhibits the activity of the disease and promotes the recovery of nerve function. New treatment strategies have been put forward for the difficulty of clinical treatment, the heavy disability and low life treatment.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R743.3

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相關(guān)期刊論文 前1條

1 Yu-Jing Li;Guo-Qiang Chang;Yuanchu Liu;Ye Gong;Chunsheng Yang;Kristofer Wood;Fu-Dong Shi;Ying Fu;Yaping Yan;;Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage[J];Neuroscience Bulletin;2015年06期

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本文編號：2104994