神经疾病的免疫干预

发布时间：2018-07-07 12:42

本文选题：急性脑卒中 + 免疫炎症反应　；参考：《天津医科大学》2016年博士论文

【摘要】：(第一部分)急性脑卒中的免疫干预(Clinical trial NCT02002390)研究目的与内容:大量的动物实验研究和临床观察证明急性脑卒中后的免疫炎性反应与患者的临床表现和预后紧密相关。目前脑卒中治疗手段是非常有限,许多脑保护治疗措施都是失败的。那么干预免疫和炎症反应是否能为治疗脑卒中提供了新的手段呢,这对脑卒中的临床治疗提出了新的挑战及机遇。芬戈莫德是鞘氨醇1-磷酸受体(S1PR)调节剂,第一个通过了FDA的治疗多发性硬化的口服药物。它通过作用于淋巴细胞亚群S1P受体从而抑制淋巴细胞从次级淋巴器官释放而抑制淋巴细胞浸润脑组织,同时该药物具有降低血脑屏障通透性以及对神经元的直接保护作用,能够减小病灶体积并促进细胞再生。基于以上理论,我们在临床开始一系列脑卒中的免疫干预试验来验证免疫干预治疗的临床效果及临床实践的可行性,本临床实验属于前瞻性探究性实验,包括出血性脑卒中的和缺血性脑卒中的研究两项。研究方法:芬戈莫德治疗脑出血的临床概念性研究:共纳入符合入选标准定的脑出血患者23例,匹配临床和CT特点后把患者分成对照组,和芬戈莫德组。首次服药前和服药后对外周循环淋巴细胞亚群检测,判断药物对细胞亚群的作用。对患者进行GCS、NIHSS、m BI和m RS评分。同时在7、14天时复查患者的头部MRI,利用FLAIR序列评估水肿体积。并且记录患者服药后的不良反应和并发症。芬戈莫德治疗脑梗死临床概念性研究:纳入了符合入选标准22名急性期前循环脑梗死患者。匹配临床和MRI特点后把患者分成对照组和芬戈莫德组。首次服药前和服药后对外周循环淋巴细胞亚群检测,判断药物对细胞亚群的作用。并对患者进行NIHSS、m BI和m RS评分。同时在7天时复查患者的头部MRI,利用FLAIR序列评估病灶体积的扩大和利用T1对比增强序列计算出r T1%来评价病灶部位的血管渗出,并且记录患者服药后的不良反应和并发症。研究结果和结论:芬戈莫德治疗脑出血的临床概念性研究:服用芬戈莫德的患者与对照组比较,明显的降低外周血液中的CD4~+、CD8~+、CD19~+淋巴细胞亚群的数量并显示出有效治疗作用。在发病7天时,服用芬戈莫德的全部患者的GCS都为15分,而对照组只有50%的患者为15分(p=0.01),以及7天时芬戈莫德的患者与对照组比较NIHSS评分明显降低。在90天时芬戈莫德治疗组病人神经功能几乎完全恢复。芬戈莫德治疗组的7天水肿体积明显低于对照组(47ml vs 108ml,p=0.04),7天和14天水肿体积指数明显低于对照组。在不良反应事件方面,两组并无统计学差异芬戈莫德治疗脑梗死临床概念性研究:芬戈莫德组患者在服药72小时后,CD4~+、CD8~+、CD19~+细胞总数分别下降了67%、70%、76%,在7天的核磁扫描发现芬戈莫德组病灶体积扩增明显受到抑制(9 vs 27 cm3,p=0.05),微血管的渗出明显受到抑制(r T1%,11.5 vs 20,p=0.005)。伴随着急性期7天内的病理损害减轻,临床的神经功能也明显改善。在对11个药物组患者安全性方面的观察,未发现药物的不良反应,未增加感染的几率及脑梗死的并发症。(第二部分)自体间充质干细胞对视神经脊髓炎谱系疾病的探究性治疗(Clinical trial NCT02249676)研究目的与内容:视神经脊髓炎是一种中枢神经系统的炎性自身免疫性疾病,病变多局限于视神经和脊髓.这个病发病率较低,但它是毁灭性的,导致积累残疾,5年死亡率约为30%。幸存者通常留下严重后遗症,包括失明,四肢瘫痪和呼吸衰竭。目前临床无有效治疗药物。骨髓间充质干细胞具有免疫调节及促进组织修复的作用,因此我们首次利用了自体骨髓间充质干细胞对视神经脊髓炎患者进行治疗。向15例难治性视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSDs)患者回输实验室处理后的自体骨髓间充质干细胞(bone mesenchymal stem cell,BMSC),初步探讨BMSC对视神经脊髓炎谱系疾病的疗效及可行性。研究方法:招募符合入选标准的视神经脊髓炎谱系疾病的患者15人,取骨髓20ml,在GMP实验室进行体外培养间充质干细胞(mesenchymal stem cells,MSC),在培养至3-4代,干细胞总数已经达到1.0×108个,经过细胞表型的鉴定为合格的MSC,并经过毒、微生物、细胞核的畸变率检测,达到临床应用的标准后,给与患者一次性静脉输入,输入后从疾病的发作及残疾的修复两方面从功能到结构对视神经、脑和脊髓3个部位进性1年的随访,并且记录患者治疗的不良反应和并发症。采用SPSS17.0统计软件包对数据进行统计分析。检验水准取α=0.05,P0.05为有统计学意义。研究结果:15名患者都培养出来合格的MSC细胞,并且顺利的完成了静脉的输入,经过一年的随访,我们发现患者于治疗前相比:平均复发率下降了(1.1 vs 0.3,p=0.002),并且在脊髓和视神经上的T2高信号和强化病灶的数量也减少了;伴随患者的残疾程度改善(Expanded Disability Status Scale,EDSS:4.3 vs 4.9,p=0.021;Visual acuity:0.4 vs 0.5,p=0.007),患者的视网膜纤维层厚度增加了(73 vs81μm,p0.001)、视神经的直径增粗了(69 vs 73 mm,p0.001)和脊髓的上经段的横截面积扩大了(2.3 vs 2.6 mm2,p0.001)。在整个治疗及随访过程中我们没有发现与MSC治疗想过的严重不良反应。研究结论:自体间充质干细胞治疗视神经脊髓炎谱系疾病患者是安全的,可行的,该治疗明显的抑制了疾病的活动,促进了神经功能的恢复。对于这种临床治疗困难,残疾程度重、生活治疗低的疾病提出了新的治疗策略。
[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.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R743.3

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