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Combined Clinical, Viral And Immunological Studies In Neuromuscular Diseases

神经肌肉疾病的临床、病毒和免疫学联合研究

基本信息

批准号：
7594640
负责人：
Mary Kay Floeter
金额：
$ 78.02万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7594640
关键词：
Affect Alzheimer&apos s Disease Amyloid Antibodies Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Process Autoimmunity B-Lymphocytes Brain Cardiomyopathies Clinical Clinical Trials Clonal Expansion Data Defect Demyelinating Polyneuropathy Deposition Desmin Disease Double-Blind Method Enrollment Epitopes Etiology Functional disorder GABA Receptor Genes Genetic Genotype Glycolipids Human Immune Immune System and Related Disorders Immunoglobulin M In Situ In Vitro Inclusion Body Myositis Inherited Inpatients Intermediate Filaments Intravenous Immunoglobulins Laboratories Longitudinal Studies Magnetic Resonance Spectroscopy Mature T-Lymphocyte Measurement Monoclonal Antibodies Muscle Muscle Fibers Muscle Proteins Mutation Myopathy Myositis Natural History Neurocognitive Neuromuscular Diseases Neuropathy Numbers Pathway interactions Patients Peptide Library Peptides Phase Phenotype Phobic anxiety disorder Play Protein Disulfide Isomerase Proteins Proteomics Role Secondary to Series Serum Severities Spectrum Analysis Stiff-Person Syndrome Subgroup T-Cell Antigen Receptor Specificity T-Lymphocyte Testing Therapeutic Therapeutic Studies Viral alpha Dystroglycan chemokine combinatorial cytokine design disability gamma-Aminobutyric Acid glycosylation humanized monoclonal antibodies in vivo neurotoxicity receptor response rituximab

项目摘要

Clinical, laboratory and therapeutic studies were conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Studies in FY07 involved patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; c) demyelinating polyneuropathies; and d) the stiff-person syndrome(SPS). In inflammatory myopathies, the specificity of the T cell Receptors and the in situ clonal expansion of the endomysial T cells are examined longitudinally. The studies have shown that in IBM the T cells are driven by specific antigens. To search for putative antigen(s), T cell clones have been established from the endomysial T cell infiltrates; candidate immunodominant peptides that drive the T cell responses and serve as autoantigens are currently explored using combinatorial peptide libraries. It has been found that in IBM chemokines and costimulatory molecules such as ICOS, ICOS-L and PDI are upregulated and the muscle fiber may function as Antigen Presenting cell. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an interrelationship between these molecules was explored. A linear relationship was found between cytokines, chemokines and amyloid-related degenerating molecules not only in vivo in the patient's muscles but also in vitro in human myotubes. At the clinical level, a longitudinal study examining the natural history of IBM has been completed. To suppress the myocytotoxic effect of T cells, a therapeutic and investigational clinical trial has begun using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. The study has been completed and is being analysed. In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was performed using Rituximab, a humanized monoclonal antibody against B cell clones. The study is now completed and the data are being analysed. Preliminary analysis demonstrates that Rituximab is effective in the disease in some subgroups and exerts its action by enhancing immunoregulatory T cells. In an effort to find responsible autoantigens in patients with Stiff Person Syndrome (SPS), T cell clones were established from the CSF and being tested against combinatorial peptide libraries. Using proteomics in the patients' serum, the antigenic peptide GABARAP (GABA-Receptor Associated Protein), was found to be reduced. Further, anti-GABARAP antibodies were detected in up to 65% of SPS patients. These antibodies may destabilize the GABAA receptors and play a role in inducing the dysfunction of GABAergic pathways and the reduced level of GABA in the patients' brains as demonstrated with MRS spectroscopy. A new double-blind clinical trial using the B cell-depleting monoclonal antibody Rituximab has been completed and all 23 patients have been enrolled. The data is undergoing analysis. The origin of phobias, a common feature in SPS patients, was being explored using a series of neurocognitive measurements. It was found that the phobias are secondary to disability and not due to the primary disease. In patients with hereditary IBM due to mutations in the GNE gene we observed a defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A pilot clinical trial using intravenous immunoglobulin in an effort to increase muscle glycosylation was completed in 4 patients. The results are promising and are currently analyzed. A phenotype/genotype correlation has been completed in patients with hereditary myopathies due to pathogenic mutations in the desmin gene. It has been concluded that desmin myopathy is a distinct disease affecting intermediate filaments and the type of mutations may dictate clinical severity or presence of cardiomyopathy.

进行了临床、实验室和治疗研究，以确定各种神经肌肉疾病的病因学（自身免疫、神经毒性、遗传学），并设计或应用有效的治疗方法。2007财年的研究涉及以下患者：a）炎症性肌病，重点是包涵体肌炎（IBM）; B）遗传性空泡性肌病，重点是由于GNE突变和结蛋白相关肌病引起的遗传性IBM; c）脱髓鞘性多发性神经病; d）僵人综合征（SPS）。在炎性肌病中，纵向检查T细胞受体的特异性和肌内膜T细胞的原位克隆扩增。研究表明，在IBM中，T细胞由特定抗原驱动。为了寻找推定的抗原，已经从肌内膜T细胞浸润中建立了T细胞克隆;目前使用组合肽文库探索了驱动T细胞应答并用作自身抗原的候选免疫显性肽。已经发现，在IBM中，趋化因子和共刺激分子如ICOS、ICOS-L和PDI被上调，并且肌纤维可以作为抗原呈递细胞发挥功能。由于细胞因子与阿尔茨海默样β-APP淀粉样沉积物具有共同的抗原决定簇，因此探索了这些分子之间的相互关系。不仅在患者肌肉中，而且在体外人肌管中，细胞因子、趋化因子和淀粉样蛋白相关变性分子之间均存在线性关系。在临床层面，已经完成了一项纵向研究，检查IBM的自然史。为了抑制T细胞的肌细胞毒性作用，已经开始使用CAMPATH进行治疗性和研究性临床试验，CAMPATH是一种人源化单克隆抗体，其诱导成熟T细胞的持续消耗，从而允许耐受原性T细胞应答。这项研究已经完成，正在进行分析。在与MAG和糖脂的IgM自身抗体相关的脱髓鞘神经病中，使用利妥昔单抗（一种针对B细胞克隆的人源化单克隆抗体）进行了一项新的对照治疗研究。这项研究现已完成，正在分析数据。初步分析表明，利妥昔单抗是有效的疾病在某些亚组，并发挥其作用，通过增强免疫调节T细胞。为了在患有僵直人综合征（SPS）的患者中找到负责的自身抗原，从CSF建立T细胞克隆，并针对组合肽文库进行测试。使用患者血清中的蛋白质组学，发现抗原肽GABARAP（GABA受体相关蛋白）减少。此外，在高达65%的SPS患者中检测到抗GABARAP抗体。这些抗体可能使GABAA受体不稳定，并在诱导GABA能通路功能障碍和患者脑中GABA水平降低中发挥作用，如MRS光谱所示。一项新的使用B细胞耗竭单克隆抗体利妥昔单抗的双盲临床试验已经完成，所有23名患者都已入组。数据正在分析中。恐惧症是SPS患者的一个常见特征，其起源正在通过一系列神经认知测量进行探索。据发现，恐惧症是继发于残疾，而不是由于原发性疾病。在GNE基因突变导致的遗传性IBM患者中，我们观察到肌肉蛋白糖基化缺陷和α-肌营养不良蛋白聚糖减少。在4名患者中完成了一项使用静脉注射免疫球蛋白以增加肌肉糖基化的初步临床试验。结果是有希望的，目前正在分析。由于结蛋白基因的致病性突变，遗传性肌病患者的表型/基因型相关性已经完成。结论是结蛋白肌病是一种影响中间丝的独特疾病，突变类型可能决定临床严重程度或心肌病的存在。