Combined Clinical, Viral And Immunological Studies In Ne

联合临床、病毒和免疫学研究

• 批准号: 6841887
• 负责人: Marinos Dalakas
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 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/6841887
• 关键词: T cell receptor; amyotrophic lateral sclerosis; antiinflammatory agents; cell line; clinical research; clinical trials; degenerative motor system disease; dermatomyositis; extrapyramidal disorder; gamma aminobutyrate; gene targeting; genetically modified animals; helper T lymphocyte; human subject; human therapy evaluation; immunity; immunoglobulins; immunopathology; immunotherapy; laboratory mouse; muscle cells; myelinopathy; myositis; neuromuscular disorder; neuromuscular disorder chemotherapy; nuclear magnetic resonance spectroscopy; patient oriented research; poliomyelitis; polymyositis

Clinical, laboratory and therapeutic studies are conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Current studies involve patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) intermediate filament related disorders with emphasis on desmin-related neuromuscular disorders; 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 were examined. 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 and ICOS-L are upregulated and the muscle fiber may function as Antigen Presenting cells. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an ongoing study explores the role of amyloid in triggering endomysial inflammation. The information will be useful in pursuing anti-amyloid strategies as potential therapy for IBM. To suppress the myocytotoxic effect of T cells and their putative role in enhancing the formation of beta-APP, a therapeutic and investigational clinical trial was designed using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. In demyelinating neuropathies associated with autoantibodies,a new controlled therapeutic study has started using a humanized monoclonal antibody against B cell clones. In an effort to identify peripheral nerve antigens responsible for the neuropathy, the study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented and correlated with the clinical symptomatology. The anti-GAD antibodies appear to suppress the synthesis of GABA in vivo supporting the view that reduced GABA level is causatively related to the patients' symptoms. The manifestation of stiffness and heightened sensitivity as a result of dysfunction of the GABA-mediated inhibitory interneurons has been supported electrophysiologically by finding hyperexcitability of the brainstem interneuronal circuits. The GABA level in the brain was studied with MRS spectroscopy and the effect of therapies on GABA level is being examined. In an effort to find the responsible autoantigen in SPS patients, T cell clones were established from the CSF; the role of GAD as well as other peptides serving as antigens is explored. During the investigation of patients with IBM, two groups of distinct hereditary distal myopathies were identified. One group was related to mutations in the GNE gene resulting in abnormal glycosylation of muscle proteins. The other group, often associated with cardiomyopathy, was caused by pathogenic mutations in the desmin gene. The functional role of the mutations was studied in transfected cell lines and the solubility of mutant desmin filaments was explored. A phenotype/genotype correlation has now been completed in patients with mutant desmin. These studies have shown that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy).

临床、实验室和治疗研究是为了确定各种神经肌肉疾病的病因(自身免疫、神经毒性、遗传学)，并设计或应用有效的治疗方法。目前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)中间丝相关疾病，重点是结蛋白相关的神经肌肉疾病；c)脱髓鞘多神经病；d)僵人综合征(SPS)。在炎症性肌病中，检测T细胞受体的特异性和肌内T细胞的原位克隆性增殖。研究表明，IBM的T细胞是由特定的抗原驱动的。为了寻找可能的抗原(S)，已经从肌内T细胞浸润物中建立了T细胞克隆；目前利用组合肽库探索驱动T细胞反应并作为自身抗原的候选免疫优势肽。研究发现，在IBM中，趋化因子和共刺激分子如ICOS和ICOS-L上调，肌纤维可能起抗原提呈细胞的作用。由于细胞因子与类阿尔茨海默病的β-APP淀粉样沉积有共同的抗原决定因素，一项正在进行的研究探索了淀粉样蛋白在触发肌内膜炎症中的作用。这些信息将有助于IBM寻求抗淀粉样蛋白策略作为潜在的治疗方法。为了抑制T细胞的肌细胞毒作用及其在促进β-APP形成中的可能作用，设计了一项使用人源化单抗CamPath的治疗性和研究性临床试验，该抗体可诱导成熟T细胞的持续耗竭，从而产生耐受性T细胞反应。 在与自身抗体相关的脱髓鞘神经病中，一项新的对照治疗研究已经开始，使用人源化的针对B细胞克隆的单抗。为了确定导致神经病变的周围神经抗原，这项研究将临床反应与IgM与髓鞘上各种糖结合物的结合亲和力联系起来。 在僵人综合征(SPS)患者中，鞘内合成抗GAD特异性抗体被记录下来，并与临床症状相关。抗GAD抗体似乎抑制了体内GABA的合成，支持了GABA水平降低与患者症状相关的观点。由于GABA介导的抑制性中间神经元功能障碍而表现出的僵硬和高度敏感性的表现，已经通过发现脑干神经元间回路的超兴奋性得到了电生理学的支持。用MRS光谱学研究了大脑中的GABA水平，并正在检查治疗对GABA水平的影响。为了寻找SPS患者应负责任的自身抗原，从脑脊液中建立了T细胞克隆，并探讨了GAD和其他多肽作为抗原的作用。 在对IBM患者的调查中，发现了两组不同的遗传性远端肌病。其中一组与导致肌肉蛋白质异常糖基化的Gne基因突变有关。另一组通常与心肌病有关，是由结蛋白基因的致病突变引起的。研究了突变在细胞系中的功能作用，并对突变结蛋白细丝的溶解性进行了研究。突变结蛋白患者的表型/基因型相关性现已完成。这些研究表明，结蛋白肌病是一种影响中间丝的独特疾病(细丝病)。