Combined Clinical, Viral And Immunological Studies In Ne

联合临床、病毒和免疫学研究

• 批准号: 6671343
• 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/6671343
• 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; immunotherapy; laboratory mouse; muscle cells; myelinopathy; neuromuscular disorder; neuromuscular disorder chemotherapy; nuclear magnetic resonance spectroscopy; 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 cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, prompting an ongoing study that 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, it was found that the Schwann cells express markers for Antigen Presenting Cells while the autoinvasive CD4+ T cells express the co-stimulatory molecules CTLA and CD28 at the protein and mRNA level. The mechanism of action of IVIg in affecting these molecules and other autoantibodies has been addressed. In an effort to identify peripheral nerve antigens responsible for the demyelinating neuropathy and find effective therapies, a new controlled therapeutic study has been designed using a humanized monoclonal antibody against B cell clones. This study correlates clinical responses with the binding affinity of IgM to anti-glycoconjugate antibodies. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented. 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. A randomized-controlled clinical trial with high-dose intravenous immunoglobulin was conducted in SPS patients and demonstrated efficacy of the drug, confirming the autoimmune nature of the disease. After treatment, the anti-GAD65 antibody titers diminished. This is the first immunotherapy proven effective in the disease. In an effort to find the responsible autoantigen, T cell clones were established from the CSF of several patients with SPS; the role of GAD as well as other peptides serving as antigens is currently explored. During the investigation of patients with IBM, a group of distinct hereditary distal myopathies associated with cardiomyopathy was identified on the basis of clinicopathological criteria. Additional studies have shown that this disease is 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).

进行临床、实验室和治疗研究，以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，重点是结蛋白相关神经肌肉疾病; c）脱髓鞘性多神经病;和d）僵硬人综合征（SPS）。 在炎性肌病中，检测了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，细胞因子与阿尔茨海默样β-APP淀粉样蛋白沉积物具有共同的抗原决定簇，这促使正在进行的研究探索淀粉样蛋白在触发肌内膜炎症中的作用。这些信息将有助于寻求抗淀粉样蛋白策略作为IBM的潜在治疗方法。为了抑制T细胞的肌细胞毒性作用及其在增强β-APP形成中的假定作用，设计了使用CAMPATH的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。 在脱髓鞘神经病中，发现施万细胞表达抗原呈递细胞的标志物，而自侵袭CD 4 + T细胞在蛋白质和mRNA水平表达共刺激分子CTLA和CD 28。IVIg影响这些分子和其他自身抗体的作用机制已得到解决。为了鉴定引起脱髓鞘性神经病的周围神经抗原并找到有效的治疗方法，设计了一种新的对照治疗研究，使用抗B细胞克隆的人源化单克隆抗体。本研究将临床反应与IgM对抗糖缀合物抗体的结合亲和力相关联。 在僵直人综合征（SPS）患者中，记录了抗GAD特异性IgG抗体的鞘内合成。抗GAD抗体似乎抑制GABA的体内合成，支持GABA水平降低与患者症状有因果关系的观点。由于GABA介导的抑制性中间神经元功能障碍而导致的僵硬和敏感性提高的表现已经通过发现脑干中间神经元回路的过度兴奋性而得到电生理学支持。在SPS患者中进行了一项高剂量静脉注射免疫球蛋白的随机对照临床试验，证明了药物的疗效，证实了疾病的自身免疫性质。治疗后，抗GAD 65抗体滴度降低。这是第一种被证明对这种疾病有效的免疫疗法。为了找到负责的自身抗原，从几个SPS患者的CSF中建立了T细胞克隆;目前正在探索GAD以及其他肽作为抗原的作用。 在IBM患者的研究中，根据临床病理标准确定了一组与心肌病相关的独特遗传性远端肌病。其他研究表明，这种疾病是由结蛋白基因的致病性突变引起的。在转染细胞系中研究了突变的功能作用，并探索了突变结蛋白丝的溶解性。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（肌纤维肌病）。