Combined Clinical, Viral And Immunological Studies

综合临床、病毒和免疫学研究

• 批准号: 7007819
• 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/7007819
• 关键词: T cell receptor; amyloid proteins; antiinflammatory agents; clinical trials; congenital neuromuscular disorder; cytokine; dermatomyositis; extrapyramidal disorder; glycosylation; human subject; human therapy evaluation; immunoglobulins; immunopathology; immunotherapy; myelinopathy; myositis; neuromuscular disorder; neuromuscular disorder chemotherapy; patient oriented research; poliomyelitis; proteomics

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) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; c) demyelinating polyneuropathies; d) postpolio syndrome; and e) 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 and ICOS-L 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 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 initiated using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. This study has now started. In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was initiated 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. Up to 50% of the required patients have alerady participated. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented. It was found that GAD antibodies in serum or CSF do not correlate with the clinical symptomatology. In an effort to find responsible autoantigen in SPS patients, T cell clones were established from the CSF and tested against combinatorial peptide libraries. Using proteomics in the patients' serum, a putative antigenic peptide GABARAP (GABA-Receptor Associated Protein) was found to be reduced. Because SPS is an antibody-mediated disorder, a new double-blind clinical trial using a B cell-depleting monoclonal antibody called Rituximab was designed and is ready to begin. The origin of phobias, a common feature in SPS patients, is being explored using a series of neurocognitive measurements. In patients with postpolio syndrome and severe fatigue, a double blind study using Modafinil has been initiated. Clinical improvement is being correlated with the level of fatigue-related cytokines such as TNF-alpha and IL-6. In patients with hereditary IBM due to mutations in the GNE gene we observed defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A clinical trial is being designed in an effort to increase muscle glycosylation. 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 (filamentopathy) and that the type of mutations may dictate clinical severity or presence of cardiomyopathy.

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）脊髓灰质炎后综合征;和e）僵硬人综合征（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和ICOS-L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病样β-APP淀粉样蛋白沉积物具有共同的抗原决定簇，一项正在进行的研究探讨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，使用CAMPATH（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）启动治疗性和研究性临床试验。这项研究现已开始。 在与MAG和糖脂的IgM自身抗体相关的脱髓鞘性神经病中，使用针对B细胞克隆的人源化单克隆抗体开始了一项新的对照治疗研究。为了鉴定引起神经病变的周围神经抗原，该研究将临床反应与IgM对髓鞘上各种糖缀合物的结合亲和力相关联。高达50%的所需患者已提前参与。 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。结果表明，血清或脑脊液中GAD抗体与临床表现无关。为了在SPS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，发现推定的抗原肽GABARAP（GABA受体相关蛋白）减少。由于SPS是一种抗体介导的疾病，一项新的双盲临床试验使用一种称为利妥昔单抗的B细胞耗竭单克隆抗体，并准备开始。恐惧症的起源，SPS患者的一个共同特点，正在探索使用一系列的神经认知测量。 在患有脊髓灰质炎后综合征和严重疲劳的患者中，已经启动了使用莫达非尼的双盲研究。临床改善与疲劳相关的细胞因子如TNF-α和IL-6的水平相关。 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。正在设计一项临床试验，以增加肌肉糖基化。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纤维的独特疾病（肌纤维肌病），突变类型可能决定临床严重程度或心肌病的存在。