Mutation selection for immune response to MBP in HAM/TSP

HAM/TSP 中 MBP 免疫反应的突变选择

• 批准号: 6675091
• 负责人: MARK ALLEGRETTA
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675091
• 关键词: T cell receptor; T lymphocyte; biological signal transduction; cell cycle; cell proliferation; cellular immunity; clinical research; electrophoresis; enzyme linked immunosorbent assay; gene mutation; human T cell leukemia; human T cell lymphotropic virus type 1; human tissue; interferon gamma; interleukin 10; multiple sclerosis; myelin basic proteins; neuropathology; polymerase chain reaction; receptor expression; reporter genes; spastic paralysis; tissue /cell culture

DESCRIPTION (provided by applicant): Human T-cell lymphotropic virus type I (HTLV-1) is a human retrovirus that infects approximately 10 million people worldwide. The majority of infected individuals remain healthy lifelong asymptomatic carriers (ACs); approximately 0.25% to 3% develop an inflammatory disease of the central nervous system termed HTLV-1- associated myelopathy/tropical spastic paraparesis (HAM/TSP), and another 2% to 3% develop an aggressive mature T-cell malignancy termed adult T-cell leukemia (ATL). The virus is endemic throughout Japan, with certain regions of the country having elevated prevalence rates. Because such a large number of people are carders of this potentially devastating virus, developing an effective measure to control the endemic cycle of HTLV-1 has been imperative. Since the clinical findings in HAM/TSP resemble the clinical picture of multiple sclerosis (MS), an understanding of the neuropathogenesis of a disease with a known viral etiology may provide insights into mechanisms of pathogenesis in an autoimmune disease of unknown etiology. This is particularly relevant since T cell receptor (TCR) sequences derived from spinal cord lesions from HAM/TSP patients show similarity to TCRs from myelin basic protein (MBP)-reactive T-cells, TCRs detected within the brain lesions of MS patients, and encephalitogenic T-cell clones from rodents with experimental autoimmune encephalomyelitis. We have observed similar TCR sequences from HAMFFSP patients using a method of isolating T cells that have undergone extensive in vivo cell division. The method involves detecting cells with mutations in a selectable reporter gene, and has been used to demonstrate the presence of in vivo activated T cells responsive to MBP in MS patients. The approach may be useful for addressing a variety of questions in human immunology. The goal of this proposal is to demonstrate that the reporter gene-selected T cells from HAM/TSP patients respond to MBP much like their counterparts derived from MS patients, indicating similar pathogenic mechanisms for the two diseases. The long-term goal of the project would be to broaden the applicability of this approach for the study of other human immune responses, particularly in autoimmune disease and cancer, where an understanding of detrimental and beneficial immune responses can ultimately translate into improved treatment options based on new immunotherapeutic approaches.

描述（由申请方提供）：人类T细胞嗜淋巴细胞病毒I型（HTLV-1）是一种人类逆转录病毒，在全球范围内感染约1000万人。大多数感染个体保持健康的终身无症状携带者（AC）;大约0.25%至3%发展为中枢神经系统的炎性疾病，称为HTLV-1相关性脊髓病/热带痉挛性下肢轻瘫（HAM/TSP），另外2%至3%发展为侵袭性成熟T细胞恶性肿瘤，称为成人T细胞白血病（ATL）。该病毒在日本全国流行，该国某些地区的流行率较高。由于如此大量的人是这种潜在的破坏性病毒的携带者，因此开发一种有效的措施来控制HTLV-1的流行周期是势在必行的。由于HAM/TSP的临床表现与多发性硬化症（MS）的临床表现相似，因此了解已知病毒病因的疾病的神经发病机制可能有助于了解病因不明的自身免疫性疾病的发病机制。这是特别相关的，因为源自HAM/TSP患者的脊髓病变的T细胞受体（TCR）序列显示出与来自髓鞘碱性蛋白（MBP）反应性T细胞的TCR、在MS患者的脑病变内检测到的TCR和来自患有实验性自身免疫性脑脊髓炎的啮齿动物的致脑炎性T细胞克隆的相似性。我们已经使用分离已经经历了广泛的体内细胞分裂的T细胞的方法从HAMFFSP患者观察到相似的TCR序列。该方法涉及检测在可选择的报告基因中具有突变的细胞，并且已用于证明MS患者中存在对MBP有反应的体内活化T细胞。这种方法可能有助于解决人类免疫学中的各种问题。该提案的目的是证明来自HAM/TSP患者的报告基因选择的T细胞对MBP的反应与来自MS患者的对应物非常相似，表明这两种疾病的致病机制相似。该项目的长期目标是扩大这种方法在其他人类免疫反应研究中的适用性，特别是在自身免疫性疾病和癌症中，其中对有害和有益免疫反应的理解最终可以转化为基于新免疫学方法的改进治疗方案。