Mutation selection for immune response to MBP in HAM/TSP

描述（由申请人提供）：人类t细胞嗜淋巴病毒I型（HTLV-1）是一种人类逆转录病毒，全世界约有1000万人感染。大多数感染者仍然是健康的终身无症状携带者（ACs）；约0.25%至3%的患者发展为HTLV-1相关脊髓病/热带痉挛性截瘫（HAM/TSP）的中枢神经系统炎症性疾病，另外2%至3%的患者发展为侵袭性成熟t细胞恶性肿瘤，称为成人t细胞白血病（ATL）。该病毒在日本各地流行，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破坏性病毒的携带者，因此制定有效措施来控制HTLV-1的流行周期已势在必行。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。这一点尤其重要，因为来自HAM/TSP患者脊髓病变的T细胞受体（TCR）序列与髓鞘碱性蛋白（MBP）反应性T细胞的TCR序列、MS患者脑病变中检测到的TCR序列以及来自实验性自身免疫性脑脊髓炎啮齿动物的脑源性T细胞克隆具有相似性。我们已经从HAMFFSP患者中观察到类似的TCR序列，使用分离T细胞的方法，这些T细胞在体内经历了广泛的细胞分裂。该方法涉及检测可选择报告基因突变的细胞，并已用于证明MS患者体内对MBP有反应的活化T细胞的存在。该方法可用于解决人类免疫学中的各种问题。本研究的目的是证明来自HAM/TSP患者的报告基因选择T细胞对MBP的反应与来自MS患者的对应T细胞非常相似，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研究其他人类免疫反应方面的适用性，特别是在自身免疫性疾病和癌症方面，在这些方面，对有害和有益免疫反应的了解最终可以转化为基于新的免疫治疗方法的改进治疗方案。

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.