Host Defense Regulation by HTLV-1

HTLV-1 的宿主防御调节

• 批准号: 7726081
• 负责人: Joseph David Rosenblatt
• 金额: $ 26.02万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726081
• 关键词: Acetylesterase; Acute; Acute leukemia; Adult; Affect; African American; Animal Disease Models; Antiviral Therapy; Apoptotic; Area; Biology; Brazil; CD4 Positive T Lymphocytes; Capital; Caribbean region; Characteristics; Chronic; Chronic Disease; Clinical Trials; Collaborations; Communities; Coupled; Development; Disease; Disease Progression; Disease Resistance; Disease remission; Enrollment; Event; Florida; Healthcare; Helper-Inducer T-Lymphocyte; Histones; Host Defense; Human T-Cell Leukemia Viruses; Human T-lymphotropic virus 1; Immune; Infection; Institution; Instruction; Interferon-alpha; Interferons; Investigation; Latino; Lead; Learning; Link; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Modeling; Molecular; Mus; NF-kappa B; Nuclear; Oncogene Proteins; Pathogenesis; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pre-Clinical Model; Primary Neoplasm; Principal Investigator; Process; Property; Proteins; Recurrence; Regulation; Research; Residual state; Resistance; Retinoids; Role; Sampling; Signal Transduction; Site; Subgroup; T-Cell Leukemia; T-Lymphocyte; Taxes; Testing; Therapeutic; Time; Tissues; Treatment Protocols; Tumor Suppressor Proteins; Universities; Valproic Acid; Variant; Viral; Virus; Zidovudine; aggressive therapy; base; clinical remission; defense response; experience; improved; inhibitor/antagonist; leukemia/lymphoma; novel; outcome forecast; response; translational study; tumor; tumor progression; tumorigenesis

Adult T cell leukemia-lymphoma (ATLL) is an aggressive and generally fatal tumor associated with Human T cell Leukemia Virus Type 1 (HTLV-1). ATLL, a CD4 helper T cell malignancy, presents clinically as either a chronic disease that may progress, as an acute leukemia or high grade lymphoma. ATLL pafients fare very pooriy with conventional chemotherapeutic regimens, however therapy with azidothymidine (AZT) and interferon alpha (IFN-a) has produced long-term clinical remissions in a subset of patients. Little is known of the molecular pathogenesis of ATLL. Suitable animal models for the disease have been lacking and HTLV-1 transformed lines differ substanfially from the primary tumors. Most research has centered on the role of the viral oncoprotein tax although it is not expressed in primary tumors. Research on HTLV-1 and oncogenesis is further complicated by the prolonged latency between the time of infection and the development of overt disease. In order to study this tumor and identify subgroups of ATLL that may be amenable to AZT/IFNo (or other) therapies one must have access to a large number of primary isolates. HTLV-1 related diseases are a significant health care problem in certain US communities, in afro-Caribbean and afro-Latin communities. Miami is an endemic area for the HTLV-1 virus as is Salvador, the capital of the northeastern Brazilian state, Bahia. Through a collaboration between the University of Miami and the Federal University of Bahia we have identified several important molecular features related to the pathogenesis, therapy and prognosis of ATLL. We have defined two forms of the disease, one that is responsive to AZT/IFNa and another that is resistant. Response or lack thereof correlates with nuclear NF-kB subunit composifion and IFN signaling properties. We have also found that patients in remission while on long-term antiviral therapy have persistent T cell clones detectable in peripheral blood mononuclear cells (PBMC's). We propose to study primary ATLL in pafients at our institution and at our collaborators site. We will follow patients enrolled on an anfiviral clinical trial to determine the molecular characteristics of sensitive and resistant disease. This translational study which is thematically linked to this overall proposal (IFN and innate immune signaling) has great potential to begin to elucidate the molecular processes of ATLL progression as well as define the subset of pafients most likely to benefit from therapy. RELEVANCE (See instructions): HTLV-1 related ATLL is a deadly disease that predominanfiy affects Afro-Caribbean and African Americans in our community (South Florida). The disease is also quite common in Afro-Lafin populafions. The study of ATLL presents some technical difficulties and investigation of the actual tumor requires access to primary pafient material. We present in our proposal a translafional study of the biology of AZT/IFNa sensifive and resistant ATLL coupled with a clinical trial. We have substanfial experience with this disease and our project is closely integrated with the two other proposals in this application.

成人T细胞白血病-淋巴瘤（ATLL）是一种侵袭性和通常致命的肿瘤，与人类T细胞相关。 细胞白血病病毒1型（HTLV-1）。ATLL是一种CD 4辅助性T细胞恶性肿瘤，临床表现为 可能恶化的慢性疾病，如急性白血病或高度恶性淋巴瘤。ATLL的病人非常 常规化疗方案效果不佳，但叠氮胸苷（AZT）治疗和 干扰素α（IFN-α）已经在一部分患者中产生了长期的临床缓解。很少有人知道 ATLL的分子发病机制。目前缺乏合适的动物模型，HTLV-1 转化的细胞系与原发性肿瘤实质上不同。大多数研究都集中在 病毒癌蛋白Tax，尽管它在原发性肿瘤中不表达。HTLV-1与肿瘤发生的研究 由于感染时间和显性感染发展之间的潜伏期延长， 疾病为了研究这种肿瘤并确定可能适合AZT/IFNo（或 其他）治疗必须能够获得大量的原代分离株。HTLV-1相关疾病是一种 在某些美国社区，在非裔加勒比人和非裔拉丁人社区，存在严重的卫生保健问题。 迈阿密和巴西东北部州首府萨尔瓦多一样， 巴伊亚。通过迈阿密大学和巴伊亚联邦大学之间的合作， 已经确定了几个重要的分子特征相关的发病机制，治疗和预后， ATLL。我们已经定义了两种形式的疾病，一种是对AZT/IFNa有反应，另一种是对AZT/IFNa有反应。 抵抗应答或其缺乏与核NF-kB亚单位组成和IFN信号传导相关 特性.我们还发现，长期抗病毒治疗的缓解期患者 在外周血单核细胞（PBMC）中可检测到的持久性T细胞克隆。我们建议研究 在我们的机构和我们的合作者网站上为患者提供初级ATLL。我们将跟踪入选的患者， 抗病毒临床试验，以确定敏感和耐药疾病的分子特征。这 与这一总体建议（IFN和先天免疫信号传导）主题相关的翻译研究， 很有可能开始阐明ATLL进展的分子过程，并确定 最有可能从治疗中获益的患者子集。 相关性（参见说明）： HTLV-1相关的ATLL是一种致命的疾病，主要影响非洲-加勒比和非洲裔美国人 在我们的社区（南佛罗里达）。这种疾病在非裔拉芬人中也很常见。研究 ATLL提出了一些技术上的困难，实际肿瘤的调查需要获得原发性 pafient材料。在我们的建议中，我们提出了一项关于AZT/IFNa敏感性生物学的实验性研究， 耐药ATLL加上临床试验。我们对这种疾病和我们的项目有丰富的经验 与本申请中的另外两个建议紧密结合。