Identification of Immune modulators associated with JC virus replication

与 JC 病毒复制相关的免疫调节剂的鉴定

• 批准号: 8656166
• 负责人: Jennifer Gordon
• 金额: $ 23.17万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656166
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Astrocytes; Autoimmune Diseases; B-Cell Lymphomas; B-Lymphocytes; Back; Biological Assay; Blood; Brain; Cells; Cellular biology; Cessation of life; Complication; Conditioned Culture Media; Crohn' s disease; Data; Demyelinating Diseases; Development; Elderly; Enzyme-Linked Immunosorbent Assay; Etanercept; Extracellular Matrix Proteins; Frequencies; Genetic Transcription; Hand; Harvest; Human; Humira; Immune; Immunobiology; Immunocompromised Host; Immunohistochemistry; Immunologic Surveillance; Immunomodulators; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Integrins; JC Virus; Kidney; Lead; Leukocyte Trafficking; Luciferases; Lupus; Lymphoid Tissue; MS4A1 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Microarray Analysis; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Multiple Sclerosis; Myelin; Neuraxis; Neuroglia; Non-Hodgkin' s Lymphoma; Oligodendroglia; Organ Transplantation; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Population; Production; Progressive Multifocal Leukoencephalopathy; Raptiva; Rare Diseases; Regimen; Regulation; Relapsing-Remitting Multiple Sclerosis; Reporter; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Risk; Series; Solid; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Therapeutic immunosuppression; Tysabri; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; brain tissue; central nervous system demyelinating disorder; chemokine; cytokine; effective therapy; fetal; immunosuppressed; infliximab; monocyte; prevent; public health relevance; research study; rituximab

DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by the human polyomavirus, JC virus (JCV). PML, once a rare disease of the elderly, is most frequency seen in AIDS patients and has more recently occurred in other severely immunosuppressed patients, including those on immunosuppressive therapy for the treatment of multiple sclerosis, Crohn's disease, rheumatoid arthritis, and B cell lymphomas. It is believed that immunosuppression with potent new classes of immunosuppressive agents, including the anti-CD20 molecule, rituximab, allows JC virus to replicate in patients which leads to the development of PML. We hypothesize that rituximab may indirectly lead to the development of PML by causing the release of certain cytokines or other soluble mediators which trigger JCV replication in infected astrocytes. In support of this hypothesis, our preliminary data found that conditioned media harvested from PBMCs treated with rituximab increased JCV replication in astrocytes. We have also detected upregulation of cytokines, extracellular matrix proteins, and other cellular factors by microarray analysis of JCV infected astrocytes and immunohistochemistry of PML brain tissue which further supports this hypothesis. In this study, we propose a set of cell biology and immunobiology experiments aimed at determining the effect of rituximab on immune regulation of JCV and virus reactivation through direct and indirect methods. We will examine the effect of B cell and T cell treatment with rituximab and the profile of cytokines and chemokines produced by this treatment. We will then examine the effect of these cytokines on JCV infected astrocytes to determine which immunomodulators are responsible for upregulation of JCV. Through the proposed studies, we will elucidate key chemokines and cytokines which affect JCV activity and how potent immunosuppressive therapies may cause reactivation of JCV in the brain leading to the fatal demyelinating disease, PML.

描述（由申请人提供）：进行性多灶性白质脑病（PML）是一种由人类多瘤病毒 JC 病毒（JCV）引起的致命性中枢神经系统（CNS）脱髓鞘疾病。 PML曾经是一种罕见的老年人疾病，最常见于艾滋病患者，最近也发生在其他严重免疫抑制的患者中，包括接受免疫抑制治疗的多发性硬化症、克罗恩病、类风湿性关节炎和B细胞淋巴瘤的患者。据信，使用强效新型免疫抑制剂（包括抗 CD20 分子利妥昔单抗）进行免疫抑制，可使 JC 病毒在患者体内复制，从而导致 PML 的发展。我们假设利妥昔单抗可能通过释放某些细胞因子或其他可溶性介质来触发感染星形胶质细胞中的 JCV 复制，从而间接导致 PML 的发生。为了支持这一假设，我们的初步数据发现，从用利妥昔单抗处理的 PBMC 中收获的条件培养基增加了星形胶质细胞中的 JCV 复制。我们还通过 JCV 感染的星形胶质细胞的微阵列分析和 PML 脑组织的免疫组织化学检测到细胞因子、细胞外基质蛋白和其他细胞因子的上调，这进一步支持了这一假设。在本研究中，我们提出了一系列细胞生物学和免疫生物学实验，旨在通过直接和间接方法确定利妥昔单抗对 JCV 免疫调节和病毒再激活的影响。我们将检查利妥昔单抗治疗 B 细胞和 T 细胞的效果以及该治疗产生的细胞因子和趋化因子的概况。然后我们将检查这些细胞因子对 JCV 感染的星形胶质细胞的影响，以确定哪些免疫调节剂负责 JCV 的上调。通过拟议的研究，我们将阐明影响 JCV 活性的关键趋化因子和细胞因子，以及有效的免疫抑制疗法如何导致大脑中 JCV 重新激活，从而导致致命的脱髓鞘疾病 (PML)。