CD8 T Lymphocyte Regulation of EAE Disease Phenotype

CD8 T 淋巴细胞对 EAE 疾病表型的调节

• 批准号: 6711436
• 负责人: MICHAEL D CARRITHERS
• 金额: $ 17.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711436
• 关键词: antigens; axon; cell migration; cell transplantation; central nervous system; chronic disease /disorder; clone cells; cytotoxic T lymphocyte; disease /disorder model; experimental allergic encephalomyelitis; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; histology; immunogenetics; inflammation; laboratory mouse; major histocompatibility complex; multiple sclerosis; nerve injury; pathologic process; phenotype; polymerase chain reaction; transcription factor

DESCRIPTION (provided by applicant): Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are a heterogeneous group of autoimmune, inflammatory diseases of the brain. The long-term goal of the proposed studies is to develop improved animal models to understand and treat disease subtypes, particularly those that are severe. The specific objective is to assess the role of CD8 T lymphocytes in mediating severity of EAE disease phenotype. The hypothesis is that, following initiation of central nervous system (CNS) inflammation by auto-reactive Th1 CD4 T lymphocytes, the subsequent parenchymal recruitment of CD8 T lymphocytes during a specific critical period leads to more severe clinical disease. To test this hypothesis, an adoptive transfer model of EAE was developed in (C57BL6xB10.PL) F1 mice. Preliminary data demonstrate that adoptive transfer of myelin basic protein (MBP)-specific (Acl-11) Th1 CD4 T lymphocytes can induce severe EAE in immune competent (C57BL6xB10.PL) F1 mice as compared to B10.PL mice. Histologic characterization, gene expression analysis, and CD8 depletion reveal a pathogenic role for CD8 cytotoxic T lymphocytes (CTL) in (C57BL6xB10.PL) F1 mice. These results suggest that, dependent on genetic background, CD8 T lymphocytes can mediate disease severity. Our hypothesis will be tested further in three Specific Aims. In Aim 1, we plan to use CD8-deficient and CTL effector-deficient mice to clarify the pathogenic roles of CD4 and CD8 T lymphocytes in acute lesions. Aim 2 focuses on defining the critical period of entry of CD8 T lymphocytes and associated CNS microenvironment changes in the early development of severe EAE. In Aim 3, we propose to isolate CNS-specific CD8 T lymphocyte clones, characterize them in vitro, and assess their ability to induce CNS inflammatory disease. These studies will provide a better understanding of CTL-mediated injury in inflammatory, demyelinating diseases of the CNS. In addition, this EAE model has clinical relevance because it more accurately reflects the complex roles of autoreactive CD4 and CD8 T lymphocytes in the pathogenesis of acute demyelinating lesions in multiple sclerosis. Since CTL's may initiate axonal injury in acute MS lesions with resultant chronic, progressive clinical deficits, this model should also be useful in screening potential MS therapeutics that inhibit CD4 T lymphocyte-initiated inflammation as well as CTL effector mechanisms.

描述（由申请人提供）：多发性硬化症及其动物模型，实验性自身免疫性脑脊髓炎（EAE），是一组自身免疫性，大脑炎症性疾病的异质组。拟议研究的长期目标是开发改进的动物模型，以理解和治疗疾病亚型，尤其是那些严重的亚型。具体目标是评估CD8 T淋巴细胞在介导EAE疾病表型严重程度中的作用。假设是，在自身反应性TH1 CD4淋巴细胞引起中枢神经系统（CNS）炎症之后，随后在特定关键时期内CD8 T淋巴细胞的实质募集会导致更严重的临床疾病。为了检验这一假设，在（C57BL6XB10.PL）F1小鼠中开发了EAE的收养转移模型。初步数据表明，与B10.pl小鼠相比，髓磷脂碱性蛋白（MBP）特异性（ACL-11）Th1 CD4 TH1 CD4淋巴细胞可以在免疫胜任者（C57BL6XB10.PL）F1小鼠中诱导严重的EAE。组织学表征，基因表达分析和CD8耗竭揭示了（C57BL6XB10.PL）F1小鼠中CD8细胞毒性T淋巴细胞（CTL）的致病作用。这些结果表明，取决于遗传背景，CD8 T淋巴细胞可以介导疾病的严重程度。我们的假设将在三个特定目标中进一步检验。在AIM 1中，我们计划使用CD8缺陷型和CTL效应子缺乏小鼠来阐明CD4和CD8 T淋巴细胞在急性病变中的致病作用。 AIM 2重点是定义CD8 T淋巴细胞的关键时期和相关的CNS微环境变化在严重EAE的早期发展中。在AIM 3中，我们建议分离CNS特异性CD8 T淋巴细胞克隆，在体外表征它们，并评估其诱导CNS炎性疾病的能力。这些研究将更好地理解CTL介导的炎症性，脱髓鞘性疾病的损伤。此外，该模型具有临床相关性，因为它更准确地反映了自动反应性CD4和CD8 T淋巴细胞在多发性硬化症中急性脱髓鞘病变的发病机理中的复杂作用。由于CTL可能会在急性MS病变中引发轴突损伤，导致慢性进行性临床缺陷，因此该模型也应有助于筛选抑制CD4 T淋巴细胞引起的炎症以及CTL效应机制的潜在MS疗法。