PATHOGENESIS AND IMMUNOREGULATION OF PLP-INDUCED R-EAE

PLP 诱导的 R-EAE 的发病机制和免疫调节

• 批准号: 3417805
• 负责人: STEPHEN D MILLER
• 金额: $ 18.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3417805
• 关键词: T cell receptor; T lymphocyte; anergy; antibody specificity; disease /disorder model; epitope mapping; experimental allergic encephalomyelitis; immune tolerance /unresponsiveness; immunopathology; laboratory mouse; lymphokines; multiple sclerosis; myelin proteolipid; myelinopathy; pathologic process; relapse /recurrence

Proteolipid protein (PLP) is the major protein component of CNS myelin and appears to be a major target of immune responses both in murine models of experimental autoimmune encephalomyelitis (EAE) and perhaps in human multiple sclerosis (MS). A chronic-relapsing form of EAE (R-EAE) is induced in inbred SJL/J mice following either active immunization with intact PLP or the major encephalitogenic determinant of the PLP molecule which encompasses amino acids 139-151 (PLP139-151(s)), or the adoptive transfer of T cell lines/clones specific for the PLP139-151(s) epitope. PLP-induced R-EAE follows a relapsing-remitting course of paralysis and is characterized histologically by perivascular mononuclear cell-rich infiltrates of the white matter of the central nervous system (CNS) and areas of acute and chronic demyelination. The well-understood genetics of the murine host and the similarities in both clinical course and histopathology of murine R-EAE and MS make it an ideal animal model for the study of immunopathogenic and immunoregulatory aspects of MS. We propose to examine the neuroantigen specificity, effector phenotype, T cell receptor usage, and lymphokine-producing profile of both peripheral and CNS-infiltrating neuroantigen-specific T cell-mediated immune (CMI) responses throughout the relapsing clinical course of PLP-induced R-EAE to determine if epitopes different than that which induced the initial paralytic episode are targeted during clinical relapses. We also propose to examine the conditions and mechanisms by which the induction and/or expression of PLP-induced R-EAE can be specifically downregulated (following the induction of neuroantigen-specific immunological tolerance). In addition, aspects of the molecular pathogenesis of demyelination will be addressed by defining and comparing encephalitogenic and tolerogenic PLP epitopes, and determining the effects of in vivo and in vitro tolerance induction on the ability of encephalitogenic PLP139-151(S)-specific T cell clones to produce particular lymphokines and/or subsequently mediate clinical disease. These studies should lead to a better understanding of the fine specificity, immunopathologic role, and immunoregulation of PLP-specific T cell-mediated immune responses which may be applicable to the understanding and treatment of human MS.

蛋白脂质蛋白（PLP）是中枢神经系统髓磷脂的主要蛋白质成分 并且似乎是小鼠免疫反应的主要目标 实验性自身免疫性脑脊髓炎（EAE）模型，也许在 人类多发性硬化症（MS）。 慢性复发型 EAE (R-EAE) 在主动免疫后，近交 SJL/J 小鼠中被诱导 完整的 PLP 或 PLP 分子的主要致脑炎决定因素 其涵盖氨基酸139-151 (PLP139-151(s))，或采用 转移对 PLP139-151(s) 表位具有特异性的 T 细胞系/克隆。 PLP 诱导的 R-EAE 遵循复发缓解型瘫痪过程 组织学特征为血管周围富含单核细胞 浸润中枢神经系统 (CNS) 的白质 急性和慢性脱髓鞘区域。 众所周知的遗传学 小鼠宿主的特征以及临床过程和临床过程的相似性 鼠 R-EAE 和 MS 的组织病理学使其成为理想的动物模型 MS 的免疫致病和免疫调节方面的研究。 我们 提议检查神经抗原特异性、效应器表型、T 细胞受体的使用，以及外周淋巴因子的产生情况 和中枢神经系统浸润神经抗原特异性 T 细胞介导的免疫 (CMI) PLP 诱导的 R-EAE 复发临床过程中的反应 以确定表位是否与诱导初始表位不同 麻痹发作是临床复发期间的目标。 我们还建议 检查诱导和/或 PLP 诱导的 R-EAE 表达可以被特异性下调 （在诱导神经抗原特异性免疫学 宽容）。 此外，分子发病机制的各个方面 脱髓鞘将通过定义和比较来解决 致脑炎和致耐受性 PLP 表位，并确定 体内和体外耐受诱导对能力的影响 产生脑炎 PLP139-151(S) 特异性 T 细胞克隆 特定的淋巴因子和/或随后介导临床疾病。 这些研究应该有助于更好地理解精细 PLP 特异性的特异性、免疫病理学作用和免疫调节 T 细胞介导的免疫反应可能适用于 对人类多发性硬化症的了解和治疗。