Tcell activation requirement in autoimmune demyelination

自身免疫性脱髓鞘中 T 细胞激活的要求

• 批准号: 6575793
• 负责人: MICHAEL K RACKE
• 金额: $ 33.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575793
• 关键词: CD28 molecule; T lymphocyte; apoptosis; cerebrospinal fluid; clinical research; cytokine; genetic polymorphism; human subject; immunoregulation; immunosenescence; laboratory mouse; leukapheresis; leukocyte activation /transformation; multiple sclerosis; myelin; myelinopathy; pathologic process

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) of unknown etiology. One possibility for the etiology of MS is that MS is an autoimmune disease, where T cells target myelin antigens. Whether MS is truly an autoimmune disease is still controversial. Many investigators continue to search for pathogens, which may be the trigger for the development of this disease. Our prior work in patients with RRMS has suggested that myelin reactive T cells in MS patients can be distinguished from those in healthy individuals by a lack of dependence upon costimulation for activation. Building on this prior work, we will test the hypothesis that the costimulatory requirements of these myelin-reactive T cells change over the course of disease. In particular, we are very interested in determining whether CD28-, costimulation-independent T cells arise as a result of the chronic inflammatory response that takes place during MS. We are very interested in determining whether myelin-reactive T cells develop a phenotype consistent with immunosenescence over time. In addition, building on our prior work examining programmed cell death in the experimental autoimmune encephalomyelitis (EAE) model, we will determine whether these costimulation-independent, CD28- T cells are more resistant to apoptosis. We will also examine whether polymorphisms in the CTLA-4 molecule can play a role in regulation of the T cell response in MS patients. Many of the proposed studies in MS patients will also be modeled in a murine EAE system. The results of these studies will enhance our understanding of how chronic antigenic stimulation, such as that which is suspected to occur in MS, modifies the immune response. Understanding how chronic inflammatory conditions modify myelin reactive T cells in MS patients may have broad implications for a variety of immunologically based therapies and the timing of their use in treating patients with MS.

描述（由申请人提供）：多发性硬化症（MS）是一种病因不明的中枢神经系统（CNS）炎症性脱髓鞘疾病。 MS 病因的一种可能是 MS 是一种自身免疫性疾病，其中 T 细胞靶向髓磷脂抗原。多发性硬化症是否真的是一种自身免疫性疾病仍存在争议。许多研究人员继续寻找病原体，这可能是这种疾病发生的触发因素。我们之前对 RRMS 患者的研究表明，MS 患者中的髓磷脂反应性 T 细胞与健康个体中的髓磷脂反应性 T 细胞的区别在于，其激活不依赖于共刺激。在这项先前工作的基础上，我们将检验以下假设：这些髓磷脂反应性 T 细胞的共刺激需求会随着疾病的进程而变化。特别是，我们非常有兴趣确定 CD28 共刺激独立 T 细胞是否是由于多发性硬化症期间发生的慢性炎症反应而产生的。我们非常有兴趣确定髓磷脂反应性 T 细胞是否会随着时间的推移形成与免疫衰老一致的表型。此外，基于我们之前在实验性自身免疫性脑脊髓炎 (EAE) 模型中检查程序性细胞死亡的工作，我们将确定这些不依赖于共刺激的 CD28-T 细胞是否更能抵抗细胞凋亡。我们还将研究 CTLA-4 分子的多态性是否可以在调节多发性硬化症患者的 T 细胞反应中发挥作用。许多针对多发性硬化症患者的拟议研究也将在小鼠 EAE 系统中建模。这些研究的结果将增强我们对慢性抗原刺激（例如疑似在多发性硬化症中发生的刺激）如何改变免疫反应的理解。了解慢性炎症条件如何改变多发性硬化症患者的髓磷脂反应性 T 细胞可能对各种基于免疫学的疗法及其用于治疗多发性硬化症患者的时机产生广泛的影响。