Tcell activation requirement in autoimmune demyelination

描述（由申请人提供）：多发性硬化（MS）是一种病因不明的中枢神经系统（CNS）炎性脱髓鞘疾病。MS病因的一种可能性是MS是一种自身免疫性疾病，其中T细胞靶向髓鞘抗原。MS是否真的是一种自身免疫性疾病仍然存在争议。许多研究人员继续寻找病原体，这可能是这种疾病发展的触发因素。我们先前在RRMS患者中的工作表明，MS患者中的髓鞘反应性T细胞可以通过缺乏对共刺激的依赖而与健康个体中的髓鞘反应性T细胞区分开来。在此之前的工作的基础上，我们将测试的假设，这些髓鞘反应性T细胞的共刺激需求的变化在疾病的过程中。特别是，我们非常感兴趣的是，确定是否CD 28-，共刺激非依赖性T细胞出现的结果，发生在MS的慢性炎症反应，我们非常感兴趣的是，确定是否髓鞘反应性T细胞发展的表型与免疫衰老随着时间的推移一致。此外，基于我们先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共刺激的CD 28- T细胞是否对凋亡更具抵抗力。我们还将研究CTLA-4分子的多态性是否可以在MS患者的T细胞反应的调节中发挥作用。在MS患者中进行的许多拟议研究也将在鼠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（例如疑似发生在MS中的刺激）如何改变免疫反应的理解。了解慢性炎症如何改变MS患者的髓鞘反应性T细胞可能对各种基于免疫的疗法及其用于治疗MS患者的时机具有广泛的意义。

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.