Modulation of EAE with ligand-activated NKT cells

用配体激活的 NKT 细胞调节 EAE

• 批准号: 6507492
• 负责人: Luc Van Kaer
• 金额: $ 32.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6507492
• 关键词: MHC class I antigen; T lymphocyte; antigen antibody reaction; autoantigens; autoimmunity; blocking antibody; cell sorting; cerebrosides; chemoprevention; cytokine; disease /disorder model; drug discovery /isolation; experimental allergic encephalomyelitis; flow cytometry; glycolipids; immunomodulators; immunopharmacology; immunoregulation; interleukin 7; laboratory mouse; leukocyte activation /transformation; ligands; multiple sclerosis; natural killer cells; nonhuman therapy evaluation

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a presumed autoimmune etiology. Experimental autoimmune encephalomyelitis (EAE) is frequently used as an animal model of MS. EAE can be induced in susceptible mouse strains by injection of CNS proteins or peptides together with adjuvants. Most studies have indicated that myelin-specific T helper type 1 (Th1) cells secreting IFN-gamma and TNF-alpha mediate EAE and MS. whereas myelin-specific Th2 cells producing IL-4 and IL-10 play a regulatory role. Studies with animal models have demonstrated that modulation of immune responses from a Th1-dominant to a Th2-dominant response can effectively protect mice against EAE. Natural killer T (NKT) cells are a subset of T lymphocytes that co-express surface markers characteristic of conventional T cells and NK cells. The invariant Valpha14 T cell receptor of NKT cells is specific for glycolipid antigens bound with the non-polymorphic MHC class I-like protein CD1d. While the precise immunological function of NKT cells remains unknown, these cells have been implicated in protective immune responses against pathogens and tumors, and in the regulation of autoimmune responses. Prior work conducted in the PI's laboratory has shown that ligand-specific activation of NKT cells with the glycolipid alpha-galactosylceramide (alpha-GalCer) polarizes adaptive immune responses for production of Th2 cytokines in mice. These findings suggest that alpha-GalCer can inhibit Th1 -oriented immune responses, providing an alternative way to suppress immune responses that cause pathology in organ-specific autoimmune diseases such as MS. Indeed, our preliminary results have revealed that alpha-GalCer prevents the induction of EAE in susceptible mice. Based on our published findings and preliminary results, the central hypothesis of this grant application is that NKT cells represent a novel target cell type for immunomodulation of EAE and MS. We will test this hypothesis in four Specific Aims. Aim 1 will investigate the mechanism by which ligand-activated CD1d-resticted NKT cells modulate EAE. Aim 2 will evaluate whether disease protection conferred by a-GalCer is an active suppressive process. Aim 3 will determine the potential synergy of alpha-GalCer with other immunomodulatory reagents for prevention of EAE disease. Aim 4 will evaluate the ability of alpha-Ga1Cer analogues to protect mice against EAE. These studies will provide a better understanding of the immunological functions of NKT cells and the mechanisms that mediate autoimmunity. At the completion of this project, we expect to have identified a set of reagents (NKT cell ligands, cytokines, blocking antibodies) that can be utilized to specifically activate or inhibit different effector functions of NKT cells. These reagents will permit the selective activation of distinct adaptive immune responses in vivo, which could be exploited for therapeutic intervention in MS and other human autoimmune diseases.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病，推测其病因为自身免疫性。实验性自身免疫性脑脊髓炎（Experimental autoimmune encephalomyelitis， EAE）常被用作ms的动物模型，EAE可通过注射CNS蛋白或多肽及佐剂在易感小鼠株中诱导。大多数研究表明，分泌ifn - γ和tnf - α的髓磷脂特异性T辅助型1 （Th1）细胞介导EAE和ms，而产生IL-4和IL-10的髓磷脂特异性Th2细胞起调节作用。动物模型研究表明，将免疫反应从th1显性调节为th2显性，可以有效保护小鼠免受EAE的侵害。自然杀伤T细胞（NKT）是T淋巴细胞的一个子集，它共同表达传统T细胞和NK细胞的表面标记。NKT细胞的不变Valpha14 T细胞受体对与非多态性MHC i类蛋白CD1d结合的糖脂抗原具有特异性。虽然NKT细胞的确切免疫功能尚不清楚，但这些细胞与针对病原体和肿瘤的保护性免疫反应以及自身免疫反应的调节有关。先前在PI实验室进行的工作表明，糖脂α -半乳糖神经酰胺（α - galcer）对NKT细胞的配体特异性激活使小鼠产生Th2细胞因子的适应性免疫反应极化。这些发现表明α - galcer可以抑制Th1导向的免疫反应，为抑制引起器官特异性自身免疫性疾病（如ms）病理的免疫反应提供了另一种方法。事实上，我们的初步结果显示α - galcer可以阻止易感小鼠EAE的诱导。根据我们发表的研究结果和初步结果，本次资助申请的中心假设是NKT细胞代表了EAE和ms免疫调节的新靶细胞类型。我们将在四个特定目标中验证这一假设。目的1将研究配体激活的cd1限制性NKT细胞调节EAE的机制。目的2将评估a-GalCer提供的疾病保护是否是一个主动抑制过程。目的3将确定α - galcer与其他免疫调节试剂在预防EAE疾病中的潜在协同作用。目的4将评估α - ga1cer类似物对小鼠EAE的保护能力。这些研究将有助于更好地了解NKT细胞的免疫功能和介导自身免疫的机制。本项目完成后，我们期望能够鉴定出一套试剂（NKT细胞配体、细胞因子、阻断抗体），能够特异性激活或抑制NKT细胞的不同效应功能。这些试剂将允许在体内选择性激活不同的适应性免疫反应，这可以用于MS和其他人类自身免疫性疾病的治疗干预。