Immunoregulatory NK cells in Multiple Sclerosis

描述（由申请人提供）：本提案的目的是研究自然杀伤（NK）细胞在多发性硬化症（MS）中的免疫调节作用。NK细胞是参与抗病毒和恶性肿瘤发生的重要效应细胞。然而，NK细胞似乎在先天免疫应答和适应性免疫应答之间的串音中起关键作用，并可能有助于维持免疫耐受。在自身免疫性疾病（包括多发性硬化症）患者和易诱导自身免疫的动物中，已经报道了NK数量和/或功能的重要缺陷。此外，一些治疗药物（ifn - β，亚胺胺和Daclizumab）被证明可以有效抑制MS中的炎症，刺激NK细胞功能。然而，NK细胞参与维持免疫耐受的机制尚不清楚。我们推测NK细胞对T细胞反应的免疫调节缺陷是MS发病的一个重要因素。我们的长期目标是应用NK介导的免疫调节机制来开发新的/更有效的ms治疗方法，这项应用的目标是阐明人类NK细胞和T细胞之间相互作用的关键细胞和分子机制和规则，以确定NK介导的T细胞反应调节是否对生理条件下维持免疫耐受很重要。此外，我们想要确定nk介导的免疫调节机制在未治疗的MS患者中是否存在缺陷，以及Daclizumab治疗是否可以恢复这些缺陷。这一目标将在3个具体目标中实现：(1)确定NK细胞对T细胞启动Th17表型的影响；(2)确定nk介导的自身反应性T细胞杀伤的程度和机制；(3)通过分析未经治疗的MS患者中Daclizumab单药治疗的II期临床试验的配对基线和治疗样本，并将Daclizumab对这些免疫调节机制的影响与临床和临床旁（即MRI）测量的MS疾病活动性相关联，确定目标1和2中定义的nk介导的免疫调节机制的体内相关性。这些研究将为NK细胞如何参与维持免疫耐受以及NK细胞功能缺陷如何导致自身免疫的发展提供新的见解。我们期望这些知识将转化为MS和其他自身免疫性疾病的新疗法的开发。

DESCRIPTION (provided by applicant): The objective of this proposal is to investigate the immunoregulatory role of natural killer (NK) cells in Multiple Sclerosis (MS). NK cells are important effector cells participating in the protection against viruses and the development of malignancies. However, NK cells appear to be critically involved in the crosstalk between innate and adaptive immune responses and may help to maintain immune tolerance. Important defects in NK numbers and/or function have been reported in patients with autoimmune disorders, including MS, and in animals susceptible to induction of autoimmunity. Additionally, several therapeutic agents that were shown to effectively suppress inflammation in MS (IFN-beta, linomide and Daclizumab) stimulate NK cell function. However, the mechanism(s) by which NK cells may participate in the maintaining of the immune tolerance remain undefined. We hypothesize that the defective immunoregulation of T cell responses by NK cells is an important factor in MS pathogenesis. Our long-term goal is to apply mechanistic insight into NK-mediated immunoregulation to develop new/more effective therapies for MS. The goal of this application is to elucidate the key cellular and molecular mechanisms and rules of interaction between human NK cells and T cells in order to determine if NK-mediated regulation of T cell responses is important for the maintenance of immune tolerance under physiological conditions. Additionally, we want to determine if NK-mediated immunoregulatory mechanisms are deficient in untreated MS patients and whether Daclizumab therapy restores these deficiencies. This goal will be achieved in 3 Specific Aims: (1) Determine the effect of NK cells on T cell priming toward Th17 phenotype; (2) Define the extent and mechanism of NK-mediated killing of autoreactive T cells and (3) Determine the in vivo relevance of the NK-mediated mechanisms of immunoregulation defined in Aims 1&2 by analyzing paired baseline and treatment samples from the Phase II clinical trial of Daclizumab monotherapy in untreated MS patients, and by correlating the effect of Daclizumab on these immunoregulatory mechanisms with clinical and paraclinical (i.e. MRI) measures of their MS disease activity. These studies will provide new insight into how NK cells participate in the maintenance of immune tolerance and how deficiencies in NK cell function can lead to the development of autoimmunity. We expect that this knowledge will translate into the development of new therapies for MS and other autoimmune diseases.