Regulation of Marginal Zone B Cells by NK T Cells

NK T 细胞对边缘区 B 细胞的调节

• 批准号: 7056083
• 负责人: GIOVANNI FRANCHIN
• 金额: $ 5.59万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056083
• 关键词: B lymphocyte; antigens; autoimmune disorder; autoimmunity; cell cell interaction; genetically modified animals; laboratory mouse; natural killer cells; postdoctoral investigator; systemic lupus erythematosus

DESCRIPTION (provided by applicant): The goal of this proposal is to further investigate the hypothesis that CD1d-restricted NKT cells exert a negative regulatory role over MZB cells. This mechanism might play a central role in the maintenance of tolerance, and its deregulation could be involved in triggering or sustaining autoimmunity as suggested by animal models of diabetes and experimental allergic encephalitis (EAE). Preliminary data from Dr. Porcelli's lab indicate that NKT/MZB cell interaction may also play a key role in preventing the development of humoral autoimmunity, such as that which is characteristic of lupus. MZB cells have been shown to be an important source of autoreactive pathogenic antibodies in lupus, and a variety of studies indicate that the NK T cells that may regulate this B cell population is defective in mice that are predisposed to develop SLE. The proposed study will assess the influence of NK T cells on the responses of MZB cells against well characterized T-independent (TI-2) antigens. This approach will allow a detailed series of experiments to investigate the potential role of NKT cells over MZB cells. A series of in vitro and in vivo analyses using TI-2 antigens to challenge C57BL/6 mice will be performed and compared to results in lupus prone mice (NZB/W F1) and NKT deficient (Jalpha281 KO) mice. Finally, it is predicted that NKT cells could prove to be a potential therapeutic target for some autoimmune diseases including lupus, and this hypothesis will be tested by using artificial activators of NKT cells and investigating their effect in MZB activation by T1-2 antigens.

描述（由申请人提供）：该提案的目的是进一步研究以下假设：CD1D限制的NKT细胞对MZB细胞发挥负调节作用。这种机制可能在维持耐受性中起着核心作用，并且其放松管制可能与诱发或维持自身免疫性有关，如糖尿病动物模型和实验性过敏性脑炎（EAE）所暗示的那样。 Porcelli博士实验室的初步数据表明，NKT/MZB细胞相互作用也可能在防止体液自身免疫的发展中起关键作用，例如狼疮的特征。 MZB细胞已被证明是狼疮中自动反应性致病抗体的重要来源，并且各种研究表明，可能调节该B细胞群体的NK T细胞在易于发展的小鼠中有缺陷。拟议的研究将评估NK T细胞对MZB细胞对良好特征T独立（TI-2）抗原的反应的影响。这种方法将允许一系列详细的实验研究NKT细胞对MZB细胞的潜在作用。将进行一系列使用TI-2抗原来挑战C57BL/6小鼠的体外和体内分析，并将其与狼疮俯卧小鼠（NZB/W F1）和NKT缺陷（Jalpha281 KO）小鼠的结果进行比较。最后，可以预测，NKT细胞可能被证明是包括狼疮在内的某些自身免疫性疾病的潜在治疗靶点，并且该假设将通过使用NKT细胞的人工激活剂来检验，并研究其通过T1-2抗原在MZB激活中的作用。