ROLE OF B7 IN THE INDUCTION OF MS

B7 在 MS 诱导中的作用

• 批准号: 6100071
• 负责人: David A. Hafler
• 金额: $ 22.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6100071
• 关键词: B lymphocyte; CD4 molecule; CD8 molecule; CHO cells; anergy; antigen presentation; clinical research; enzyme linked immunosorbent assay; flow cytometry; gene expression; human subject; immunofluorescence technique; immunoregulation; interleukin 12; leukocyte activation /transformation; molecular pathology; multiple sclerosis; polymerase chain reaction

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by lymphocyte infiltration and tissue destruction in the central nervous system (CNS). The myelin reactive T cells found in the blood and cerebrospinal fluid of MS patients re in a different state of activation as compared to T cells in normal individuals and thus are thought to be directly involved in the disease pathogenesis. Our long-term goal is to understand the molecular basis for the in vivo activation of autoreactive T cells in MS, providing the basis for rational therapeutic intervention. This project is based on the hypothesis that costimulatory molecules provide the second signal which activates autoreactive T cells which are required to induce autoimmune disease. As we have recently discovered increased expression of B7-1 in acute Ms lesion, the requirement for expression of B7-1 and B7-2 molecules and IL-12 by human glial cells will be examined. In the next aim, the molecular basis for the activated in vivo state of autoreactive T cells in MS patients will be further investigated by comparing myelin antigen-autoreactive peripheral blood T cells in MS patients to controls and determining their capacity to expand in response to antigen presented by CHO cells transfected with MHC class II, DR21, alone or with B7-1 or B7-2 costimulatory molecules and DR2. We will also examine regulatory role of B7-2 expressed on activated T cells, which may be of significance for the disturbed immunoregulation described in MS. Our preliminary data demonstrate that B7-2 expressed on T cells has a lower molecular weight than B7-2 expressed on B cells or CHO cells, and has lost its binding affinity for CD28 but not CTLA4. In our last aim, we will further investigate negative regulatory functions of B7-2 expressed on T cells in a novel CD8 anergy system. These aims will provide basic information on the role of costimulation and anergy induction in CD4 and CD8 T cells as it may apply to understanding immunoregulation of MS, a human autoimmune disease.

多发性硬化症（MS）是一种慢性炎性疾病，其特征是 中枢神经中的淋巴细胞浸润和组织破坏 系统（CNS）。 在血液中发现的髓磷脂反应性T细胞， MS患者的脑脊液以不同的活化状态为 与正常个体的T细胞相比，因此被认为是 直接参与疾病发病机理。 我们的长期目标是 了解自动反应的体内激活的分子基础 MS中的T细胞为理性治疗干预提供了基础。 该项目基于以下假设 提供第二个信号，该信号激活自动反应性T细胞 需要诱导自身免疫性疾病。 正如我们最近发现的那样 急性MS病变中B7-1的表达增加，要求 人神经胶质细胞的B7-1和B7-2分子和IL-12的表达将 被检查。 在下一个目标中，激活的分子基础 MS患者的体内自动反应性T细胞状态将进一步 通过比较髓磷脂抗原运动性外周血T进行了研究 MS患者的细胞进行对照并确定其扩展的能力 响应于用MHC类转染的CHO细胞提出的抗原 II，DR21，单独或与B7-1或B7-2共刺激分子和DR2。 我们 还将检查在活化的T细胞上表达的B7-2的调节作用， 这对于所描述的受干扰的免疫调节可能具有重要意义 在MS中。 我们的初步数据表明，在T细胞上表达的B7-2具有 比在B细胞或CHO细胞上表达的B7-2低的分子量，以及 已经失去了对CD28的结合亲和力，但却没有CTLA4。 在我们的最后一个目标中，我们 将进一步研究B7-2在 新型CD8消极系统中的T细胞。 这些目标将提供基本 有关CD4和 CD8 T细胞可能适用于了解MS的免疫调节A 人自身免疫性疾病。