T CELL COST IMMULATION ON MURINE LUPUS

鼠狼疮 T 细胞成本模拟

• 批准号: 2550295
• 负责人: David I Daikh
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2550295
• 关键词: CD28 molecule; CD4 molecule; antigen antibody reaction; antigen presentation; antigen receptors; autoantigens; autoimmunity; biological signal transduction; genetic strain; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; pathologic process; systemic lupus erythematosus

Systemic Lupus Erythematosis is a systemic autoimmune disease of unknown cause characterized by the production of antibodies directed against a variety of self antigens. A spontaneous form of lupus which closely parallels the human disease also occurs in the lupus-prone B/W mouse. Production of autoantibodies in humans and the B/W mouse is dependent on activated CD4+ helper T cells. Activation of these T-cells requires interactions between the T-cell antigen receptor and antigen presented by an antigen-presenting cell, as well as a second signal which can be provided by interactions between B7 molecules on antigen- presenting cells and the CD28 molecule on the T-cell. Blockade of the first signal by antibodies against the CD4 molecule is effective in preventing or reversing lupus in the B/W mouse, an observation which in part led to therapeutic trials with anti-CD4 antibodies in humans with autoimmune disease. Blockade of the second activation signal by a soluble molecule called aLA4Ig has recently been shown to dramatically slow the progression of lupus in B/W mice as well as treat established disease. The mechanism of this effect, however, is unknown. T cell costimulation can also be provided by interactions between CD4O and its cognate ligand gp39, but the role of these molecules in autoimmunity is also unknown. The objective of the current proposal is to further define the mechanism by which interruption of T-cell costimulation can block the development of autoimmunity. This objective encompasses five specific aims: Specific Aim 1. To determine the relative contributions of B7-1 and B7-2 to the development of autoimmunity in lupus-prone NZB/NZW (B/W) mice. Specific Aim 2. To determine if blockade of CD28 and/or CTLA4 early in life can induce tolerance to autoantigens. Specific Aim 3. To determine the effects of costimulation blockade on T cell cytokine production in lupus-prone mice Specific Aim 4. To determine the role of Th1 and Th2 cells in the development and maintenance of murine lupus. Specific Aim 5. To determine whether interruption of multiple costimulation signals can have a synergistic effect on murine lupus. These studies will not only define the critical costimulation signal(s) necessary for the development of murine lupus, but should point to new, more specific therapeutic approaches in humans.

系统性红斑狼疮是一种全身性自身免疫性疾病。 以产生定向抗体为特征的未知原因 对抗各种自身抗原。一种自发性的狼疮 与人类疾病密切相关的也发生在易患狼疮的B/W人群中 老鼠。在人类和B/W小鼠中产生自身抗体是 依赖于激活的CD4+辅助T细胞。这些T细胞的激活 需要T细胞抗原受体和抗原之间的相互作用 由抗原提呈细胞提出，以及第二个信号 它可以通过抗原上B7分子之间的相互作用来提供- 呈现细胞和T细胞上的CD28分子。封锁线 通过针对CD4分子的抗体发出的第一个信号对 预防或逆转B/W小鼠狼疮的观察 在一定程度上导致了在人类中进行抗CD4抗体的治疗试验 患有自身免疫性疾病。通过以下方式阻止第二激活信号 一种名为aLA4Ig的可溶性分子最近被证明 显著减缓B/W小鼠狼疮的进展并进行治疗 已确定的疾病。然而，这种效应的机制尚不清楚。 T细胞共刺激也可以通过CD4O之间的相互作用来提供 及其同源配体gp39，但这些分子在 自身免疫性也是未知的。当前提案的目标是 进一步明确T细胞中断的机制 共刺激作用可阻断自身免疫的发展。这一目标 包括五个具体目标：具体目标1.确定 B7-1和B7-2在肿瘤发生发展中的相对贡献 狼疮易感NZB/NZW(B/W)小鼠的自身免疫。具体目标2.至 确定早期阻断CD28和/或CTLA4是否会导致 对自身抗原的耐受性。具体目标3.确定 共刺激阻断狼疮易感患者T细胞细胞因子的产生 小鼠的特异性目标4.确定Th1和Th2细胞在 小鼠狼疮的发生和维持。具体目标5.至 确定多个共刺激信号的中断是否可以 对小鼠狼疮有协同作用。这些研究不仅将 定义临界共刺激信号(S) 小鼠狼疮的发展，但应该指向新的，更具体的 人类的治疗方法。