T CELL COST IMMULATION ON MURINE LUPUS
鼠狼疮 T 细胞成本模拟
基本信息
- 批准号:2671480
- 负责人:
- 金额:$ 7.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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,
未知原因,其特征是产生定向抗体
对抗多种自身抗原一种自发的狼疮,
与人类疾病密切平行的是,狼疮倾向的B/W
老鼠.人类和B/W小鼠自身抗体的产生是
依赖于活化的CD 4+辅助性T细胞。激活这些T细胞
需要T细胞抗原受体和抗原之间的相互作用
由抗原呈递细胞呈递的第一信号,以及第二信号,
这可以通过抗原上B7分子之间的相互作用来提供,
T细胞上的CD 28分子。封锁
通过针对CD 4分子的抗体的第一信号有效地
在B/W小鼠中预防或逆转狼疮,
在一定程度上导致了抗CD 4抗体的人体治疗试验
自身免疫性疾病第二激活信号的阻断,
一种叫做aLA 4 Ig的可溶性分子最近被证明
显著减缓B/W小鼠狼疮的进展,
建立疾病。然而,这种效应的机制尚不清楚。
T细胞共刺激也可以通过CD 40和CD 41之间的相互作用来提供。
及其同源配体gp 39,但这些分子在
自身免疫也是未知的。本提案的目的是
为了进一步确定T细胞的中断机制,
共刺激可以阻断自身免疫的发展。这一目标
包含五个具体目标:具体目标1。确定
B7-1和B7-2对发育的相对贡献
狼疮易感NZB/NZW(B/W)小鼠的自身免疫。具体目标2。到
确定在生命早期阻断CD 28和/或CTLA 4是否可以诱导
对自身抗原的耐受性。具体目标3。以确定影响
共刺激阻断对狼疮易感者T细胞细胞因子产生的影响
小鼠特异性目标4.为了确定Th 1和Th 2细胞在
小鼠狼疮的发展和维持。具体目标5.到
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
定义关键共刺激信号,
发展的小鼠狼疮,但应该指出新的,更具体的
人类的治疗方法。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('David I Daikh', 18)}}的其他基金
A Controlled Trial of CBT for MS Inflammation
CBT 治疗多发性硬化症炎症的对照试验
- 批准号:
7111692 - 财政年份:2003
- 资助金额:
$ 7.43万 - 项目类别:
A Controlled Trial of CBT for Multiple Sclerosis Inflammation
CBT 治疗多发性硬化症炎症的对照试验
- 批准号:
7287441 - 财政年份:2003
- 资助金额:
$ 7.43万 - 项目类别:
A Controlled Trial of CBT for Multiple Sclerosis Inflammation
CBT 治疗多发性硬化症炎症的对照试验
- 批准号:
8144984 - 财政年份:2003
- 资助金额:
$ 7.43万 - 项目类别:
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