MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION
MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION
批准号:
6099466
负责人:
FRANK W. FITCH
金额:
$14.48万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-09-01 至 2000-08-31
关键词:
B lymphocyte CD8 molecule MHC class I antigen T lymphocyte antigen presenting cell cell cycle proteins cell population study cellular immunity clone cells cytokine genetically modified animals homologous transplantation laboratory mouse neutralizing antibody pore forming protein protein biosynthesis skin transplantation spleen transplantation surface antigens tissue /cell culture transplant rejection
中文摘要
T细胞、B细胞和抗原提呈细胞之间的相互作用启动
由细胞因子和细胞介导和调节的免疫反应
表面相互作用。CD4T细胞亚群已在
分泌型淋巴因子的基础。CD8 T细胞亚群尚未被
详细地描述了。这项研究的总体目标是
项目2是描述调节的功能的机制
与同种异体移植排斥反应有关的T淋巴细胞
强调CD8 T细胞。我们将定义CD8 T细胞亚群
与单个主要组织相容性复合体(MHC)抗原反应为
以及确定控制这些T细胞反应的机制
细胞子集。我们将主要研究对I类MHC抗原的反应,
尤其是H-2LD。为实现这一目标,提出了三个具体目标
总目标:1)测定细胞因子和细胞表面分子
参与激活初始和预置的CD8T细胞的反应
用H-2LD类L MHC抗原,用来自其转基因小鼠的T细胞
CD8 T细胞表达抗原特异的转基因(TG)α/βT
与H-2LD同种异体抗原反应的细胞受体(TCR)。朴素CD8 T
细胞将从未经准备的脾和淋巴结中获得。敏化
CD8T细胞将从淋巴引流部位获得
排斥异体皮肤移植或经腹膜后的脾移植
注射同种异体细胞。特定淋巴因子的作用(包括
IL-1、IL-2、IL-4、IL-10和IL-12)和细胞表面分子(包括
B7-1、B7-2、CD28、CTLA-4、LFA-1、ICAM-1)促进增殖,
淋巴因子的产生,并获得细胞溶解活性
使用中和单抗(MAb)和各种
抗原提呈细胞群(APC);2)获得克隆
代表各种CD8 T细胞亚群,并比较
用控制幼稚的克隆来调节这些克隆的各种功能
CD8T细胞。为实现具体目标1而提出的实验应
定义基本条件(淋巴因子和细胞表面分子)
刺激CD8TG T细胞产生淋巴因子
CD4T辅助(Th)细胞亚群,即白细胞介素性(IL)
Th1和IL-4、IL-5、IL-6和IL-10的干扰素-γ
对于Th2。使用此信息,我们将定义导致
有选择地激活一个或另一个子集,我们将推导出
能分泌不同淋巴因子阵列的CD8TG T细胞克隆。我们
将确定代表CD8亚群的克隆的功能,测量
淋巴因子的产生、B细胞帮助的提供和细胞溶解活性
由穿孔素和Fas介导。我们还将评估各种不同的能力
CD8亚群对初始CD_4和CD_8 T细胞及CD_4应答的调节
和CD8体外克隆;以及3)基于通过
另一个具体目标是制定抑制同种异体移植的策略
拒绝。可能的治疗方法包括使用与
与细胞发生反应的特定细胞因子和/或单抗或其他试剂
特定T细胞亚群或APC的表面结构。
英文摘要
Interactions among T cells, B cells, and antigen-presenting cells initiate
immune responses which are mediated and regulated by cytokines and by cell
surface interactions. Subsets of CD4+ T cells have been identified on the
basis of secreted lymphokines. Subsets of CD8+ T cells have not been
characterized in detail. The general goal of the research proposed in
Project 2 is to characterize the mechanisms that regulate the functions of
T lymphocytes which are responsible for rejection of allografts, with
emphasis placed on CD8+ T cells. We will define CD8+ T cell subsets
reacting to individual major histocompatibility complex (MHC) antigens as
well as determining the mechanisms that control the responses of these T
cell subsets. We will study mainly the response to class I MHC antigens,
particularly H-2Ld. Three Specific Aims are proposed to accomplish this
general goal: 1) To determine the cytokines and cell surface molecules
that are involved in activating naive and primed CD8+ T cells reactive
with H-2Ld class l MHC antigen, using T cells from transgenic mice whose
CD8+ T cells express an antigen-specific, transgenic (Tg), alpha/beta T
cell receptor (TCR) which reacts with H-2Ld alloantigen. Naive CD8+ T
cells will be obtained from unprimed spleen and lymph nodes. Sensitized
CD8+ T cells will be obtained from lymph nodes draining the site of a
rejecting skin allograft or from the spleen following intraperitoneal
injection of allogeneic cells. The role of specific lymphokines (including
IL-1, IL-2, lL-4, lL-1O and lL-12) and cell surface molecules (including
B7-1, B7-2, CD28, CTLA-4, LFA-1, ICAM-1) in activation for proliferation,
lymphokine production, and acquisition of cytolytic activity will be
determined, using neutralizing monoclonal antibodies (mAb) and various
populations of antigen-presenting cells (APC); 2) To derive clones
representing various CD8+ T cell subsets and compare the mechanisms that
regulate various functions of these clones with those controlling naive
CD8+ T cells. The experiments proposed to accomplish Specific Aim 1 should
define the essential conditions (lymphokines and cell surface molecules)
for stimulating CD8+ Tg T cells to produce those lymphokines that have
distinguished subsets of CD4+ T helper (Th) cells, namely interleukin (IL)
2 and interferon-gamma (IFN-gamma) for Th1 and IL-4, lL-5, lL-6, and lL-10
for Th2. Using this information, we will define conditions that lead
selectively to activation of one or another subset, and we will derive
clones of CD8+ Tg T cells that secrete different lymphokines arrays. We
will determine functions of clones representing CD8+ subsets, measuring
lymphokine production, provision of B cell help, and cytolytic activity
mediated by perforin and Fas. We also will evaluate the ability of various
CD8+ subsets to regulate responses of naive CD4+ and CD8+ T cells and CD4+
and CD8+ clones in vitro; and 3) Based on the information obtained through
the other Specific Aims, to develop strategies for suppressing allograft
rejection. Possible therapies include the use of mAb reactive with
particular cytokines and/or mAb or other reagents that react with cell
surface structures on the particular T cell subsets or APC.
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会议论文
ANERGY AND SIGNALING IN MURINE T CELL SUBSETS
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批准号:6352593
-
项目类别:
-
资助金额:$17.7万
-
财政年份:2000
-
负责人:FRANK W. FITCH
-
依托单位:
ANERGY AND SIGNALING IN MURINE T CELL SUBSETS
-
批准号:6201184
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项目类别:
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资助金额:$17.7万
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财政年份:1999
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负责人:FRANK W. FITCH
-
依托单位:
ANERGY AND SIGNALING IN MURINE T CELL SUBSETS
-
批准号:6099749
-
项目类别:
-
资助金额:$17.7万
-
财政年份:1998
-
负责人:FRANK W. FITCH
-
依托单位:
CORE--ANALYTICAL REAGENTS FACILITY
-
批准号:6099471
-
项目类别:
-
资助金额:$14.48万
-
财政年份:1998
-
负责人:FRANK W. FITCH
-
依托单位:
CORE--ANALYTICAL REAGENTS FACILITY
-
批准号:6234971
-
项目类别:
-
资助金额:$10.03万
-
财政年份:1997
-
负责人:FRANK W. FITCH
-
依托单位:
MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION
-
批准号:6234966
-
项目类别:
-
资助金额:$10.03万
-
财政年份:1997
-
负责人:FRANK W. FITCH
-
依托单位:
ANERGY AND SIGNALING IN MURINE T CELL SUBSETS
-
批准号:6235195
-
项目类别:
-
资助金额:$17.05万
-
财政年份:1997
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479596
-
项目类别:
-
资助金额:$68.43万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479593
-
项目类别:
-
资助金额:$60.07万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479591
-
项目类别:
-
资助金额:$41.9万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479594
-
项目类别:
-
资助金额:$69.86万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479595
-
项目类别:
-
资助金额:$71.89万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:3479592
-
项目类别:
-
资助金额:$58.56万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES
-
批准号:2091459
-
项目类别:
-
资助金额:$73.12万
-
财政年份:1987
-
负责人:FRANK W. FITCH
-
依托单位:
MOLECULAR BASIS FOR T LYMPHOCYTE FACTOR ACTIVITY
-
批准号:3127651
-
项目类别:
-
资助金额:$8.97万
-
财政年份:1982
-
负责人:FRANK W. FITCH
-
依托单位:
MOLECULAR BASIS FOR T LYMPHOCYTE FACTOR ACTIVITY
-
批准号:3127649
-
项目类别:
-
资助金额:$13.53万
-
财政年份:1982
-
负责人:FRANK W. FITCH
-
依托单位:
MOLECULAR BASIS FOR T LYMPHOCYTE FACTOR ACTIVITY
-
批准号:3127652
-
项目类别:
-
资助金额:$10.2万
-
财政年份:1982
-
负责人:FRANK W. FITCH
-
依托单位:
MOLECULAR BASIS FOR T LYMPHOCYTE FACTOR ACTIVITY
-
批准号:3127648
-
项目类别:
-
资助金额:$13.12万
-
财政年份:1982
-
负责人:FRANK W. FITCH
-
依托单位:
MOLECULAR BASIS FOR T LYMPHOCYTE FACTOR ACTIVITY
-
批准号:3127650
-
项目类别:
-
资助金额:$10.63万
-
财政年份:1982
-
负责人:FRANK W. FITCH
-
依托单位:
ANTIBODY FORMATION BY LYMPHOID CELLS
-
批准号:3124185
-
项目类别:
-
资助金额:$16.89万
-
财政年份:1978
-
负责人:FRANK W. FITCH
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依托单位:
海外基金