CLONOTYPIC REGULATION OF ENCEPHALITOGENIC T LYMPHOCYTES

脑源性 T 淋巴细胞的克隆型调节

基本信息

批准号：
6920758
负责人：
Halina Offner
金额：
$ 45.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-01-01 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6920758
关键词：
T cell receptor T lymphocyte antireceptor antibody cytokine cytokine receptors disease /disorder model experimental allergic encephalomyelitis genetically modified animals immunoregulation laboratory mouse multiple sclerosis

项目摘要

DESCRIPTION (provided by applicant): Inflammatory T cells express receptors (TCR) that recognize foreign molecules, but may also be misdirected to react against self molecules, eg. myelin proteins, causing autoimmune diseases such as multiple sclerosis (MS). One natural regulatory mechanism that limits this process involves a second set of T cells that recognizes the TCR expressed by the inflammatory T cells. These regulatory "TCR reactive" T cells can be readily boosted in vivo with recombinant TCR proteins or peptides that correspond to variable (V) region genes that are over expressed by the pathogenic self reactive T cells. After activation with defined TCR sequences, TCR reactive T cells secrete inhibitory factors (cytokines) that can locally inhibit both the target pathogenic T cells as well as bystander inflammatory T cells that may express a different TCR directed at different myelin antigens. Treatment with TCR proteins has been shown to be highly effective at preventing and treating rodent models of MS, called experimental autoimmune encephalomyelitis (EAE). These studies have provided crucial data for treating patients with MS, where trials are currently in progress. Recent studies in mice that express a transgenic TCR BV chain for myelin basic protein (MBP) have demonstrated that TCR-reactive T cells develop through rearrangement of non-transgenic AV genes that pair mainly with the transgenic BV chain. Other groups have demonstrated the critical importance of newly rearranged CD4+ TCR alpha/beta+ regulatory T cells in preventing spontaneous EAE in TCR double transgenic mice that cannot produce regulatory T cells. It is thus hypothesized that TCR reactive T cells constitute the major portion of this important regulatory T cell population that thus far has not been characterized for antigen specificity. Two specific aims are proposed: Aim 1. Contribution of TCR-specific regulatory CD4+ T cells to EAE resistance. CD4+ T cells specific for TCR AV and BV determinants will be functionally evaluated in TCR double transgenic B10.PL mice specific for MBP-Ac1-11, where TCR-reactive T cells are naturally enriched, and in double transgenic mice backcrossed onto the RAG‑1-/- background, where TCR-reactive T cells cannot be positively selected. Defined TCR reactive T cell populations will be used to transfer protection to recipient mice susceptible to spontaneous or induced EAE. Aim 2. Contribution of cytokines, chemokines, and chemokine receptors to TCR mechanism. Intact and knockout B6 mice with MOG-induced EAE will be vaccinated with BV8S2 protein to assess the role of selected cytokines, chemokines, and chemokine receptors that have been implicated in the protective TCR mechanism. In knockout mice where TCR protection is lost, wild type T cell populations will be added back to confirm efficacy. These proposed studies will provide new and definitive insights into the biological importance and function of TCR-reactive T ceils in preventing and treating spontaneous and induced EAE, and will guide further human studies.

描述（由申请人提供）：炎症 T 细胞表达受体（TCR）识别外来分子，但也可能被误导进行反应对抗自身分子，例如。髓磷脂蛋白，引起自身免疫性疾病，例如如多发性硬化症（MS）。限制这种情况的一种自然调节机制该过程涉及第二组 T 细胞，其识别由炎症T细胞。这些调节性“TCR 反应性”T 细胞可以重组 TCR 蛋白或肽可轻松在体内增强对应于过度表达的可变（V）区基因致病性自身反应性T细胞。用定义的 TCR 序列激活后， TCR 反应性 T 细胞分泌抑制因子（细胞因子），可局部抑制靶致病性 T 细胞以及旁观者炎症 T 细胞可能表达针对不同髓磷脂抗原的不同 TCR 的细胞。 TCR 蛋白治疗已被证明可以非常有效地预防治疗多发性硬化症的啮齿动物模型，称为实验性自身免疫脑脊髓炎（EAE）。这些研究为治疗提供了重要数据患有多发性硬化症的患者，目前正在进行试验。最近的研究表达髓鞘碱性蛋白 (MBP) 转基因 TCR BV 链的小鼠证明 TCR 反应性 T 细胞通过重排而发育主要与转基因 BV 链配对的非转基因 AV 基因。其他研究小组已经证明了新重排的 CD4+ TCR 的至关重要性 α/β+ 调节性 T 细胞预防 TCR 双中自发性 EAE 不能产生调节性T细胞的转基因小鼠。因此假设 TCR 反应性 T 细胞构成了这一重要的主要部分迄今为止尚未表征的调节性 T 细胞群抗原特异性。提出了两个具体目标：目标 1. 的贡献 TCR 特异性调节 CD4+ T 细胞对 EAE 耐药性。 CD4+ T 细胞特异性 TCR AV 和 BV 决定因素将在 TCR 双中进行功能评估 MBP-Ac1-11 特异性转基因 B10.PL 小鼠，其中 TCR 反应性 T 细胞自然富集，并且在双转基因小鼠中回交到 RAG-1-/- 背景，TCR 反应性 T 细胞不能呈阳性已选择。确定的 TCR 反应性 T 细胞群将用于转移对易受自发性或诱发性 EAE 影响的受体小鼠提供保护。目标2。细胞因子、趋化因子和趋化因子受体对 TCR 的贡献机制。患有 MOG 诱导的 EAE 的完整和敲除 B6 小鼠将接种疫苗与 BV8S2 蛋白一起评估所选细胞因子、趋化因子和与 TCR 保护机制有关的趋化因子受体。在 TCR 保护丧失的基因敲除小鼠中，野生型 T 细胞群将被添加回去以确认功效。这些拟议的研究将提供新的以及对生物学重要性和功能的明确见解 TCR 反应性 T 细胞预防和治疗自发性和诱导性 EAE，并将指导进一步的人类研究。

项目成果

期刊论文数量（138）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Response of rat encephalitogenic T cells to synthetic peptides of guinea pig myelin basic protein.

大鼠脑炎 T 细胞对豚鼠髓磷脂碱性蛋白合成肽的反应。

DOI：
10.1111/j.1749-6632.1988.tb27091.x
发表时间：
1988
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Vandenbark,AA;Hashim,G;Offner,H
通讯作者：
Offner,H

A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE.

合成雄激素衍生物和天然雄激素代谢物可抑制复发缓解型 EAE。

DOI：
10.1016/s0165-5728(02)00214-x
发表时间：
2002
期刊：
Journal of neuroimmunology
影响因子：
3.3
作者：
Offner,Halina;Zamora,Alex;Drought,Heather;Matejuk,Agata;Auci,DominickL;Morgan,ElizabethE;Vandenbark,ArthurA;Reading,ChristopherL
通讯作者：
Reading,ChristopherL

Specificity of human T cell clones reactive to immunodominant epitopes of myelin basic protein.

人类 T 细胞克隆对髓磷脂碱性蛋白免疫显性表位反应的特异性。

DOI：
10.1002/jnr.490280215
发表时间：
1991
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Chou,YK;Henderikx,P;Vainiene,M;Whitham,R;Bourdette,D;Chou,CH;Hashim,G;Offner,H;Vandenbark,AA
通讯作者：
Vandenbark,AA

TCR peptide therapy in human autoimmune diseases.

TCR 肽治疗人类自身免疫性疾病。

DOI：
10.1023/a:1010951706830
发表时间：
2001
期刊：
Neurochemical research
影响因子：
4.4
作者：
Vandenbark,AA;Morgan,E;Bartholomew,R;Bourdette,D;Whitham,R;Carlo,D;Gold,D;Hashim,G;Offner,H
通讯作者：
Offner,H

TCR peptide therapy decreases the frequency of encephalitogenic T cells in the periphery and the central nervous system.

TCR 肽疗法可降低外周和中枢神经系统中致脑炎 T 细胞的频率。