Antibody induced T cell mediated neonatal autoimmunity

抗体诱导 T 细胞介导的新生儿自身免疫

基本信息

批准号：
7161766
负责人：
KENNETH S.K. TUNG
金额：
$ 31.57万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-15 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7161766
关键词：
Address Adult Aleurites Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocyte Epitopes B-Lymphocytes Dependency Disease Doctor of Medicine Doctor of Philosophy Employee Strikes Environmental Risk Factor Epitopes Event Face Fc Receptor First Name Frequencies Genetic Heart Block Herpes zoster disease Human Resources IL2RA gene Immunoglobulin G Infusion procedures Life Lupus Mediating Memory Modeling Mus Names Neonatal Ovarian Ovarian Diseases Ovary Pathogenesis Prevention Principal Investigator Printing Relative (related person)Research Personnel Research Project Grants Role Specificity T memory cell T-Cell Depletion T-Lymphocyte Testing Thymectomy Universities Villus Virginia Zona Pellucida concept day injured neonate response

项目摘要

Our recent studies on autoJmmune ovarian disease (AOD) have accrued evidence that stimulation by antigen and environmental factor early in life predisposes genetically-susceptible mice to early- and late-onset autoimmune disease, and this is explicable by the relative paucity of the CD4+CD2.5+ regulatory T cells present early in life. We have now made a new and striking observation that further strengthens the paradigm. Autoantibody (autoAb) to the ovarian zona pellncida 3 (ZP3) B cell epitope (335-342) was found to preferentially injure ovaries in neonatal mice while sparing ovaries of adult mice. Interestingly, although the ovarian disease is triggered by ZP3 autoAb, disease expression depends on the presence of T cells in the neonate, and is associated with de nero neonatal autoimmane T cell response to ovarian antigen. In addition, induction of this neonatal AOD is B cell epitope-specific; thus autoAb to a second ZP3 native B cell epitope (171-180) is non-pathogenic. Even more exciting, neonatal AOD develops only when the autoAb first reaches the neonatal mice in the first 5 days of life. Theorem, maternal autoAb can trigger in neonates pathogenic autoi_une T ¿¿11_sponse and neonatal AOD; the di_ _duction i_ B cell epito_snecific, and only imvacts neonatal mi_ _t are known to be defi¿i_ in _gulato_ T cells. We now propose the following experimental approaches to further investigate these new and exciting observations. H_ we will test the hypothesis that neonatal AOD is triggered by epitope-specific autoAb, which forms immune complexes with endogenous Ag, to induce ZP3 specific pathogenic T celt response and tong-term autoimmune memory. Second, we will test the hypothesis that activation of antigen presenting cells by immune complex is dependent on their Fc receptor, and this event is required for neonatal AOD induction. Third, we will test the hypothesis that CD4+ CD25+ regulatory T cell deficiency in neonatal mice explains the propensity of neonatal mice to develop autoimmune response and disease. This proposal will therefore address fundamental mechanisms responsible for autoimmune induction and prevention, and specifically, neonatal autoimmane diseases including systemic lupus-related congenital heart block. PERFORCE Si_(S) (organizatiocnit,y,state) Universityof Virginia CiaariottesvilteV, irginia KEY PERSONNEL, See tnstruotions, Use cont/nuat/onpages as neededto provide the requited information in the format shown below. Start with Principal Investigator, List all other key personnel inalphabette,al order, tast name first, Name Organization Role on Projeot Kenneth S,K. Tung, M.D. Universityof Virginia PrincipalInvestigator Yulius Sctiady, Ph.D. University of Virginia Co- Principal Investigator Eilccn Samy, MS Universityof Virginia Co- investigator __$t_t_/Nmt. _icabtetoS_R/STTR Orgy. See_. [:]Villi [_No - PHS 398 (Roy. 05/01) Page _ Form Page2 o o P_paJ Jnves_gator/ProgrDamJr_k_(rLast,firstm, _e): Tung, Kenneth S.K. The name of the principalinvestigator/progrsm directormust be provided at the top of each printed page and each continuationpage. RESEARCH GRANT TABLE OF CONTENTS Page Nurnbet_ Face Page .................................................................................................................................................. 1 Description,

我们最近关于自身卵巢疾病（AOD）的研究积累了证据，表明抗原和生命早期的环境因素使遗传敏感的小鼠易于早期和晚期自身免疫性疾病，这是由CD4+ CD2.5+调节性T细胞的相对缺乏明确的。我们现在有做出了一个新的醒目的观察，进一步增强了范式。自动抗体（AutoAB）到卵巢Zona 发现pellncida 3（ZP3）B细胞表位（335-342）在保留新生儿小鼠时优先损害卵巢成年小鼠的卵巢。有趣的是，尽管卵巢疾病是由ZP3 AutoAb触发的，但疾病表达取决于新生儿中T细胞的存在，并且与新生儿自动IMMANE T细胞反应有关到卵巢抗原。另外，这种新生儿AOD的诱导是B细胞表位特异性的。因此自动启动到第二个zp3 天然B细胞表位（171-180）是非致病性的。更令人兴奋的是，新生儿AOD仅在AutoAB时才出现首先在生命的前5天到达新生儿小鼠。定理，母体自动ab可以触发新生儿的致病性 autoi_une t€11_sponse和neonatal aod; di_ _ duction i_ b cell epito_snecific，只有imvacts 已知新生儿Mi__t在_gulato_ t细胞中被定为i_。我们现在提出以下实验进一步研究这些新的令人兴奋的观察的方法。 H_我们将检验新生儿的假设 AOD是由表位特异性自动ab触发的，该自动蛋白具有内源性AG的免疫复合物，以诱导ZP3 特定的致病性TCELT反应和倾斜度的自身免疫记忆。其次，我们将检验以下假设通过免疫复合物激活抗原呈递细胞取决于其FC受体，需要此事件用于新生儿AOD诱导。第三，我们将测试CD4+ CD25+调节性T细胞缺乏症的假设新生儿小鼠解释了新生小鼠发展自身免疫反应和疾病的希望。这个建议因此，将解决负责自身免疫诱导和预防的基本机制，特别是新生儿自发疾病，包括系统性狼疮相关的先天性心脏障碍。 perforce si_（s）（组织，y，state）弗吉尼亚大学 IRGINIA CIAARIOTTESVILTEV 关键人员，请参阅TNSTRUTIONS，根据需要使用cont/nuat/onpages以下面显示的格式提供所需的信息。从首席调查员开始，列出所有其他关键人物Inalphabette，al order，tast Name首先姓名组织角色在Projeot上肯尼斯S，K。Tung，弗吉尼亚大学首席研究员 Yulius Sctiaty博士弗吉尼亚大学合伙研究员埃尔奇·萨米（Eilccn Samy），弗吉尼亚大学女士共同研究员 __ $ T_T_/NMT。 _icabtetos_r/sttr狂欢。看_。 [：] villi [_no -PHS 398（Roy。05/01）Page _形式Page2 o o p_paj jnves_gator/progrdamjr_k_（rlast，firstm，_e）：钨，肯尼斯S.K. 在每个印刷页面的顶部和每个ContinuationPage的顶部提供主评估器/Progrsm DirectRormust的名称。研究赠款目录页面nurnbet_ 脸部页面................................................................................................................................................................................................................................................................................................................................................................................... 描述，