TOLERANCE INDUCTION TO RESTRUCTURE IMMUNE RESPONSES

诱导耐受以重建免疫反应

• 批准号: 7716130
• 负责人: Judith M. Thomas
• 金额: $ 11.08万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716130
• 关键词: Achievement; Adult; Affect; Antigens; Autoimmune Diseases; CD3 Antigens; Cells; Cellular Structures; Computer Retrieval of Information on Scientific Projects Database; Elements; Funding; Goals; Grant; Gusperimus; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Memory; Immunotoxins; Institution; Interleukin-10; Intervention; Knowledge; Lead; Macaca mulatta; Maintenance; Modeling; Monoclonal Antibody HuM291; Muromonab-CD3; Population; Pre-Clinical Model; Publishing; Recombinants; Regulation; Regulatory Element; Research; Research Personnel; Resources; Role; Self Tolerance; Source; T memory cell; T-Lymphocyte; Therapeutic; Tissues; Translating; Transplantation Tolerance; United States National Institutes of Health; Vaccines; base; in vivo; nonhuman primate; pre-clinical; restoration; stem

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autoimmune diseases affect up to 5% of the population. They stem from alterations in immune regulation that lead to a breakdown of self-tolerance to tissue antigens. The goal of these studies is to develop a preclinical strategy, based on tolerance induction, that will be applicable to the treatment of human autoimmune disease. Toward this goal, we have established a preclinical model for studying tolerance and regulatory T cells in nonhuman primates (NHP). Although initially developed as a means to induce stable transplantation tolerance, the model allows us to explore basic questions about T cell tolerance in NHP. We hypothesize that our highly effective tolerance induction strategy allows the T cell component of the immune system to reset in the presence of antigen and IL-10, providing a window of opportunity to drive Tregs and establish stable tolerance. We propose that this unique therapeutic approach in NHP will translate to human autoimmune disease. The proposed studies will examine homeostatic T cell expansion in vivo in the context of IL-10 and Tregs to determine which regulatory elements are central to the maintenance of NHP tolerance to tissue antigens. The specific aims are as follows: Aim 1: To determine T cell regulatory mechanisms during the restoration of T cell homeostasis and induction of immune tolerance following anti-CD3 immunotoxin (IT) plus Deoxyspergualin (DSG) therapy in adult rhesus (RH) macaques. Aim 2: To examine the use of recombinant IL-10 therapy as a supplement to IT plus DSG treatment to enhance the consistency of activating T regulatory cells and obtaining stable tolerance. Aim 3: To determine the effect of IT plus DSG treatment on T cell memory. The studies are original in that, to our knowledge, there is no published information on CD3+ NKT, CD4+CD25+ and CD8+CD28- regulatory cell populations in NHP. This situation persists, despite the importance of NHP as the penultimate preclinical model for examination of tolerance and vaccine interventions. The proposed studies are expected to yield new information to optimize the achievement of tolerance and to modify immunologic memory. These questions - the elements that regulate tolerance during homeostatic repopulation, the role of antigen, and the effect of these on immunologic memory - are the focus of this proposal.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 自身免疫性疾病影响高达 5% 的人口。它们源于免疫调节的改变，导致对组织抗原的自我耐受性崩溃。这些研究的目标是开发一种基于耐受诱导的临床前策略，该策略将适用于人类自身免疫性疾病的治疗。为了实现这一目标，我们建立了一个临床前模型来研究非人灵长类动物 (NHP) 的耐受性和调节性 T 细胞。尽管该模型最初是作为诱导稳定移植耐受的一种手段而开发的，但该模型使我们能够探索有关 NHP 中 T 细胞耐受的基本问题。我们假设我们高效的耐受诱导策略允许免疫系统的 T 细胞成分在抗原和 IL-10 存在的情况下重置，从而提供驱动 Tregs 和建立稳定耐受的机会窗口。我们建议 NHP 的这种独特治疗方法将转化为人类自身免疫性疾病。拟议的研究将在 IL-10 和 Tregs 的背景下检查体内稳态 T 细胞的扩增，以确定哪些调节元件对于维持 NHP 对组织抗原的耐受性至关重要。具体目标如下： 目标 1：确定成年恒河猴 (RH) 猕猴接受抗 CD3 免疫毒素 (IT) 加脱氧精胍菌素 (DSG) 治疗后恢复 T 细胞稳态和诱导免疫耐受过程中的 T 细胞调节机制。目标 2：检验重组 IL-10 疗法作为 IT 加 DSG 治疗的补充，以增强激活 T 调节细胞的一致性并获得稳定的耐受性。目标 3：确定 IT 加 DSG 治疗对 T 细胞记忆的影响。这些研究的原创性在于，据我们所知，目前还没有关于 NHP 中 CD3+ NKT、CD4+CD25+ 和 CD8+CD28- 调节细胞群的公开信息。尽管 NHP 作为检查耐受性和疫苗干预的倒数第二个临床前模型非常重要，但这种情况仍然存在。拟议的研究预计将产生新的信息，以优化耐受性的实现并改变免疫记忆。这些问题——在稳态再增殖过程中调节耐受性的因素、抗原的作用以及这些因素对免疫记忆的影响——是本提案的重点。