GENETIC, VIRAL & IMMUNOLOGIC STUDIES IN NEW ZEALAND MICE

遗传、病毒

• 批准号: 6844914
• 负责人: SYAMAL K DATTA
• 金额: $ 35.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844914
• 关键词: B lymphocyte; anergy; apoptosis; autoantibody; autoimmune disorder; biotechnology; biotherapeutic agent; dendritic cells; genetically modified animals; helper T lymphocyte; histopathology; humoral immunity; immunofluorescence technique; immunogenetics; immunologic assay /test; immunologic substance development /preparation; laboratory mouse; leukocyte depletion therapy; nucleosomes; synthetic vaccines; systemic lupus erythematosus; thymus

DESCRIPTION (provided by applicant): The objectives are to understand why the lupus immune system responds abnormally to nucleosomes, the major products of physiologically programmed apoptosis, and how can such autoimmune responses be specifically down-regulated? Identification of the dominant epitopes in nucleosomes critical for cognate interactions between autoimmune T helper (Th) cells and anti-DNA B cells of lupus provided us the essential tools for two novel discoveries leading to the proposed experiments. 1). It is widely believed that negative selection is intact in lupus. We have now found that the thymuses of lupus-prone mice are unable to delete transgenic thymocytes bearing nucleosome-specific T-cell receptor (TCR), although central tolerance for other antigens is intact. For the first time, mechanism/s of this peculiarly selective defect in central tolerance for nucleosomes in the lupus-prone thymus will be defined using new lines of TCR-transgenic mice we have generated. Mice of normal backgrounds bearing the transgenes will be studied first to define mechanism/s of negative selection of T cells specific for nucleosomes, the major products of ongoing apoptosis in the thymus, and to define the spectrum of negatively selecting epitopes. Novel mechanisms of peripheral tolerance in these new transgenic mice bearing lupus TCR will also be studied, particularly a functional uncoupling of signaling by autoimmune TCR from full T cell activation. 2). We have found that therapeutic tolerance with very low doses of select nucleosomal peptides can down-regulate active lupus by unique mechanisms. The critical epitopes that are recognized in MHC unrestricted manner by pathogenic autoantibody-inducing Th cells of lupus are also recognized by autoimmune B cells, and such shared epitopes are potent tolerogens for therapy. We will determine how pathogenic autoantibody inducing help is impaired by very low-dose vs. high-dose tolerance therapy with the nucleosomal peptide epitope/s we have identified, a). Role of anergy or deletion of lupus T and B cells; b). role of long-lasting regulatory (suppressor) T cell subsets with unique markers that are generated by peptide therapy; and c). the roles of tolerogenic dendritic cells and B cells in the generation of unusual regulatory T cells will be defined. The studies will address fundamental questions regarding autoimmunity and tolerance to an ubiquitous product of apoptosis, and would help in developing antigen-specific therapy of lupus.

描述（由申请人提供）： 目的是了解为什么狼疮免疫系统对核小体（生理程序性细胞凋亡的主要产物）反应异常，以及如何特异性下调这种自身免疫反应？核小体中对自身免疫 T 辅助 (Th) 细胞和狼疮抗 DNA B 细胞之间的同源相互作用至关重要的主要表位的鉴定为我们提供了两个新发现的必要工具，这两项新发现导致了拟议的实验。 1）。人们普遍认为，狼疮中的负选择是完整的。我们现在发现，尽管对其他抗原的中枢耐受性完好无损，但易患狼疮的小鼠的胸腺无法删除带有核小体特异性 T 细胞受体 (TCR) 的转基因胸腺细胞。首次，我们将使用我们培育的新 TCR 转基因小鼠系来定义易患狼疮的胸腺中核小体中央耐受的这种特殊选择性缺陷的机制。首先将研究携带转基因的正常背景小鼠，以确定对核小体（胸腺中持续凋亡的主要产物）特异的 T 细胞负选择的机制，并确定负选择表位的范围。还将研究这些携带狼疮 TCR 的新转基因小鼠的外周耐受新机制，特别是自身免疫 TCR 信号与完全 T 细胞激活的功能解偶联。 2）。我们发现，极低剂量的精选核小体肽的治疗耐受性可以通过独特的机制下调活动性狼疮。狼疮致病性自身抗体诱导性 Th 细胞以 MHC 不受限制的方式识别的关键表位也被自身免疫 B 细胞识别，此类共享表位是治疗的有效耐受原。我们将确定使用我们已鉴定的核小体肽表位的极低剂量与高剂量耐受疗法如何损害致病性自身抗体诱导帮助，a)。狼疮 T 和 B 细胞无反应或缺失的作用； b).肽疗法产生的具有独特标记的持久调节（抑制）T 细胞亚群的作用；和c)。耐受性树突状细胞和 B 细胞在异常调节性 T 细胞生成中的作用将得到明确。这些研究将解决有关自身免疫和对普遍存在的细胞凋亡产物的耐受性的基本问题，并将有助于开发狼疮的抗原特异性疗法。