GENETIC, VIRAL & IMMUNOLOGIC STUDIES IN NEW ZEALAND MICE

描述（由申请人提供）： 目的是了解为什么狼疮免疫系统异常反应的核小体，生理程序性细胞凋亡的主要产品，以及如何可以这样的自身免疫反应，特别是下调？核小体中的优势表位的鉴定对狼疮的自身免疫性T辅助细胞（Th）和抗DNA B细胞之间的同源相互作用至关重要，为我们提供了两个新发现的必要工具，导致拟议的实验。1）。人们普遍认为，负选择在狼疮中是完整的。我们现在发现，狼疮易感小鼠的胸腺不能删除携带核小体特异性T细胞受体（TCR）的转基因胸腺细胞，尽管对其他抗原的中枢耐受是完整的。这是第一次，机制/S的这种特殊的选择性缺陷，在中枢耐受核小体在狼疮倾向的胸腺将被定义使用新的TCR转基因小鼠，我们已经产生的线。首先研究携带转基因的正常背景的小鼠，以确定对核小体特异性的T细胞的负选择机制，核小体是胸腺中正在进行的细胞凋亡的主要产物，并确定负选择表位的谱。还将研究这些携带狼疮TCR的新转基因小鼠外周耐受性的新机制，特别是自身免疫TCR与完全T细胞活化的信号传导的功能性解偶联。 2）。我们已经发现，用非常低剂量的选择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。狼疮的致病性自身抗体诱导Th细胞以MHC非限制性方式识别的关键表位也被自身免疫B细胞识别，并且这样的共享表位是用于治疗的有效耐受原。我们将确定致病性自身抗体诱导的帮助如何被非常低剂量与高剂量的耐受性疗法与我们已经鉴定的核小体肽表位削弱，a）。狼疮T和B细胞的无反应性或缺失的作用; B）。具有由肽疗法产生的独特标志物的持久调节（抑制）T细胞亚群的作用;和c）.将确定致耐受性树突细胞和B细胞在产生异常调节性T细胞中的作用。这些研究将解决关于自身免疫和对普遍存在的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治疗。

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.