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对核小体做出异常反应，核小体是生理性程序性凋亡的主要产物，以及如何特别下调这种自身免疫反应？核小体中对自身免疫T辅助细胞(Th)和狼疮抗DNA B细胞之间同源相互作用至关重要的优势表位的鉴定为我们提供了两项新发现的必要工具，从而导致了拟议的实验。1)。人们普遍认为，负选择在狼疮中是完好无损的。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。首次使用我们建立的新的TCR转基因小鼠品系来确定这种易患狼疮的胸腺中核小体中枢耐受的特殊选择性缺陷的机制/S。首先将对携带转基因的正常背景小鼠进行研究，以确定核小体特异性T细胞的负选择机制/S，这是胸腺持续凋亡的主要产物，并确定负选择表位的谱。这些新的携带狼疮TCR的转基因小鼠的外周耐受的新机制也将被研究，特别是通过自身免疫TCR从完全的T细胞激活中解偶联信号。 2)。我们发现，用极低剂量的精选核小体多肽治疗耐受可以通过独特的机制下调活动性狼疮。病原性自身抗体诱导的狼疮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，这些共享表位是治疗的有效耐受性。我们将利用我们已经确定的核小体多肽表位确定致病性自身抗体诱导Help的极低剂量与高剂量耐受治疗是如何受损的/S，a)。狼疮T、B细胞无能或缺失的作用；具有独特标记的长效调节(抑制)T细胞亚群在多肽治疗中的作用；以及c)耐受性树突状细胞和B细胞在异常调节性T细胞的产生中的作用将被确定。这些研究将解决有关自身免疫和对一种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.