Peptide Gene Vaccination in Lupus

描述(由申请人提供)：我们在这份建议书中的长期目标 是为了阐明调节自身抗体的T细胞的性质和作用 系统性红斑狼疮(SLE)的产生，以开发治疗方法 调节这些T细胞，并确定潜在的新治疗策略 对于系统性红斑狼疮。 系统性红斑狼疮是一种影响多个器官的慢性自身免疫性疾病。器官损伤 主要是由自身抗体引起的，特别是对天然DNA的抗体。这个 这些致病的抗DNA抗体的产生受 自身反应性T辅助细胞。这些T辅助细胞与衍生的多肽发生反应 来自抗DNA抗体的重链可变区或来自 组蛋白。耐受或灭活这些Th细胞的特异性多肽 配体延缓系统性红斑狼疮模型小鼠的疾病发展和延长生存期， 比如NZB/W雌性小鼠。然而，诱导和维持 耐受性需要多次静脉注射。大剂量注射这些多肽； 这既麻烦又昂贵。此外，治疗NZB/W的初步尝试 有类似静脉注射的肾炎的小鼠。多肽方案有 不是很成功。 因此，与其耐受CD4T辅助细胞来控制自身抗体 生产，我们将测试VH多肽特异性CD8T细胞是否阻断或 抑制或杀死自身抗体的产生 分泌自身抗体的B细胞。具体地说，我们将测试假设 编码自身抗体VH区肽的微型基因激活调节或 细胞毒性CD8 T细胞，特异性抑制自身抗体的产生和 抑制狼疮小鼠的疾病。 我们将构建重组腺病毒或裸DNA载体，编码 VH多肽，并确定它们激活调节性或细胞毒性的能力 CD8 T细胞，降低抗DNA抗体，并影响疾病 狼疮鼠。为了进一步增强CD8 T细胞的激活，我们将构建 多肽泛素融合基因，可能增强调节或诱导 通过将肽路由到MHC I类途径来实现细胞毒性T细胞反应。 激活调节性和细胞毒性T淋巴细胞的方法研究进展 将为控制SLE患者的疾病提供新的、更具体的方法 可能在疫苗接种、癌症免疫治疗和 治疗免疫介导性疾病。这些研究还将阐明 自身反应性CD8 T细胞在系统性红斑狼疮中的作用

DESCRIPTION (provided by applicant): Our long-term objectives in this proposal are to elucidate the nature and role of T cells that regulate autoantibody production in systemic lupus erythematosus (SLE), to develop approaches to modulate these T cells, and identify potentially novel therapeutic strategies for SLE. SLE is a chronic autoimmune disease that affects multiple organs. Organ damage is mostly caused by autoantibodies, particularly antibodies to native DNA. The production of these disease-causing anti-DNA antibodies is regulated by auto-reactive T helper cells. These T helper cells react with peptides derived from the heavy chain variable (VH) regions of anti-DNA antibodies or from histones. Tolerizing or inactivating these Th cells by their specific peptide ligands delays disease development and prolongs survival in mouse mod s of SLE, such as the NZB/W female mouse. However, the induction and maintenance of tolerance requires multiple i.v. injections of large doses of these peptides; this is cumbersome and expensive. Moreover, initial attempts to treat NZB/W mice that have established nephritis with a similar i.v. peptide regimen have not been successful. Therefore, instead of tolerizing CD4+ T helper cells to control autoantibody production, we will test whether CD8+ T cells specific for VH peptides block or terminate autoantibody production I y suppressing or killing autoantibody-secreting B cells. Specifically we will test the hypothesis that minigenes that encode autoantibody VH region peptides activate regulatory or cytotoxic CD8+ T cells that specifically inhibit autoantibody production and suppress disease lupus mice. We will construct recombinant adenovirus or naked DNA vectors that encode the VH peptides, and determine their ability to activate regulatory or cytotoxic CD8+ T cells, decrease anti‑DNA antibodies, and influence disease in lupus mice. To further augment CD8+ T cell activation, we will construct peptide ubiquitin fusion genes, which might enhance induction of regulatory or cytotoxic T cell responses by routing peptide into the MHC class I pathway. Development of methods that activate regulatory and cytotoxic T lymphocytes will provide new, more specific ways to control disease in patients with SLE and might have general applicability in vaccination, cancer immunotherapy and treatment of immune-mediated disorders. The studies will also elucidate the role of self-reactive CD8+ T cells in SLE.