Peptide Gene Vaccination in Lupus

描述（由申请人提供）：我们在本提案中的长期目标 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，以开发方法， 调节这些T细胞，并确定潜在的新的治疗策略， 对于SLE。 SLE是一种慢性自身免疫性疾病，影响多个器官。器官损伤 主要由自身抗体引起，特别是天然DNA的抗体。的 这些致病性抗DNA抗体的产生受到以下因素的调节： 自身反应性T辅助细胞这些T辅助细胞与衍生的肽反应， 来自抗DNA抗体的重链可变（VH）区或来自 组蛋白通过其特异性肽耐受或灭活这些Th细胞 配体延迟SLE小鼠模型中的疾病发展和存活， 例如NZB/W雌性小鼠。然而， 耐受性需要多次静脉注射大剂量的这些肽; 这是麻烦且昂贵的。此外，最初治疗NZB/W的尝试 用类似的静脉注射肽方案建立肾炎的小鼠 没有成功。 因此，代替耐受性CD 4 + T辅助细胞来控制自身抗体， 在生产中，我们将测试对VH肽特异性的CD 8 + T细胞是否阻断或 通过抑制或杀死来终止自身抗体产生 分泌自身抗体的B细胞。具体来说，我们将测试假设， 编码自身抗体VH区肽的小基因激活调节或 特异性抑制自身抗体产生的细胞毒性CD 8 + T细胞， 抑制疾病狼疮小鼠。 我们将构建重组腺病毒或裸DNA载体， VH肽，并确定其激活调节或细胞毒性的能力， CD 8 + T细胞，减少抗DNA抗体，并影响疾病， 狼疮鼠为了进一步增强CD 8 + T细胞活化，我们将构建 肽泛素融合基因，这可能会提高诱导的调节或 通过将肽路由到MHC I类途径中来产生细胞毒性T细胞应答。 开发激活调节性和细胞毒性T淋巴细胞的方法 将提供新的、更具体的方法来控制SLE患者的疾病 并且可能在疫苗接种、癌症免疫治疗和 治疗免疫介导的疾病。这些研究还将阐明 自身反应性CD 8 + T细胞在SLE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.