MURINE MODELS OF GENERALIZED AUTOIMMUNITY

广义自身免疫的小鼠模型

• 批准号: 3155997
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 30.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155997
• 关键词: MHC class II antigen; T cell receptor; active immunization; antisense nucleic acid; apoptosis; autoantibody; autoimmune disorder; autoimmunity; bacterial antigens; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene deletion mutation; gene induction /repression; genetic strain; genetically modified animals; helper T lymphocyte; immune response genes; immunotherapy; infant animal; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; lymphokines; model design /development; molecular cloning; molecular pathology; nucleic acid hybridization; peptide chemical synthesis; systemic lupus erythematosus; tissue /cell culture; transfection

The primary roles of MHC molecules, T cell antigen receptors (TCR) and certain lymphoaccumulation-inducing mutations (lpr,gld) in the pathogenesis of murine lupus have been firmly established. This continuation application on murine models of generalized autoimmunity will further address the molecular basis and biologic pathways by which these genes contribute to the pathogenesis of this complex disorder. The origin and mechanism of action of the autoimmunity promoting/inducing lpr and gld double-negative TCR-alpha beta+ cells will be pursued by assessing their thymic education, V-beta TCR gene expression profiles, and ability to stimulate normal helper T cells to produce T and B cell growth/differentiation-promoting lymphokines. H-2 congenic lines of lupus mice will be developed to further define the role of H-2 haplotypes in this disease, particularly of I-E and its reactive V-beta clonotypes. Our experiments to date of V-beta gene expression profiles in lupus mice indicate disease/age-associated expansions for T cell clones expressing certain V-betas, but their role in disease pathogenesis and means of induction need to be determined. Subtractive approaches with experimentally-induced tolerance-related clonal deletions by neonatal injection of self- or foreign-superantigens will be employed to address this issue. Once disease-associated V-beta clonotypes have been identified, attempts to develop new lupus immunotherapies based on the elimination of such clones in adult mice with anti-V-beta-specific antibodies, or their control by active immunization with synthetic V-beta peptide vaccines, will be undertaken, The recently established SCID mouse/human lupus model will also be used to define human lupus-associated V-beta clonotypes and their autoimmune potential.

MHC 分子、T 细胞抗原受体 (TCR) 和 某些淋巴细胞蓄积诱导突变（lpr、gld） 小鼠狼疮的发病机制已被牢固确立。 这 广泛性自身免疫小鼠模型的继续应用 将进一步解决分子基础和生物学途径 这些基因促成了这种复杂疾病的发病机制。 自身免疫的起源和作用机制 促进/诱导lpr和gld双阴性TCR-αβ+细胞 将通过评估他们的胸腺教育、V-beta TCR 基因来进行追踪 表达谱以及刺激正常辅助 T 细胞的能力 产生 T 细胞和 B 细胞生长/分化促进淋巴因子。 H-2 将开发狼疮小鼠的同源系以进一步定义 H-2 单倍型在这种疾病中的作用，特别是 I-E 及其 反应性V-β克隆型。 我们迄今为止的 V-beta 基因实验 狼疮小鼠的表达谱表明疾病/年龄相关 表达某些 V-β 的 T 细胞克隆的扩增，但它们的作用 疾病的发病机制和诱导方式需要确定。 与实验诱导的耐受性相关的减法方法 通过新生儿注射自身或外源超抗原进行克隆删除 将被用来解决这个问题。 一旦与疾病相关的V-β 克隆型已被鉴定，尝试开发新的狼疮 基于消除成年小鼠中此类克隆的免疫疗法 与抗V-β特异性抗体，或通过活性控制它们 将进行合成V-β肽疫苗的免疫接种， 最近建立的SCID小鼠/人类狼疮模型也将被使用 定义人类狼疮相关的 V-β 克隆型及其自身免疫 潜在的。