CYTOKINE MECHANISMS IN SYSTEMIC AUTOIMMUNITY

描述：(改编自申请者摘要)Th1/Th2细胞因子平衡 被认为是决定易感性、进展性的重要因素 和自身免疫性疾病的预后。目前尚不清楚Th的哪个子集 细胞在系统性自身免疫性疾病如系统性红斑狼疮中发挥着更为关键的作用。 到目前为止获得的非决定性结果表明，Th1和Th2型 细胞因子可能参与其中，并且这种细胞因子的调节作用是 非常复杂。我们现在想要探索的假设 应用：系统性自身免疫性疾病SLE是一种多阶段疾病 Th1和Th2细胞因子作用的不同方面和不同过程 疾病发展的各个阶段。我们提出了一种遗传学的方法来研究 自身免疫性疾病发生机制的研究 基因操控的小鼠。信号换能器和激活器 转录(STAT)蛋白是一类负责 用于介导许多细胞因子诱导的反应。最近，有几个组织 产生的小鼠缺乏一种或另一种Stat基因。Stat-4基因敲除小鼠 缺乏IL-12功能，包括IFNG诱导和Th1 差异化。另一方面，Stat-6基因敲除小鼠缺乏 IL4诱导包括Th2分化在内的多种功能。我们有遗传上的 转移Stat-4和Stat-6零突变对狼疮易感性的影响 (NZBXNZW)F1的背景可以说是最好的可用动物模型 SLE。为此，新西兰的两个混合同源菌株NZM2410和 使用NZM2328，并创建了四个新的基因敲除小鼠系， 状态4-/-。NZM2410、STAT6-/-.NZM2410、STAT4-/-.NZM2328和 STAT6-/-.NZM2328，采用标记辅助选择协议(MASP) 促进和控制理想同系小鼠发育的策略 菌株。在拟议的研究中，我们打算描述发展和 这四种基因操纵的新基因中自身免疫性疾病的研究进展 并评估与免疫相关的免疫调节机制 自身免疫的发展。此应用程序集成了 结合遗传学和细胞因子生物学专业知识的多学科团队 自身免疫性疾病发展方面(雅各布博士的小组) B细胞免疫学和自身抗体(里夫斯博士组)和T细胞和NK细胞 免疫生物学(Dennert博士的小组)。

DESCRIPTION: (Adapted from applicant's abstract) The Th1/Th2 cytokine balance is believed to be a prominent factor in determining susceptibility, progression and prognosis in autoimmune diseases. It remains unclear which subset of Th cells play a more critical role in systemic autoimmune diseases such as SLE. Inconclusive results obtained so far suggest that both Th1 and Th2-type cytokines may be involved, and that the regulatory roles of such cytokines are very complex. The hypothesis we would like to explore in the present application is that the systemic autoimmune disease SLE is a multistage disease process in which Th1 and Th2 cytokines effect different aspects and different stages of disease development. We propose a genetic approach to study the mechanisms of autoimmune disease development employing a novel set of genetically manipulated mice. Signal transducers and activators of transcription (STAT) proteins are a class of transcription factors responsible for mediating many cytokine-induced responses. Recently, several groups have produced mice that lack one or the other Stat gene. The Stat-4 knockout mice are deficient in IL-12 functions including IFNg induction and Th1 differentiation. The Stat-6 knockout mice, on the other hand, are deficient in IL4 induced functions including Th2 differentiation. We have genetically transferred Stat-4 and Stat-6 null mutations onto the lupus susceptibility background of (NZBXNZW)Fl which is arguably the best available animal model for SLE. For this purpose two New Zealand Mixed congenic strains, NZM2410 and NZM2328, were used and four novel knockout mouse lines were created, the Stat4-/-. NZM2410, the Stat6-/-.NZM2410, the Stat4-/-.NZM2328 and the Stat6-/-.NZM2328, employing a marker-assisted selection protocol (MASP) strategy to accelerate and control the development of the desired congenic mice strains. In the proposed studies, we intend to characterize the development and progression of autoimmune disease in these four genetically manipulated new mouse lines, and to evaluate immune regulatory mechanisms pertinent to the development of autoimmunity. This application integrates the talents of a multidiscipline team combining expertise in genetics and cytokine biological aspects of autoimmune disease development (Dr. Jacob's group) with expertise in the B cell immunology and autoantibodies (Dr. Reeves' group) and T and NK cell immunobiology (Dr. Dennert's group).