Regulation of B Cell Function by Interleukin 12

描述(由申请人提供)：本项目的目的是 确定白介素12对S疗效的作用机制 用于预防病毒和细菌感染的粘膜佐剂。我们的 先前的研究结果表明，小鼠鼻腔内注射抗原和 IL-12增强血清和呼吸道抗体反应，并增强 预防流感病毒和肺炎链球菌。IGA似乎 在IL-12介导的保护和调节中发挥重要作用 IL-12诱导的炎性“危险”信号。来自IgA缺陷的巨噬细胞 小鼠在刺激下过度表达炎性细胞因子。此外，在 体外免疫球蛋白A处理小鼠巨噬细胞系抑制其分泌 TNF-α、IL-1、IL-6、一氧化氮、一氧化氮合酶。这个 抑制作用似乎与抑制核因子-kB活性有关 免疫球蛋白A与巨噬细胞表面的相互作用这里面的实验 这项研究将详细研究免疫球蛋白A在体内控制的能力 发炎。IgA-/-小鼠对炎症的易感性将是 反复接种IL-12+/-内毒素后进行检测。诱导发炎 将通过生存分析，炎性细胞因子和 各种组织的组织学检查。外源性免疫球蛋白A的免疫应答能力 预防毒性或改善先前存在的炎症也将在 小鼠在疾病诱导过程中接种IgA。保护机制 将在缺乏FCR共同伽马链的菌株中进行分析，这是 在人类中负责调节IgA细胞信号，在缺乏菌株中 不能跨上皮细胞转运IgA的聚合型IGR 进入粘膜组织的屏障。最后，我们将确定细胞内的 抑制核因子-kB活性的信号通路和 免疫球蛋白A与巨噬细胞结合后炎性细胞因子的表达特例 人们将关注IgA招募磷酸酶的可能性 类似于B、T和NK细胞抑制受体的酶。结果是 这项研究将为了解IL-12和IgA在糖尿病中的作用提供重要的见解。 控制免疫力，并可能对人类健康产生直接影响。

DESCRIPTION (provided by applicant): The purpose of this project is to determine the mechanisms responsible for interleukin-12's effectiveness as a mucosal adjuvant for protection against viral and bacterial infection. Our previous results have shown that intranasal treatment of mice with antigen and IL-12 enhances serum and respiratory antibody responses, and augments protection against influenza virus and Streptococcus pneumoniae. IgA appears to play an important role in IL-12-mediated protection and also in regulating inflammatory "danger" signals induced by IL-12. Macrophages from IgA-deficient mice over-express inflammatory cytokines upon stimulation. Furthermore, in vitro IgA treatment of murine macrophage cell lines inhibits production of TNF-a, IL-1, IL-6, nitric oxide, and nitric oxide synthase by these cells. The inhibitory effect appears to involve suppression of NF-KB activity after interaction of IgA with the macrophage cell surface. The experiments in this study will now investigate in detail the ability of IgA to control in vivo inflammation. The susceptibility of IgA-/- mice to inflammation will be examined after repeated inoculation of IL-12 +/- LPS. Induction of inflammation will be assessed by survival analysis, expression of inflammatory cytokines and histological examination of various tissues. The ability of exogenous IgA to prevent toxicity or ameliorate pre-existing inflammation will also be tested in mice by IgA inoculation during disease induction. The mechanism for protection will be analyzed in strains lacking the FcR common gamma chain, which is responsible in humans for mediating IgA cell signaling, and in strains lacking the polymeric IgR, which are unable to transport IgA across epithelial cell barriers into mucosal tissues. Finally, we will determine the intracellular signaling pathways that are responsible for inhibition of NF-KB activity and inflammatory cytokine expression after IgA binding to macrophages. Particular attention will be placed on the possibility that IgA recruits phosphatase enzymes in analogy to B, T, and NK cell inhibitory receptors. The results of this study will provide important insight into the roles of IL-12 and IgA in controlling immunity, and could have immediate impact on human health.