Regulation of B Cell Function by Interleukin 12

描述（由申请人提供）：本项目的目的是 确定负责白细胞介素-12的有效性的机制， 粘膜佐剂用于保护免受病毒和细菌感染。我们 先前的结果表明，用抗原鼻内处理小鼠， IL-12增强血清和呼吸道抗体应答， 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 IL-12诱导的炎症"危险"信号。IgA缺陷型巨噬细胞 小鼠在刺激时过度表达炎性细胞因子。更以 小鼠巨噬细胞系的体外IgA处理抑制了 TNF-α、IL-1、IL-6、一氧化氮和一氧化氮合酶。的 抑制作用似乎涉及抑制NF-κ B活性， IgA与巨噬细胞表面的相互作用。这个实验 本研究将详细研究IgA在体内控制 炎症IgA-/-小鼠对炎症的易感性将是 在重复接种IL-12 +/-LPS后进行检测。炎症诱导 将通过存活分析、炎性细胞因子的表达和 各种组织的组织学检查。外源性IgA的能力， 预防毒性或改善预先存在的炎症也将在 在疾病诱导期间通过IgA接种小鼠。保护机制 将在缺乏FcR共同γ链的菌株中进行分析， 在人类中负责介导IgA细胞信号传导，而在缺乏 不能跨上皮细胞转运IgA多聚IgR 屏障进入粘膜组织。最后，我们将确定细胞内 负责抑制NF-κ B活性的信号通路， IgA与巨噬细胞结合后的炎性细胞因子表达。特别 人们将关注IgA招募磷酸酶的可能性 类似于B、T和NK细胞抑制性受体的酶。的结果 这项研究将为IL-12和IgA在 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.