CELL CD86 AND CYTOKINE RESPONSIVENESS

描述（改编自申请人的摘要）：我们的长期目标 研究的目的是更好地了解 交感神经递质去甲肾上腺素（NE）调节免疫系统 功能在我们的实验室里，最近有两个关键的发现， 需要在体内积极地进行。首先是β 2肾上腺素能 NE或选择性激动剂对B细胞上β-2 AR的刺激， 体外诱导Th 2/IL-4依赖性IgG 1的量增加，但不 Thl/IFN-γ依赖性IgG 2a，通过涉及B增加的机制 细胞对IL-4的反应性以及B水平的增加 细胞相关的CD 86（B7-2）表达和信号传导。第二，IgG 2a生产 当刺激TH 1细胞上的β-2 AR增加时， IgG 2a促进细胞因子IFN-γ的产生水平。还有， 体内Th 1/B细胞或Th 2/B细胞模型系统中NE的耗竭 抑制血清IgG_（2a）和IgG_（1）的水平，但抑制脾滤泡的IgG_（2a）和IgG_（1）的水平， 在Th 2/B细胞模型中，扩增和生发中心形成受到影响 系统而已。我们建议将目前的研究重点放在解决 体外实验中的初步关键发现可以在体内得到验证， 为了确定B细胞中的CD 86信号传导是否影响B细胞的反应性， 细胞对IFN-4，但不对IFN-γ。我们提出了一个两部分的假设进行测试。 首先，NE通过与β 2 AR结合，在体内增加IgG 1的水平。 本发明的目的在于提供一种用于增强B细胞上的CD 86表达和B细胞中的信号传导的方法。 第二，NE通过与β-2 AR结合来增加体内IgG 2a的水平 以增加产生的IFN-γ的水平，而不影响 B细胞对IFN-γ的应答水平。为了确定β-2 AR和 CD 86刺激使B细胞对Th 2介导的信号产生应答，但不 对于Th-1介导的信号，将使用体内模型系统，其中scid 小鼠保持NE-完整或NE-耗尽，然后用 β-2 AR（阴性）-Th 2细胞或β-2 AR（阳性或阴性）-Th 1细胞和β-2 AR（阳性或阴性）-B细胞。复溶后，这些小鼠将被给予 各种免疫刺激物和药理学激动剂和拮抗剂。的 这项研究的意义在于它将帮助我们了解一个 可能调节IgG 1和IgG 2a水平的内源性稳态机制 中和或溶解传染性疾病所必需的免疫力。 生物，分别，以及如何失调，这种稳态 这一机制可能有助于IgG 1-vs. IgG 2a介导的免疫和神经系统疾病。

DESCRIPTION(adapted from applicant's abstract): The long-term objective of our research is to achieve a better understanding of the mechanism by which the sympathetic neurotransmitter norepinephrine (NE) regulates immune system function. In our laboratory, two key discoveries have been made recently in vitro and need to be pursued aggressively in vivo. First, beta-2-adrenergic receptor (beta-2 AR) stimulation on a B cell by NE or a selective agonist in vitro induces an increase in the amount of Th2/IL-4-dependent IgG1, but not Thl/IFN-gamma-dependent IgG2a, via a mechanism that involves an increase in B cell responsiveness to IL-4, as well as an increase in the level of B cell-associated CD86 (B7-2) expression and signaling. Second, IgG2a production in vitro increases when the beta-2 AR on a TH1 cell is stimulated to increase the level of production of the IgG2a-promoting cytokine IFN-gamma. Also, depletion of NE in either a Th1/B cell of Th2/B cell model system in vivo inhibits the level of both serum IgG2a and IgG1, but splenic follicular expansion and germinal center formation are affected in the Th2/B cell model system only. We propose to focus the present study on resolving whether or not the initial key discoveries made in vitro can be validated in vivo, as well as to determine if CD86 signaling in a B cell affects the responsiveness of a B cell to IF-4, but not to IFN-gamma. We propose to test a two part hypothesis. First, NE increases the level of IgG1 in vivo by binding to the beta-2 AR on a B cell to increase the level of CD86 expression on, and signaling in, a B cell. And second, NE increases the level of IgG2a in vivo by binding to the beta-2 AR on a Thl cell to increase the level of IFN-gamma produced, without affecting the level of B cell responsiveness to IFN-gamma. To determine if beta-2 AR and CD86 stimulation render the B cell responsive to Th2-mediated signals, but not to Th-1 mediated signals, an in vivo model system will be used in which a scid mouse is kept NE-intact or is NE-depleted before being reconstituted with either beta-2 AR(neg)-Th2 cells or beta-2 AR(pos or neg)-Thl cells and beta-2 AR(pos or neg)-B cells. After reconstitution, these mice will be administered various immunologic stimuli and pharmacologic agonists and antagonists. The significance of the proposed research is that it will help us to understand an endogenous homeostatic mechanism that may regulate the level of IgG1 and IgG2a immunity that is necessary for either the neutralization or lysis of infectious organisms, respectively, as well as how dysregulation of this homeostatic mechanism may contribute to the development and progression of IgG1-vs. IgG2a-mediated diseases of the immune and nervous system.