NEUROMODULATION OF THE ANTIBODY RESPONSE

抗体反应的神经调节

• 批准号: 6170050
• 负责人: VIRGINIA M SANDERS
• 金额: $ 17.93万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170050
• 关键词: B lymphocyte; SCID mouse; antibody formation; beta adrenergic receptor; cell adhesion molecules; cell line; clone cells; cytokine; gene targeting; helper T lymphocyte; immunoglobulin isotypes; laboratory mouse; leukocyte activation /transformation; neuroimmunomodulation; norepinephrine; receptor expression; sympathetic nervous system

DESCRIPTION (applicant's abstract): Our long term goal is to understand the mechanism by which a line of communication is maintained between the immune system and the sympathetic nervous system, as well as the mechanism by which disruption of this communication link affects immune homeostasis. Sympathetic nerve fibers release norepinephrine within lymphoid organs during an immune response to bind to adrenergic receptors expressed on immune cells. Findings from this laboratory show that B cells and clones of CD4+ T-helper (Th)-1 cells express detectable levels of the beta-2-adrenergic receptor (b2AR) protein and mRNA, while clones of Th2 cells do not. Our results also show that b2AR stimulation on the B cell, but not the Th2 cell, increases the frequency of B cells that differentiate into IgM-, IgG1-, and IgE-secreting cells through a mechanism that appears to involve a b2AR-induced increase in B7-2 expression on the B cell. In contrast, b2AR stimulation on the Th1 cell appears to play a more critical role to increase the frequency of B cells that differentiate into IgG2a-secreting cells. However, in both the Th1 and Th2 cell-dependent antibody response, enhancement appears to depend on the activation state of the cells at the time of b2AR stimulation. These findings have led us to propose the hypothesis that norepinephrine stimulation of the b2AR on lymphocytes is essential for the induction of maximal antibody production against a Th cell-dependent antigen. The specific aims of this research will be 1) To determine if the presence of the b2AR on lymphocytes is essential for norepinephrine to enhance the antibody response by using mice in which the b2AR gene has been disrupted; 2) To determine the mechanism responsible for antibody enhancement by testing if the increase in B cell activity is induced directly by b2AR stimulation on the B cell and/or induced indirectly by the B cell influencing Th cell activity and/or by b2AR stimulation on the Th1 cell; and 3) To determine the mechanism by which the antibody enhancement is influenced by the time of b2AR stimulation in relation to the state of Th cell and B cell activation. For all experiments, cells from b2AR knockout mice will be used to confirm findings obtained from cells of normal mice. These studies will provide not only insight into the mechanisms important to homeostatic regulation by norepinephrine of the Th cell-dependent antibody response, but also insight into the rational development of approaches by which changes in antibody production associated with immune and nervous system diseases can be prevented and reversed.

描述（申请人摘要）：我们的长期目标是了解 一种机制，通过这种机制， 免疫系统和交感神经系统，以及 这种通讯联系的中断影响免疫的机制 体内平衡交感神经纤维释放去甲肾上腺素 在免疫反应过程中淋巴器官与肾上腺素能受体结合， 免疫细胞上表达的受体。实验室的结果显示 B细胞和CD 4+辅助性T（Th）-1细胞克隆表达可检测的 β-2-肾上腺素能受体（b2 AR）蛋白和mRNA水平，而 Th 2细胞的克隆则没有。我们的研究结果还表明，b2 AR刺激 在B细胞上，而不是在Th 2细胞上，增加B细胞的频率 通过免疫细胞化学方法分化为IgM、IgG 1和IgE分泌细胞。 似乎涉及b2 AR诱导的B7-2增加的机制 在B细胞上表达。相反，Th 1细胞上的b2 AR刺激 似乎在增加B的频率方面起着更关键的作用 分化为IgG 2a分泌细胞的细胞。然而，在这两个 Th 1和Th 2细胞依赖性抗体应答，出现增强 依赖于b2 AR时细胞的激活状态 刺激.这些发现使我们提出了一个假设， 去甲肾上腺素刺激淋巴细胞上的b2 AR对于 诱导针对Th细胞依赖性免疫应答的最大抗体产生， 抗原的本研究的具体目标是：1）确定 淋巴细胞上b2 AR的存在对于去甲肾上腺素 为了增强抗体反应，使用了b2 AR基因 （2）确定责任机制; 通过测试B细胞活性是否增加来增强抗体 通过刺激B细胞上的b2 AR直接诱导和/或诱导 间接通过影响Th细胞活性的B细胞和/或通过b2 AR 刺激Th 1细胞;和3）确定 抗体增强作用受b2 AR刺激时间的影响 与Th细胞和B细胞活化状态有关。为所有 实验中，来自b2 AR敲除小鼠的细胞将用于确认 从正常小鼠的细胞中获得的结果。这些研究将提供 不仅深入了解了体内平衡调节的重要机制， 由去甲肾上腺素引起的Th细胞依赖性抗体反应， 深入了解合理发展的办法， 与免疫和神经系统疾病相关的抗体产生 可以预防和逆转。