NEUROMODULATION OF THE ANTIBODY RESPONSE

抗体反应的神经调节

• 批准号: 6570490
• 负责人: VIRGINIA M SANDERS
• 金额: $ 16.22万
• 依托单位: OHIO STATE UNIVERSITY
• 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/6570490
• 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，通过该机制可以在两个 免疫系统和交感神经系统，以及 此通信链路中断影响免疫力的机制 动态平衡。交感神经纤维在体内释放去甲肾上腺素 免疫反应中的淋巴器官与肾上腺素能结合 免疫细胞上的受体表达。这个实验室的发现表明 B细胞和CD4+T辅助细胞(Th)-1细胞克隆表达可检测 β2肾上腺素能受体(B2AR)蛋白和mRNA的水平，而 Th2细胞的克隆则不能。我们的结果还表明，B2AR刺激 在B细胞上，而不是Th2细胞上，增加了B细胞的频率 通过一种细胞因子分化为分泌IgM、IgG1和IgE的细胞 似乎涉及B2AR诱导B7-2增加的机制 B细胞上的表达。相比之下，B2AR对Th1细胞的刺激 似乎在增加B的频率方面起到了更关键的作用 分化为IgG2a分泌细胞的细胞。然而，在这两种情况下 Th1和Th2细胞依赖性抗体反应增强 取决于B2AR时细胞的激活状态 刺激。这些发现使我们提出了这样的假设 去甲肾上腺素对淋巴细胞B2AR的刺激是 诱导针对Th细胞依赖的最大抗体产生 抗原。这项研究的具体目标将是：1)确定 淋巴细胞上B2AR的存在是去甲肾上腺素所必需的 利用携带B2AR基因的小鼠增强抗体应答 已经中断；2)确定导致 通过检测B细胞活性的增加是否 由B2AR刺激B细胞直接诱导和/或诱导 间接通过B细胞影响Th细胞活性和/或通过B2AR 刺激Th1细胞；3)确定其作用机制。 抗体增强受B2AR刺激时间的影响 与Th细胞和B细胞的活化状态有关。为所有人 实验中，B2AR基因敲除小鼠的细胞将被用来证实 从正常小鼠的细胞中获得的发现。这些研究将提供 不仅洞察对动态平衡调节很重要的机制 由去甲肾上腺素引起的Th细胞依赖性抗体反应，也 洞察理性发展的方法，通过这些方法改变 与免疫和神经系统疾病相关的抗体产生 是可以预防和逆转的。