VIP--A MEDIATOR OF NEUROIMMUNE INTERACTIONS

VIP——神经免疫相互作用的中介者

• 批准号: 2887556
• 负责人: Doina Ganea
• 金额: $ 16.27万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887556
• 关键词: animal genetic material tag; cytotoxic T lymphocyte; drug receptors; gene induction /repression; hormone receptor; hormone regulation /control mechanism; interleukin 2; interleukin 4; laboratory mouse; leukocyte activation /transformation; neuroimmunomodulation; neuropeptide receptor; polymerase chain reaction; receptor expression; tissue /cell culture; transcription factor; vasoactive intestinal peptide

DESCRIPTION (Applicant's abstract): Experimental and clinical observations suggest a functional crosstalk between the nervous and the immune system, largely mediated through shared ligands and receptors. Cytokines generated or gaining access to the CNS regulate the growth, survival, an d function of the CNS cells. Conversely, neuropeptides/ neurotransmitters released or produced within the lymphoid organs may regulate the function of immune cells. Previous studies reported in vitro immuno-modulation by neuropeptides. Several reports, including Dr Ganea's studies, indicate that some neuropeptides such as substance P stimulate immune functions, whereas other neuropeptides such as the vasoactive intestinal peptide (VIP) exert primarily an anti-inflammatory action. The in vitro anti-inflammatory role of VIP is supported by clinical data, which indicate an association of low VIP levels with highly reactive immune responses, and of high VIP levels with certain immunodeficiencies. Although several authors reported effects of VIP on immune responses little is known about the VIP immunomodulatory role in vivo, the regulation of VIP and VIP receptor expression in immune cells, and about the molecular mechanisms involved in VIP immunomodulation. Dr Ganea's studies indicate that VIP and the pituitary adenylate cyclase-activating polypeptide (PACAP), a recently discovered VIP-related neuropeptide, inhibit the production of selected cytokines such as IL-2 and IL-4 by unprimed CD4+ T cells stimulated in vitro through the T cell receptor. We hypothesize that antigenic stimulation upregulates VIP production and/or VIP receptor expression in vivo within the lymphoid organs, and that VIP/VIP-R interactions inhibit CD4+ T cell proliferation and cytokine production. In Specific Aim A we propose to examine whether antigenic stimulation induces VIP release in vivo, and whether antigen-stimulated CD4+ T cells function as VIP sources. In Specific Aim B we propose to study the regulation of VIP-R1 and VIP-R2 expression in antigen-stimulated CD4+ T cells and T cell lines, and the involvement of these receptors in mediating the inhibitory effect of VIP/PACAP on IL-2 production. In Specific Aim C we propose to investigate the nature of the VIP cellular targets, and the molecular mechanisms, including the transduction pathways and transcriptional factors involved in the inhibitory effect of VIP/PACAP on IL-2 gene expression. The establishment of VIP and related neuropeptides as active participants in limiting a normal immune response and therefore preventing excessive tissue damage, and the elucidation of the molecular mechanisms involved, could have significant therapeutical consequences, particularly in autoimmune diseases.

描述（申请人的摘要）：实验和临床观察 建议在神经和免疫系统之间进行功能性串扰， 在很大程度上是通过共享配体和受体介导的。 细胞因子产生 或获得CNS的访问权限调节生长，生存和D的功能 中枢神经系统细胞。 相反，神经肽/神经递质释放或 在淋巴机器人器官内产生的可能调节免疫功能 细胞。 先前的研究报告了体外免疫调节 神经肽。 包括加尼亚博士的研究在内的几份报告表明， 某些神经肽（例如PESTANCE P）刺激免疫功能，而 其他神经肽，例如血管活性肠肽（VIP） 主要是一种抗炎作用。 体外抗炎作用 VIP的临床数据支持，这表明低相关 具有高反应性免疫反应和高VIP水平的VIP水平 具有某些免疫缺陷。 尽管有几位作者报道了影响 VIP关于免疫反应的VIP对VIP免疫调节知之甚少 在体内的作用，VIP和VIP受体表达在免疫中的调节 细胞，以及参与VIP免疫调节的分子机制。 Ganea博士的研究表明，VIP和垂体腺苷酸盐 循环酶激活多肽（PACAP），最近发现的VIP相关 神经肽，抑制所选细胞因子（例如IL-2和）的产生 IL-4通过未灌注的CD4+ T细胞在体外通过T细胞刺激 受体。 我们假设抗原刺激上调了VIP 在淋巴机内的体内产生和/或VIP受体表达 器官，该VIP/VIP-R相互作用抑制CD4+ T细胞增殖 和细胞因子产生。 在特定目的A中，我们建议检查是否 抗原刺激在体内诱导VIP释放，以及是否是否 抗原刺激的CD4+ T细胞充当VIP来源。 在特定的目标b中 我们建议研究在VIP-R1和VIP-R2表达中的调节 抗原刺激的CD4+ T细胞和T细胞系，以及参与 这些受体介导VIP/PACAP对IL-2的抑制作用 生产。 在特定的目的C中，我们建议调查 VIP细胞靶标和分子机制，包括 抑制性的转导途径和转录因子 VIP/PACAP对IL-2基因表达的影响。 建立VIP和 相关的神经肽作为活跃参与者限制正常免疫 反应，因此防止组织过度损害，并 阐明所涉及的分子机制，可能具有显着的 治疗后果，特别是在自身免疫性疾病中。