PSYCHONEUROIMMUNOLOGY--INNERVATION & AUTOIMMUNE DISEASE

心理神经免疫学--神经支配

基本信息

批准号：
2033909
负责人：
DIANNE LORTON
金额：
$ 15.27万
依托单位：
BANNER SUN HEALTH RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 1997-10-31
项目状态：
已结题

项目摘要

Extensive studies from our laboratories have shown the presence of noradrenergic (NA) and substance P (SP) innervation of lymphoid organs. Numerous studies have reported that these neuro-transmitters can modulate immune functions. Conversely, Besedovsky and coworkers have shown that an immune response can alter neurotransmitter levels in reacting target lymphoid organs. We, and others, have evidence to support a role for NA and SP innervation of lymphoid organs in age-related immuno-suppression, and a variety of autoimmune disease models, such as experimental adjuvant- induced arthritis (EA). Both clinical studies of rheumatoid arthritis (RA) and experimental evidence of EA indicate involvement of NA and SP innervation in the pathophysiology of this disease. Clinical findings which are consistent with nervous system involvement in RA include: (1) a symmetric distribution of synovitis; (2) hemiplegic patients who later develop RA are spared the inflammatory process in joints on the paretic side; and (3) onset and exacerbation of the disease are often preceded by psychological trauma. It is well documented that NE and SP can modulate chronic inflammatory response and degree of destruction in the joints associated with RA and EA. Many experimental studies have employed systemic methods of denervation to demonstrate a role for these neurotransmitter systems, which would denervate several potential sites of action for these transmitters, including the joint, primary and secondary lymphoid organs, and central outflow to autonomic ganglia. Recently our laboratory has revealed that SP innervation of draining lymph nodes (LNs) is necessary for full expression of EA. This proposal further investigates the influence of NA and SP innervation of draining LNs in development and severity of EA in Lewis rats. Specifically, we propose to examine: (1) the effect of regional denervation of SP or NA innervation of popliteal and inguinal LNs on the expression of EA using chemical denervation, neurochemical analysis of SP and NE and assessing the time of onset, progression, and severity of EA in Lewis rats; and (2) the effect of EA and local inflammatory responses on NA and SP innervation of draining LNs, and subsequent immune responses in LNs, using double-label immunocytochemistry, neurochemical analysis of SP and NE, and beta-adrenoceptor and SP receptor binding assays. Functional studies will examine immuno-responsiveness of EA rats for correlation with neurochemical and anatomical measures of SP and NA innervation. These studies will provide a better understanding of the feedback circuitry involved in the development of EA, the functional consequences of EA in secondary lymphoid organs, and the role of SP and NA innervation during this disease processes. The ultimate significance of such studies lies in use of in vivo pharmacologic manipulation of neurotransmitters or neuromodulators that innervate lymphoid tissue, as a means of altering immune function and host defense, and the possible implications for development of therapeutive approaches for intervention of autoimmune diseases, such as RA.

我们实验室的广泛研究表明甲肾上腺素能（Na）和P（SP）淋巴器官的神经支配。许多研究报告说，这些神经递质可以调节免疫功能。相反，贝斯多夫斯基和同事表明免疫反应可以改变反应靶点的神经递质水平淋巴器官。我们和其他人都有证据支持NA的角色淋巴机器人在与年龄有关的免疫抑制中的SP神经支配，以及多种自身免疫性疾病模型，例如实验辅助 - 诱导关节炎（EA）。类风湿关节炎（RA）的两项临床研究 EA的实验证据表明NA和SP的参与这种疾病的病理生理学神经。临床发现与神经系统参与RA一致的包括：（1）a 滑膜炎的对称分布；（2）偏瘫患者后来发育ra在偏to的关节中幸免于炎症过程边; （3）疾病的发作和加剧通常是在心理创伤。有充分的文献证明NE和SP可以调节慢性炎症反应和关节破坏程度与RA和EA相关。许多实验研究已经采用全身去神经的方法来证明这些作用神经递质系统，它将取消几个潜在地点这些发射器的作用，包括关节，主要和次级淋巴器官，中心流向自主神经节。最近我们的实验室表明，淋巴结淋巴结（LNS）的SP神经对于完全表达EA是必要的。该提案进一步调查了 NA和SP神经在发育中排水LN的影响以及刘易斯大鼠EA的严重程度。具体而言，我们建议检查：（1） popliteal和使用化学神经保护的腹股沟LN在EA表达上， SP和NE的神经化学分析，并评估发作时间刘易斯大鼠的EA的进展和严重程度；（2）EA和EA的影响局部炎症反应对排水LN的Na和SP神经支配，以及随后使用双标签免疫细胞化学的LN中的免疫反应， SP和NE的神经化学分析，以及β-肾上腺素受体和SP受体绑定测定。功能研究将检查的免疫反应性 EA大鼠与SP的神经化学和解剖学度量相关和NA神经。这些研究将提供更好的理解 EA的发展，功能性的反馈电路 EA在继发性淋巴机构中的后果以及SP和Na的作用在这种疾病过程中的神经。最终意义的这样的研究在于使用体内药理操作神经递质的神经递质或神经调节剂，将淋巴组织神经化，作为A 改变免疫功能和宿主防御的手段，并可能对开发治疗方法的影响自身免疫性疾病，例如RA。