Autonomic dysreflexia and SCI immune suppression

描述（由申请人提供）：循环糖皮质激素（GC）中的儿茶酚胺“风暴”和峰值具有免疫抑制作用，并由身体或心理应激引起。在四肢瘫痪和高位截瘫患者中，常见的是在脊髓损伤（SCI）后数周或数月出现自主神经反射异常（AD）的复发。AD是一种严重的生理应激，可引起去甲肾上腺素（NE）和GC释放的显著失调。这可能解释了为什么高水平SCI患者表现出全身免疫抑制的迹象，并且感染的风险增加。AD的免疫抑制作用也会使旨在增强宿主防御的预防性疫苗的效力最小化或阻断。本申请将测试新的假设，即AD是SCI后免疫抑制的有效和复发机制。提出了两个具体目标来检验这一假设。在这两个目标中，小鼠将接受高水平（T3）或低水平（T9）SCI。在目标1中，我们将比较经历自发性AD的T3 SCI小鼠和未发展AD的T9 SCI小鼠之间的免疫功能。我们将通过遥测血压监测来监测清醒、自由活动动物的AD发作。AD的频率和持续时间将根据之前24小时内获得的BP描记确定。对于在前24小时内发生至少两次AD发作的小鼠，将采集血液以测量循环抗体和白细胞。将收集来自T9 SCI小鼠的时间匹配的出血用于比较。我们还将使用来自脾脏的纯化淋巴细胞完成淋巴细胞功能的终末分析（42 dpi）。在目标2中，我们将有意地在T3 SCI小鼠中引发AD，然后随后用设计用于引发抗病毒或抗细菌抗体产生的预防性疫苗免疫它们。再次，将在T3和T9小鼠之间进行比较。这将测试AD是否不利地影响免疫系统对导致SCI后发病率/死亡率的病原体作出反应的能力。如果成功的话，我们将确定一个机制，潜在的特发性SCI诱导的免疫抑制和随后增加感染的易感性。此外，我们还将确定增强流感或肺炎疫苗效力的治疗靶点。 公共卫生相关性： 这项建议将确定自主神经反射异常是否会抑制免疫功能，自主神经反射异常是高位脊髓损伤患者的严重并发症。这些研究的数据将用于开发治疗人类脊髓损伤的新型临床疗法。

DESCRIPTION (provided by applicant): Catecholamine "storms" and spikes in circulating glucocorticoids (GCs) are immune suppressive and are elicited by physical or psychological stress. In tetraplegics and high-level paraplegics, it is common for recurrent bouts of autonomic dysreflexia (AD) to develop weeks or months after spinal cord injury (SCI). AD is a profound physiological stress that elicits marked dysregulated release of norepinephrine (NE) and GCs. This might explain why those with high-level SCI exhibit signs of systemic immune suppression and are at increased risk for infection. The immune suppressive effects of AD also would minimize or block the efficacy of prophylactic vaccines designed to boost host-defense. This application will test the novel hypothesis that AD is a potent and recurrent mechanism of post-SCI immune suppression. Two specific aims are proposed to test this hypothesis. In both aims, mice will receive high (T3) or low level (T9) SCI. In Aim 1, we will compare immune function between T3 SCI mice that experience spontaneous AD and T9 SCI mice that do not develop AD. We will monitor episodes of AD in awake, freely moving animals by telemetric monitoring of blood pressure. The frequency and duration of AD will be determined from BP traces obtained during the previous 24 hours. For those mice that develop at least two bouts of AD in the preceding 24 hours, blood will be collected to measure circulating antibodies and leukocytes. Time matched bleeds from T9 SCI mice will be collected for comparison. Using purified lymphocytes from spleen, we will also complete terminal analyses (42 dpi) of lymphocyte function. In Aim 2, we will intentionally trigger AD in T3 SCI mice then subsequently immunize them with prophylactic vaccines designed to elicit production of anti-viral or anti-bacterial antibodies. Again, comparisons will be made between T3 and T9 mice. This will test whether AD adversely affects the ability of the immune system to respond to pathogens that cause morbidity/mortality after SCI. If successful, we will have identified a mechanism underlying idiopathic SCI-induced immune suppression and subsequent increased susceptibility to infection. Also, we will have identified therapeutic targets for bolstering the efficacy of influenza or pneumonia vaccines. PUBLIC HEALTH RELEVANCE: This proposal will determine whether autonomic dysreflexia, a serious complication suffered by patients with high level spinal cord injury, suppresses immune function. Data from these studies will be used to develop novel clinical therapies to treat spinal cord injury in humans.