Autonomic dysreflexia and SCI immune suppression

描述(由申请人提供)：儿茶酚胺“风暴”和循环糖皮质激素(GC)的峰值是免疫抑制，并由身体或心理压力引起。在四肢瘫痪和高位截瘫患者中，自主神经反射障碍(AD)在脊髓损伤(SCI)后数周或数月内反复发作是很常见的。AD是一种深刻的生理应激，可引起去甲肾上腺素(NE)和糖皮质激素(GCs)的显著失调释放。这可能解释了为什么那些患有高水平脊髓损伤的人表现出全身免疫抑制的迹象，并面临更高的感染风险。AD的免疫抑制作用也会降低或阻止旨在增强宿主防御的预防性疫苗的效果。这一应用将检验AD是脊髓损伤后免疫抑制的一种有效和反复机制的新假说。为了检验这一假说，本文提出了两个具体目标。在这两个目标中，小鼠将接受高水平(T3)或低水平(T9)的SCI。在目标1中，我们将比较经历自发性AD的T3脊髓损伤小鼠和没有发展为AD的T9脊髓损伤小鼠的免疫功能。我们将通过遥测血压监测来监测清醒的、自由活动的动物的AD发作。AD的频率和持续时间将根据在过去24小时内获得的BP轨迹来确定。对于那些在过去24小时内至少发作两次AD的小鼠，将采集血液以检测循环抗体和白细胞。将收集T9脊髓损伤小鼠的时间匹配的出血进行比较。使用从脾中提纯的淋巴细胞，我们还将完成淋巴细胞功能的终端分析(42dpi)。在目标2中，我们将故意在T3脊髓损伤小鼠中触发AD，然后用旨在诱导产生抗病毒或抗细菌抗体的预防性疫苗对它们进行免疫。同样，将在T3和T9小鼠之间进行比较。这将测试AD是否会对免疫系统对导致脊髓损伤后发病率/死亡率的病原体做出反应的能力产生不利影响。如果成功，我们将确定特发性脊髓损伤诱导的免疫抑制和随后增加感染易感性的潜在机制。此外，我们还将确定提高流感或肺炎疫苗效力的治疗目标。 公共卫生相关性： 这项提议将确定自主神经反射障碍是否会抑制免疫功能。自主神经反射障碍是高位脊髓损伤患者的严重并发症。来自这些研究的数据将被用于开发治疗人类脊髓损伤的新的临床疗法。

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.