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.
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.
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