The effects of sleep and tumour necrosis factor-Ã on the lymphatic system

grantor: University of TorontoThe scientific literature suggests that the sleeping-waking brain interacts with the immune system. In animal studies, cytokines such as TNF-α and IL-1 promote sleep and induce an acute phase proinflammatory response. In humans, levels of these cytokines in the peripheral vascular compartment are increased with nocturnal sleep vs wakefulness. Furthermore, in humans there are diurnal sleep/wake related changes in lymphocyte distribution in the peripheral vascular system. Since much of the cellular immune functions are found in the lymphatic compartment, we investigated how sleep/wakefulness relates to lymphocyte distribution and whether cytokines, e.g. TNF-α, would not only promote sleep but could also impact immune function by its drainage into the extracranial lymphatics. In the first study, we determined the influence of physiological sleep and wakefulness on lymphocyte distribution in the vascular and lymphatic compartments. Using a sheep experimental system, we identified electrophysiological sleep/wake brain states and simultaneously collected lymph and blood samples. During sleep, lymphocyte cell output and lymph flow rates decreased compared to wakefulness. There were no differences in lymphocyte distribution patterns in the blood or in the lymph between sleep and wake states. The objective of the second study was to determine whether TNF-α, a somnogenic cytokine in rats and rabbits, would induce sleep in the sheep and be transported from the CSF into the extracranial lymphatics. TNF-α induced a significant increase in slow wave sleep in the sheep at post injection hour 4 and 5. Radiolabeled TNF-α (125I-TNF-α) injected into the lateral ventricle was detected in cervical lymph within 30 minutes of administration and peaked within 2 to 3 hours. 125I-TNF-α counts were elevated in the nodes of the head and neck region. In the third study we investigated the effect of TNF-α on the efflux of protein tracer (albumin) from the CSF into the blood in rats. TNF-α injected into the lateral ventricle of the rat significantly increased tracer recovery in the venous blood. These results suggest that elevations in TNF-α in the brain increase the transfer of CSF protein into the blood. These studies show an alternative pathway by which cytokines in the CNS can influence immune function. In addition to neural and endocrine signals and the secretion of immunomodulatory cytokines into peripheral blood, this research shows that peripheral immune function may be mediated in part by cytokines draining directly into the cervical lymphaticsPh.D