Abstract: Less well established alternative neuromodulatory pathways are neuropeptide-mediated axon reflexes of sensory neurons, gut immunotrafficing, gut transmucosal transport of endogenous bacterial toxin, and the direct secretion of immunoregulatory cytokines by the brain. TNF-α and IL-1ra enter peripheral blood after their intracerebroventricular (i.c.v.) injection. Closed head injury or stroke increases blood IL-6 and the acute phase response; neuroblastomas immunosuppress by secreting TGF-β. The IL-6 that appears in the blood after i.c.v. IL-1 in the rat is partly derived by secretion from the brain into the superior sagital sinus (Romero et al.; 1996. Am. J. Physiol. 270: R518) and is not dependent on peripheral sympathetic activation. Central endothelium and choroid plexus are potential sources of sagital sinus IL-6. TNF-α, which appears in blood after i.c.v. LPS, but not IL-1β, is due largely to toxin leaving the brain compartment and activating peripheral immunoreactive tissues. Antigens and cytokine immunoregulators drain into cervical lymph. Changes in glial milieu induced by intrinsic neuronal activity could by secretion from brain to blood modulate peripheral immunoreactivity.