Gender-dependent IL-12 secretion by APC is regulated by IL-10.

Female SJL mice preferentially mount Th1-immune responses and are susceptible to the active induction of experimental allergic encephalomyelitis. By contrast, young adult male SJL are resistant to experimental allergic encephalomyelitis due to an APC-dependent induction of Th2 cells. The basis for this gender-dependent differential T cell induction was examined by analysis of macrophage APC cytokine secretion during T cell activation. APC derived from females secrete IL-12, but not IL-10, during T cell activation. By contrast, APC derived from males secrete IL-10, but not IL-12, during T cell activation. Activation of T cells with APC derived from the opposite sex demonstrated that these cytokines were derived from the respective APC populations. Furthermore, inhibition of IL-10, but not TGF-beta, during T cell activation resulted in the secretion of IL-12 by male-derived APC. APC from naive male mice, in which IL-10 was reduced in vivo before isolation, also secrete IL-12, demonstrating altered APC cytokine secretion was due to an environment high in IL-10 before Ag encounter. Finally, APC derived from castrated male mice preferentially secrete IL-12 during T cell activation. These data demonstrate a link between gonadal hormones and APC activity and suggest that these hormones alter the APC, thereby influencing cytokine secretion during initial T cell activation.

Neuroendocrine modulation of chronic relapsing experimental autoimmune encephalomyelitis: a critical role for the hypothalamic-pituitary-adrenal axis.

Murine relapsing EAE can be profoundly suppressed by restraint stress (RST) administered beginning prior to neuroantigen immunization. This study determined what hormone pathway(s) mediate disease suppression. Our results showed that nadolol (NAD), a beta2-adrenergic antagonist, did not reverse the RST-induced suppression of EAE. However, administration of either RU486 or aminoglutethimide, which block the action of peripheral glucocorticoids, resulted in a partial reversal of EAE suppression. Administration of exogenous corticosterone mimicked the effects of RST, in terms of suppression of EAE, decrease in lymphoid cell numbers and decrease in Thl cytokine production. Therefore, the HPA axis plays a more profound role in the RST-induced suppression of EAE than does the sympathetic nervous system.

Neuroendocrine influences on experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is an inflammatory disease of the CNS mediated by autoreactive T lymphocytes directed against the neuroantigen, myelin basic protein (MBP). EAE is inducible in the Lewis rat, which exhibits an acute monophasic disease, and in selected mouse strains, which show a remitting-relapsing or chronic course of paralysis. We examined the effects of neuroendocrine modulation by restraint stress on these models of EAE. In Lewis rats, daily cycles of restraint resulted in significant suppression of both clinical and histopathologic changes of EAE. Suppression of EAE was more pronounced in the female than in the male rat, which follows from the higher endogenous corticosterone levels in the female. Mechanistic studies suggested that stress affected the processing of MBP or the T-cell idiotype. In the relapsing murine model of EAE, B10.PL mice were restrained beginning either before MBP challenge or after the establishment of relapsing disease. We observed a striking inhibition of EAE clinical signs in mice stressed before challenge relative to nonstressed controls. Interestingly, approximately 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Stress administered after relapsing EAE was established had no protective effect. In vitro parameters revealed that only stress initiated before disease induction significantly reduced the frequency of MBP-specific lymphocytes in the spleen and lymph nodes. Both Th1 and Th2 cytokine responses were suppressed in stressed mice. T-cell receptor transgenic mice exposed to restraint showed a marked decreased in the number and functional activity of transgene-positive lymphocytes. In summary, elevated levels of endogenous neuroendocrine hormones exert a profoundly suppressive effect on both acute and chronic models of autoimmune CNS injury.