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.
SummaryReasons for performing the study: Hypothalamic-pituitary-thyroid (HPT) axis dysfunction is associated with morbidity and mortality in critically ill people. To date, investigations of HPT axis in critically ill foals are limited. Objectives: To document the occurrence of low thyroid hormone concentrations (presumptive nonthyroidal illness syndrome; NTIS) in critically ill newborn foals and investigate whether NTIS is associated with severity of disease and outcome. Hypothesis: NTIS occurs frequently in foals with sepsis and is associated with sepsis score and outcome. Reverse T3 (rT3) concentrations will be increased in septic foals and highest in nonsurvivors. Methods: Thyroid hormones (total and free thyroxine [TT4 and fT4], total and free tri-iodothyronine [TT3 and fT3], reverse T3 [rT3]) were prospectively measured in healthy, sick nonseptic and septic foals. Clinical and laboratory information was retrieved from the medical records. Hormones were measured by validated radioimmunoassays. Results: Concentrations of all thyroid hormones except rT3 (P = 0.69) were decreased in septic and sick nonseptic foals (P<0.01). Reductions in hormone concentrations were associated with an increased sepsis score (P<0.01). Nonsurviving septic foals had lower TT4, fT4, TT3 and fT3 concentrations than surviving septic foals (P<0.01). rT3 concentrations were higher in nonsurviving septic premature foals than surviving septic premature foals (P<0.05). Conclusions: NTIS (euthyroid sick syndrome) is frequently observed in critically ill and premature foals, and associated with severity of disease and mortality. Potential relevance: More research is needed to better understand the mechanism of this finding and determine whether manipulation of the HPT axis or thyroid replacement therapy could be beneficial.
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