Department of Medical Microbiology and Immunology, Neuroscience Program, 2078 Graves Hall, 333 West Tenth Avenue, The Ohio State University College of Medicine, Columbus, Ohio 43210-1239 USA
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.
