Researchers around the world continue knitting together connections between
the immune system, the brain, and psychiatric disorders.
Several streams of thought over the last two decades have contributed to a
more solid understanding of those complex interrelationships, said Esther
Sternberg, M.D., chief of the Section on Neuroendocrine Immunology and
Behavior at the National Institute of Mental Health.
"One area is the study of autoimmune diseases in the brain, like
multiple sclerosis, vasculitis, and lupus," said Sternberg in an
interview with Psychiatric News.
For a long time, it was believed that immunological response to central
nervous system injury was a leading agent in the death of nerve cells, she
said. Today that picture is more complex. In the right circumstances, immune
molecules and immune cells can help prevent cell death, depending on the
extent and timing of the stimulus to the immune system relative to the
A second track explores sickness behavior. The withdrawal, loss of
appetite, impaired cognition, and changes in mood that accompany fever are
caused by the immune response to it and mimic depression, said Sternberg.
A recent test in an animal model used a vaccine to immunize rats against
analogues of depression. It provides the "first demonstration that
immune activity could be harnessed in a safe and efficient manner to treat
depression," reported Michal Schwartz, Ph.D., a professor of
neurobiology at the Weizmann Institute of Science in Rehovot, Israel, and
colleagues in the February 15 Biological Psychiatry.
The results "open a whole new set of molecular targets" for
possible treatments, said Sternberg. "This is the most exciting area of
research into depression."
The research grew out of Schwartz's earlier work on spinal-cord damage, in
which she observed that sensitized T cells generated by injury could either
damage or protect neurons, depending on when they were activated.
Still other work indicated that auto-reactive T cells help protect injured
central nervous system tissue, maintain hippocampal neurogenesis, and increase
expression of brain-derived neurotrophic factor (BDNF).
The researchers vaccinated rats with altered myelin basic protein peptide
(A91), chosen because it was already known to activate T cells.
Just as vaccines that prevent infectious diseases use attenuated viruses to
stimulate the body's defenses, Schwartz and colleagues used this weakened
agonist to stimulate T cells but not make the immune system overreact and
cause autoimmune disease in brain neurons.
To begin with, immunization proved to have no effect on naïve,
Next, Lewis rats (a type frequently used to study autoimmune diseases) were
stressed with a varying mix of strobe lights, intermittent white noise, food
or water deprivation, a cage tilt of 45 degrees, and other stimuli. This
chronic mild stress caused a reduction in two measures of behavior analogous
to depressive symptoms: sucrose preference—considered a measure of
anhedonia—and reduced mobility in the forced swim test—a test of
Control rats were injected with a saline solution. Immunized Lewis rats
showed a higher sucrose preference compared with that of controls, but no
improvement in the forced swim test.
Since Lewis rats have a blunted HPA-axis response to stress, the
researchers then repeated the experiment with Sprague-Dawley rats, more
commonly used in tests of chronic mild stress. In this group, immunized
animals had significantly better scores on both the sucrose preference and
forced swim tests than did control rats. However, both groups did equally well
on other tests of movement in the home-cage or a novel environment, indicating
lessened motivation by the saline-injected control animals but not reduced
basic locomotor activity, Schwartz said.
The researchers also examined the rats' brains to observe the levels of
BDNF in the dentate gyrus of the hippocampus. Hippocampal BDNF and
neurogenesis are known to decrease following chronic mild stress, but stressed
rats immunized with A91 had significantly higher levels of BDNF and more cell
proliferation than controls.
This finding may further explain the observation in humans that
antidepressant drugs take several weeks to work because their effect depends
on growth of new neurons in the hippocampus.
Both Schwartz and colleagues and Sternberg acknowledged that a good deal of
refinement will be needed to turn these initial results into therapy.
"In terms of a proof-of-principle, it is a well-designed
trial," said Sternberg. "The question is not if it works. It does,
but a lot more work needs to be done before immunization could be used for
"Further studies are necessary to identify the best antigen, regimen,
timing, and carrier capable of providing the most effective and risk-free
therapeutic vaccination for the protection against chronic stress that often
leads to depression," the authors concluded.
An abstract of "Vaccination as a Novel Approach for Treating
Depressive Behavior" is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223(08)00832-9/abstract>.▪