Scientific American: T Cells for Brain Cells

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January 02, 2006





T Cells for Brain Cells





Can Autoimmunity fend off Neurodegeneration?





By JR Minkel



In 2002 a clinical trial of an experimental Alzheimer's vaccine was

halted when a few patients began experiencing brain inflammation, a

result of the immune system mounting an attack against the body. Now

some researchers claim that inducing a mild autoimmune reaction could

actually protect the central nervous system from a spectrum of

neurodegenerative conditions, from glaucoma and spinal cord injury to

Parkinson's and Alzheimer's disease. " This is a hot-button issue

right now, " says Gendelman of the University of Nebraska

Medical Center in Omaha.

It all started with glaucoma. Once thought to result primarily from

high pressure in the eyeball constricting the optic nerve, the

disease has lately come to be seen as a form of neurodegeneration,

propagating from the injured optic nerve to healthy cells in the

brain. Before monkey studies had demonstrated as much,

neuroimmunologist Michal Schwartz of the Weizmann Institute in

Rehovot, Israel, observed in the late 1990s that crushing a small

portion of a rat optic nerve creates a large zone of sickened cells.

She and her team also found that T cells, the immune system's

attackers, gathered at these wounds.

Curious if the small accumulation was helpful or hurtful, the

researchers injected different types of T cells into rats with optic

nerve injury. Surprisingly, rats given T cells specific to myelin,

the fatty sheath coating neurons, retained three times as many

functional retinal ganglion cells as rats injected with other T

cells. In subsequent experiments, rats genetically engineered to lack

T cells, as well as rats insensitive to myelin autoimmune reactions,

fared worse in glaucoma models than normal rats did.

Introducing antimyelin T cells to people would most likely cause

brain inflammation, so Schwartz looked for a compound that would

induce a weaker reaction. Copaxone, a peptide drug approved for the

treatment of multiple sclerosis, fit the bill because the body's

immune response against it also weakly targets myelin. And indeed,

rodents vaccinated with Copaxone after insults to their optic nerves

retained more retinal ganglion cells than untreated animals did.

Schwartz argues that the effect exploits a natural " protective

autoimmunity " and has championed it as a more general measure for

protecting the brain from disease. Too much autoimmunity causes brain

disease, but too little may exacerbate the gamut of neurodegenerative

conditions, she asserts. " It's a beautiful hypothesis, " remarks

Hartmut Wekerle of the Max Planck Institute for Neurobiology in

sried, Germany, but one that has split neuroimmunologists. " I

think Schwartz's theory is right because it's been shown in a number

of animal models, " says Weiner of the Center of Neurologic

Diseases at the Brig ham and Women's Hospital in Boston. " There's a

reasonable chance it'll work in humans. " In further support,

Gendelman's group reported in 2004 that transferring Copaxone-

specific immune cells to mice protects neurons in a model of

Parkinson's disease.

The evidence is mixed, however. Spinal cord researcher

Popovich of Ohio State University has been unable to mimic results

from Schwartz's lab, in which transferred T cells protect spinal cord

tissue. " We get what the conventional wisdom would expect: we get

more problems, " Popovich reports. The discrepancy probably results

from subtle differences in the models employed, which implies that

the effect is not robust enough to treat spinal cord injuries, he

contends.

Mice have been cured of their versions of many diseases that still

afflict humans, notes neuropathologist V. Hugh of the

University of Southampton in England. And unlike lab rat strains,

individual people vary in their immune responses, creating the risk

that vaccination will cause harmful autoimmune reactions, as occurred

in the interrupted Alzheimer's trial. acknowledges, however,

that in some cases, " the regulation of inflammation is not as precise

as it might be. If you can induce T cells to produce anti-

inflammatory molecules, that may be a good thing. "





Gendelman sees obstacles ahead before the great potential of

protective autoimmunity, as he describes it, can be exploited. " How

this occurs is a big black box, " he says. The positive evidence has

piqued some biotech interest, though: Israel's Teva Pharmaceutical

Industries is investigating Copaxone and a similar peptide in models

of glaucoma and several other neurodegenerative conditions. If the

company moves ahead with clinical trials, that black box may open up.



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