Gene Changes Linked To Deficient Immune Suppression In MS
06/24/05 Portland, Ore.OHSU scientists say low FOXP3 means fewer disease-fighting cells, but new drug may help.
Oregon Health & Science University researchers have measured genetic changes reflecting a drop in the body's ability to suppress inflammatory cells that attack nerve fibers and promote progression of multiple sclerosis.
In a study published in the July issue of the Journal of Neuroscience Research, OHSU scientists, in collaboration with The Immune Response Corp. of Carlsbad, Calif., found that MS patients have lower expression of the FOXP3 gene found in a subset of T-cells that may regulate defense against MS and other autoimmune diseases, such as diabetes and arthritis. They say that when FOXP3 is reduced due to abnormalities in its expression, the suppressive activity of regulatory T-cells, or T-regs, also plummets.
"This is an important marker," said Arthur Vandenbark, Ph.D., professor of neurology and molecular microbiology and immunology, OHSU School of Medicine, and senior research career scientist at the Portland Veterans Affairs Medical Center. "This is the first publication that links FOXP3 with reduced suppression in MS."
But there may be a solution to the FOXP3 loss. NeuroVax, a T-cell receptor peptide vaccine co-discovered by Vandenbark and colleagues at The Immune Response Corp., was shown in a separate study to increase FOXP3 expression levels among MS patients receiving injections of the drug for a year.
"When we vaccinate with the T-cell receptor peptides - the NeuroVax - we can restore the FOXP3 levels," said Vandenbark, who presented the results of the NeuroVax and Journal of Neuroscience Research studies to the European Neurological Society this week in Vienna. "So not only have we identified the marker to show that there are fewer of these T-reg cells present in MS patients, but we're providing a solution for correcting the problem, at least in some patients."
Added Richard Bartholomew, Ph.D., executive director of research and development for The Immune Response Corp. and a study co-author: "What we think NeuroVax is doing is stimulating regulatory T-cells that then down-regulate proliferation of the pathogenic T-cells. The link between FOXP3 and T-regs is quite important to our program."
T-cells are white blood cells produced by the human body to defend against infection. Scientists believe a sub-group of "pathogenic" T-cells cause MS by attacking myelin, the fatty sheath insulating nerve fibers in the brain and spinal cord. As a result, the fibers can't conduct impulses, leading to such chronic neurological symptoms as memory loss, dizziness, fatigue, depression, bladder dysfunction, vision problems, pain and imbalance.
Studies in the last decade have confirmed that T-reg cells provide a control mechanism that prevents expansion of autoimmune T-cells, including those that target myelin within the brain and spinal cord. But only recently have scientists begun recognizing the direct involvement of T-regs in suppressing pathogenic T-cells. "There has been no specific marker for them," Vandenbark said.
For the Journal of Neuroscience Research study, researchers compared the blood of 19 healthy donors, including 15 women and four men ages 22 to 61, with that of 19 MS patients, including 16 women and three men ages 23 to 61. The MS patients had relapsing-remitting, primary progressive or secondary progressive MS and were not receiving any treatments for the disease at sampling time. The CD4+ and CD25+ T-regs isolated from the MS patients were found to contain abnormalities in FOXP3 mRNA and protein expression as well as reductions in suppressive activity.
FOXP3 has been shown in several studies to be an unequivocal marker for T-reg cell function - mice and humans lacking the gene are susceptible to a fatal autoimmune lymphoma. But no studies have, until now, shown that the drop in suppression by T-regs was connected to FOXP3 gene expression.
"You can't live without the FOXP3-positive cell, so we're talking about a degree of expression" in MS patients, Vandenbark pointed out. But questions remain. "How much is enough, how does that pair with the loss of regulation of pathogenic cells and how long does it take things to happen?"
And what effect does a specific FOXP3 mutation have on suppression? Geneticists have mapped about 50 mutations that lead to the FOXP3 gene's malfunction, Vandenbark noted.
"Any of them that knocks out the FOXP3 gene is a lethal mutation that causes infants to develop a spectrum of different autoimmune disorders," he said. "In MS, the FOXP3 gene is present, but it is not expressed at a level sufficient to maintain a normal level of immune regulation. NeuroVax appears to correct this problem. The interesting thing about T-reg cells is that they're not very specific. They will, for example, inhibit through cell-cell contact any CD4-positive cell that's in the process of being activated to attack self tissue. Thus, the T-reg cells may also be important in regulating inflammatory T-cells that contribute to other autoimmune diseases besides MS."
Vandenbark said future studies will continue to evaluate the effects of therapies such as NeuroVax known to influence FOXP3 expression and T-reg cell function.
According to the National MS Society, MS affects an estimated 400,000 Americans, and some 200 people are diagnosed with the disease each week. About 2.5 million people worldwide are believed to have MS.
The Journal for Neuroscience Research study was funded by the Immune Tolerance Network, The Immune Response Corp., the National Institutes of Health, the National MS Society, the Nancy Davis MS Center Without Walls and the U.S. Department of Veterans Affairs.
Dr. Vandenbark has a significant financial interest in The Immune Response Corp., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest was reviewed and a management plan implemented by the OHSU and VAMC Conflict of Interest in Research Committees.