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.