May 18, 1998 St. Louis, May 13, 1998 -- Scientists have identified a protein that may trigger the friendly fire that damages nerves in multiple sclerosis (MS). They hope that part of this protein eventually may be useful for therapy.
Immune system cells of MS patients attack the insulating coating around nerve cells in the brain and spinal cord, creating bare patches and scars. Like damaged electrical wires, these nerve cells are unable to transmit impulses efficiently, so patients develop sensory and muscle problems. The coating, called myelin, is made of lipids and proteins.
"For years, researchers have been looking for something in myelin that is more visible to the immune system in MS patients than in healthy people " such a component is likely to be central to the disease," says John L. Trotter, M.D., the Gordon R. and Thelma B. Coates Scholar and professor of neurology at Washington University School of Medicine in St. Louis. "This is the first report of such a substance."
The researchers published their findings in the April issue of the Journal of Neuroimmunology, which will appear mid-May. Trotter is lead author.
Except for trauma, multiple sclerosis is the most common cause of neurological disability among young adults, affecting 250,000 to 350,000 Americans. Depending on where the immune cells attack, the disorder can affect movement, sensation, bladder and bowel control, sexual performance, vision and many other functions.
For the past 40 years, scientists have focused on a myelin component called myelin basic protein, which causes an MS-like disease when injected into animals. But in the 1970s, Trotter became interested in another constituent called myelin proteolipid protein (PLP). It accounts for about half of the protein in myelin and, when injected, also gives animals MS symptoms, Trotter has shown. The protein has been largely ignored, however, because it doesn't dissolve in water and therefore is hard to study.
In 1991, Trotter's group was the first to show that human white blood cells or lymphocytes recognize PLP. These cells normally recognize host cells that are infected with foreign proteins such as viral components. They then proliferate, generating more T cells that recognize and destroy virus-infected cells. But in multiple sclerosis and other autoimmune disorders, T cells misidentify and attack normal tissue, like soldiers attacking their own.
In the current study, Trotter and colleagues isolated T cells from 12 MS patients. They cultured the cells and exposed them to short strings of amino acids or peptides. These peptides were identical to various parts of the PLP molecule. If the T cells recognized a particular peptide, they proliferated. In this way, the researchers were able to identify three peptides that were familiar to most of the T cells.
They then looked for T cells that recognized these peptides in blood samples from the 12 patients and from 12 people who did not have multiple sclerosis. They found that the T cell that recognized one of the peptides -- corresponding to amino acids 95 to 117 of PLP -- was at least four times more common in the patients' blood. "There also were enough of these T cells to cause disease," Trotter says.
In contrast, the immune cells of MS patients do not recognize myelin basic protein more frequently than those of people without MS.
The researchers now will isolate T cells that recognize the 95 to 117 peptide. Then they will modify the peptide so it binds to these cells without making them divide.
This peptide would be a promising drug candidate because, with their recognition sites blocked, the T cells that attack PLP might be unable to bind to and destroy myelin. Patients therefore might remain in remission. "We would like to perform a pilot study in five to six years," Trotter says.
A grant from the National Institute of Neurological Disorders and Stroke supported this research.
Trotter JL, Pelfrey CM, Trotter AL, Selvidge JA, Gushleff KC, Mohanakumar T, McFarland HF. T cell recognition of myelin proteolipid protein (PLP) and PLP peptides in the peripheral blood of MS and control subjects. Journal of Neuroimmunology 84(2), 172-178.
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