Treating Autoimmune Disease in Mice
Epitopes and Immune Response
Clinical Trials of MBP
Introduction (Back to Top)
According to a new study conducted at the Stanford University School of Medicine (Stanford, CA), treatment with portions of proteins from certain viruses and bacteria can inhibit the development of a multiple sclerosis-like autoimmune disease in susceptible mice. The research team hopes that a greater understanding of the way the peptides, or small pieces of proteins, work to inhibit autoimmunity will lead to safer, more effective treatments for people suffering from multiple sclerosis.
"We and others have shown in previous studies that viruses can trigger autoimmunity, and now we show the other side of the coin, that viruses can also protect from autoimmunity," said Lawrence Steinman, professor of neurology at the Stanford School of Medicine and lead author of the study published in the April 19 issue of the Journal of Experimental Medicine.
Multiple sclerosis is an autoimmune disease that affects some 350,000 people in the United States, and is second only to trauma as the leading cause of neurological damage in teens and young adults. The disease is caused by a malfunctioning immune response in the central nervous system. For reasons that are not fully understood, the body's immune cells begin to attack the myelin sheath that protects and isolates the neurons. Loss of myelin can cause a variety of neurological defects, including weakness, loss of coordination, and abnormalities in speech and vision that worsen as the disease progresses.
Although the exact cause of multiple sclerosis is not known, some scientists suspect the disease may be triggered by infection with a virus or bacteria whose proteins resemble an exposed part of the myelin sheath. When the body gears up to fight the infection, a few T cells are tricked into thinking the myelin is a foreign invader, and begin to destroy the vital tissue. The destruction exposes other portions of the sheath, inciting further attack by the over-zealous T cells and resulting in a deadly autoimmune cascade. Because the attacking T cells change their target over time, they eventually become less sensitive to the original infecting protein, making it difficult for researchers to pinpoint the start of the disease. Without knowing the instigating event, it is very difficult for scientists to design an appropriate therapy to inhibit the development of multiple sclerosis in humans.
But in this and previous work, the Stanford team has shown that autoimmune responses such as those that cause multiple sclerosis can be inhibited or slowed if the attacking T cells are exposed to a decoy peptide that is only slightly different from the one prompting the autoimmune response.
Treating Autoimmune Disease in Mice (Back to Top)
In their experiments, the scientists utilized a mouse disease closely resembling multiple sclerosis. When susceptible mice are injected with a cocktail of myelin-related peptides, they quickly develop experimental autoimmune encephalomyelitis, or EAE. Like multiple sclerosis in humans, EAE is characterized by loss of myelin and progressive paralysis. But when the mice were pre-exposed to similar, but not identical peptides from certain types of viruses or bacteria prior to the induction of EAE, some of them were protected from developing the disease. The degree of protection varied between individual peptides. The results with these microbial sequences correlate with the fact that some of these viruses can slow down disease progression in a patient with multiple sclerosis.
Epitopes and Immune Response (Back to Top)
There are several different pieces of myelin-related proteins that can be used to induce EAE in the susceptible mice. Previous research has identified short segments of amino acids that are recognized by specific receptors on T cells. These well-recognized segments are called epitopes, and each T cell has its favorite. When the T cell receptor sees its epitope partner on the surface of another cell, it gears up to fight the infection by dividing and secreting inflammatory factors that stimulate an active immune response. The problem in autoimmune disease is that the epitope presented belongs to one of the body's own molecules, which is unwittingly attacked by the T cell.
However, if the epitope is just slightly different than the one normally recognized, the T cell sometimes acts differently. Rather than responding to the call to action, the T cell begins to secrete alternate factors that tone down the immune response to the original epitope and prompt other immune molecules to back off. Epitopes that have this down-regulating effect are known as "altered peptide ligands," and their importance in modulating the body's immune response is just beginning to be understood.
Clinical Trials of MBP (Back to Top)
A primary epitope recognized by T cells and B cells in the brains of patients with multiple sclerosis is composed of amino acids 8799 of myelin binding protein (MBP). The characteristics and specificity of the T cell response in these patients were discovered by Steinman and Jorge Oksenberg in 1993, and were published in Nature that year.
In a previous research effort, the Steinman group used this information to modify the piece of protein so that it would function as an altered peptide ligand when presented to T cells. The National Institutes of Health is currently overseeing a phase II clinical trial of this mutated section of MBP for the treatment of multiple sclerosis.
Although the phase II trial was launched a year ago, Steinman said it is still too early to predict the results. But he believes the discovery that the microbial sequences can also have immune dampening effects is a promising sign for its success. Plus, the new idea that microbial sequences can function as altered peptide ligands should lead to greater understanding of how the immune system functions as a complex network of checks and balances to protect the body from foreign invaders.
Research Team (Back to Top)
Steinman's colleagues on the current study include fellow Stanford researchers Pedro Ruiz, Hideki Garren, David Hirscherberg, and Annette Langer-Gould. Other collaborating researchers include Mia Levite and Marcela Karpuj of the Weizman Institute of Science (Rehovot, Israel), Scott Southwood and Alessandro Sette of Epimmune Inc. (San Diego), and Paul Conlon, chief scientist at Neurocrine Biosciences (La Jolla, CA).
The phase II clinical trial is based on research conducted by Ruiz, Hirschberg, Garren, Langer-Gould, Karpuj, and Conlon. The trial is being funded by Neurocrine Biosciences, a company founded by Steinman in 1992 with technology licensed through Stanford University.
For more information, contact Lawrence Steinman, Stanford University, Stanford, CA 94305, 650-725-6401