For decades medical researchers have known that an effective way to combat multiple sclerosis (MS) would be to suppress the human immune system, since the debilitating disease is caused by the immune system 'mistakenly' attacking tissues in the spine and brain. However, this kind of treatment would cripple the body's ability to control ordinary infections, leading to more serious conditions or even death.
The ideal treatment for any autoimmune disease would preserve the immune system's ability to protect the body. In July, a team of researchers published a study in The Journal of Neuroinflammation reporting progress toward this ideal. After 'knocking out' a transcription factor called Oct1, investigators saw a significant reduction in symptoms in mice with MS-like disease. More importantly, the mice preserved most of their ability to clear viral infections.
"Our expectation was that protection from a model of MS would go hand-in-hand with poor defense against viruses, however that was not the case," said Dean Tantin, Ph.D., a geneticist in the Department of Pathology at University of Utah Health and coauthor of the paper, along with Thomas Lane, Ph.D., also of U of U Health.
Oct1 is a protein shared among mice and humans. It is found, among other places, in the T-cells, a type of white blood cell that often resides in the lymph nodes. Previous studies of Oct1 have shown that it is essential for forming immune memory of pathogens but isn't necessary for fighting them off.
The researchers deleted Oct1 from the T-cells of mice and then induced a model of multiple sclerosis, which uses protein fragments to trigger an autoimmune reaction and create the inflammation characteristic of MS. The researchers examined the mice without Oct1 and found less spinal inflammation and lesser degrees of paralysis than in the control group. These same mice also experienced half as much damage to the fatty sheath that surrounds most nerve fibers, which is a hallmark of MS..
The key step was evaluating whether the immune systems in mice without Oct1 were compromised. This was determined by testing their ability to clear viral infections that affect the nervous system. The researchers found that immune responses were normal, although slowed. All mice cleared the infection.
Tantin said this result suggests that Oct1 and the immune functions involving it could be potential targets for human drugs designed to "suppress autoimmune diseases like MS." Such drugs could leave the immune system capable of fighting infection while decreasing inflammation in the brain and spine.
Like most therapies, this hypothetical treatment would have drawbacks, Tantin notes. "If you delete this factor you impair the ability to establish new immune memory; so that is clearly a potential side effect" for future patients. However, this is not likely a major problem in treating MS because it tends to "attack older individuals who have already formed a lot of their immune memory and have been vaccinated."
It will be a long time before the results of this study lead to the development of new drugs, if ever. But Tantin believes that transcription factors offer researchers unique advantages in developing therapies.
You're going down to the DNA where the genes are regulated. Broadly speaking, going forward I think transcription factors are an opportunity to get at the root of the problem."
Dean Tantin, Ph.D
Tantin, D. et al. (2019) T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response. Journal of Neuroinflammation. doi.org/10.1186/s12974-019-1523-3.