A study in the April Nature Medicine provides data that may help explain why interferon-beta reduces relapses in only about two-thirds of the multiple sclerosis (MS) patients who receive it, while having little if any effect on the rest.
If this evidence, derived from research on a mouse model of MS, turns out to apply to humans as well, it could point the way toward a simple blood test that divides MS patients into two groups — those who will probably benefit from interferon, and those who may actually be harmed by it.
The decisive variable appears to be the type of helper T cells that cause experimental autoimmune encephalomyelitis (EAE) in mice. EAE caused by TH1 cells generally respond well to interferon-beta, while EAE caused by TH17 cells get worse with interferon-beta.
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The study was conducted at the lab headed by Lawrence Steinman, MD, George A. Zimmerman Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine.
Dr. Steinman and his colleagues induced superficially different forms of EAE in mice by activating their T cells with different cytokines — interferon-gamma and interleukin-17 (IL-17) — both of which trigger the type of myelin inflammation found in MS patients.
Mice whose EAE had been induced by T cells that secreted mainly gamma-interferon improved when they received beta-interferon. The mice whose disease was brought on by T cells that secreted mainly IL-17 got worse after the treatment.
The researchers also analyzed blood samples from 26 MS patients and found a similar pattern — those who had low levels of a type of IL-17 known as IL-17F responded well to beta-interferon, while those who had high levels of IL-17F responded poorly.
A tantalizing piece of corroborating evidence, according to Dr. Steinman, comes from patients with neuromyelitis optica — inflammation of the optic nerve —which often afflicts patients with MS.
“Patients with neuromyelitis optica have high IL-17 — that was discovered in 2005 — and there have been three papers since then that show interferon makes that disease worse,” he said.
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The potential implications of this research have aroused excitement among MS researchers. “This paper raises the possibility that some MS patients may have a form of the disease that's mediated more by TH1 T-cell response, and some have a form mediated more by a TH17 T-cell response,” said Richard A. Rudick, MD, director of The Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic's Neurological Institute, who was not involved with the study. “That's conjecture at this point, but if what has been found in animals can be extrapolated to humans, that might explain why humans respond so differently to interferon.”
Dr. Rudick also speculated that the different responses to interferon by MS patients may have a genetic basis. “We need to know how those biologic responses interact with the genetic makeup of the patients, and that needs to be turned into clinical tests that can be used to predict how someone will do on interferon,” he said.
Michael Barnett, MD, senior lecturer in neurology at the University of Sydney, is heartened by the implications for treatment he finds in the research. “They've addressed a very important issue because at present interferon is offered to all patients with relapsing disease, and about one-third ultimately do not respond to this therapy,” Dr. Barnett said. “That means valuable time is lost. The earlier effective treatment is commenced, the better patients are likely to fare in the longer term. If we can sort out who will respond to interferon from day 1, this will be a significant advance.”
The effectiveness of early treatment is especially important in light of research showing that MS inflammation continues subclinically in between overt relapses, said Timothy Vollmer, MD, professor of neurology and medical director of the Rocky Mountain MS Center in Aurora, CO, and co-director of the Rocky Mountain MS Clinic at the Anschutz Medical Center of the University of Colorado-Denver.
“In the remitting phase patients stay stable not because the disease is quiet, but because the brain masks disease through cortical remodeling,” he said. “The onset of the progressive phase represents the loss of compensatory mechanisms. In that model, the only logical conclusion is that if you want to change outcomes, you must treat early and aggressively as we do with hypertension, hyperlipidemia, and diabetes, and terminate that subclinical disease activity.”
Dr. Steinman believes the more urgent challenge involves validating the results of this research, which is why he and his colleagues are collaborating with Biogen Idec, the manufacturer of a form of interferon beta (Avonex), which has hundreds of blood samples from patients treated with interferon-beta. “I imagine other groups will try to validate this with their own specimens,” Dr. Steinman said.
• Axtell RC, de Jong BA, Raman C, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010;16(4):406–412. E-pub 2010 Mar 28.
©2010 American Academy of Neurology