August 12, 2003
By Karla Gale
Myelin proteome microarrays that characterize autoimmune responses could be used to diagnose multiple sclerosis (MS) early in the course of the disease and to develop effective tolerizing vaccines, researchers report in Nature Biotechnology, published online on August 10.
"We may be able to customize medication so that the person with MS who has an autoimmune response to one or more of myelin antigens would be treated with a drug to suppress the response to just those immune targets," senior author Dr. Lawrence Steinman told Reuters Health. "We can customize therapy so we no longer have to shut down the whole immune system."
Dr. Steinman of Stanford University School of Medicine, California, and colleagues induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by injecting mice with one of three encephalitogenic myelin antigen peptides: proteolipid protein (PSP), myelin basic protein (MBP), or spinal cord homogenate (SCH).
Seven days later, myelin proteome array analysis revealed that the specific antigen used for immunization induced different patterns in the autoantibody response against MBP, PLP and myelin oligodendrocyte glycoprotein (MOG) peptides.
After 10 weeks of relapsing EAE, the inducing peptide remained the dominant target of autoreactive B-cells, but the fine specificity of antibody responses varied between groups of mice and between individual mice within groups. The investigators attribute the diversification to the destruction of myelin and subsequent activation of the inflammatory cascade.
"Current tolerizing therapies in development are single peptide epitopes or single proteins," lead author Dr. William H. Robinson told Reuters Health, "but if the autoimmune response is diversifying to this extent, it is unlikely they will have any efficacy."
On the basis of proteomic profiles performed on day 17, the authors generated tolerizing DNA vaccines encoding the antigens against which animals' autoantibody reactivity was directed. Weekly injections led to a 42% reduction in relapses. Addition of interleukin-4 to the DNA vaccine was associated with a 65% decrease in relapse rates.
Furthermore, after 20 weeks of treatment, epitope spreading of autoreactive B-cell responses was reduced, in contrast to increased epitope spreading observed after sham treatment.
"The ability to identify a biosignature offers powerful insight into the pathogenesis of autoimmune disease, allowing us to predict prognosis, and to design therapies and monitor responses to therapy," Dr. Robinson concluded.
On the basis of these findings, Bayhill Therapeutics in Palo Alto, California, plans to begin clinical trials of a DNA tolerizing vaccine for MS within the coming year.
Nat Biotechnol 2003.
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