Saturday Apr 20th, 2002
by Tabitha M. Powledge
Microarrays demonstrate extraordinary potential not just for studying autoimmune diseases, but for treating them, says Stanford neurologist Lawrence Steinman.
In new microarray studies on brain tissues from autopsies on people with multiple sclerosis (MS), Steinman and his colleagues are seeing expression of some genes known to figure in the chronic neurodegenerative disorder - and some whose role is a mystery.
For example, as expected, genes of the major histocompatibility complex Class I and Class II are upregulated, and several myelin genes are downregulated. But many surprises are also turning up, such as activity from receptor genes for benzodiazepines, serotonin, and tumor necrosis factor.
Microarrays may also illuminate the differences between acute and chronic relapsing forms of MS, Steinman says. In acute plaques, genes for immunoglobulin and map kinase kinases, among others, are upregulated, while histamine receptors are active in chronic plaques. The work is due to be published in the May Nature Medicine.
The histamine findings, which suggest that MS could perhaps be modulated with conventional antihistamines, raise critical questions for drug companies, Steinman argues. Antihistamines "are probably worth trying," he said. "I wince when I hear that drug company pipelines are empty, because apparently they don't know what they're doing."
Pharmaceutical companies are failing to explore other applications for drugs already in existence, he says, pointing to a poster on statins from Sawsan Youssef, a postdoctoral fellow in Steinman's lab.
The popular cholesterol-lowering drug Lipitor reverses paralysis in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, Youssef will report in her poster, scheduled for presentation later this week. Youssef told BioMedNet News she is also designing microarray studies on which genes are up- and down-regulated by statins.
By providing such information, the chips will improve diagnosis and be important for clinical trials of new drugs, the researchers suggest, and may even lead to antigen-specific therapies.
Scientists have long been skeptical about a future for antigen-specific therapies because there are so many possible antigens. What happens, one audience member wanted to know, when a patient immunized against 100 antigens inevitably encounters a new one? Steinman conceded the point, but said he hoped that antigen-specific therapies would be able to give patients decades of symptom-free life before that happened.
The latest microarray work extends studies the researchers reported last fall in Science, when large-scale sequencing of cDNA libraries of plaques from the brains of MS patients disclosed a high volume of transcripts for a cytokine called osteopontin (OPN).
Mice paralyzed with EAE also have several OPN transcripts, the researchers found. Mice deficient in OPN were both EAE-resistant and had frequent remissions. OPN may regulate T helper cell-1 (TH1)-mediated demyelinating disease and targeting OPN might therefore prevent progressive MS, the researchers suggested.
The group has also moved on to proteomics, launching ambitious microarray studies of antigens. In work published last month, the "first application of such technology to multiple human disease sera," they reported on results for eight different autoimmune diseases, including systemic lupus erythematosus, diabetes, and rheumatoid arthritis.
Experimental Biology 2002
© Elsevier Science Limited 2002