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Understanding mutation leads to promising new treatment for autoinflammatory diseases

Memphis, Tennessee, August 8, 2013

Thirumala-Devi Kanneganti, PhD

St. Jude Children’s Research Hospital study yields clues for designing next-generation drugs to treat autoinflammatory diseases

St. Jude Children’s Research Hospital scientists have not only solved the mystery of how mutations in the SHP-1 gene lead to a variety of inflammatory and autoimmune disorders, but have also identified a drug that protected against an inflammatory skin disease in a mouse model.

Researchers discovered something else: Different forms of the protein interleukin-1 (IL-1) take different routes to fuel inflammation. That finding overturned the widely held assumption that the alpha and beta versions of IL-1 work through the same pathway. The research appeared in the June 13 edition of the scientific journal Nature.

“These are thrilling results because we showed that blocking a single molecule, in this case IL-1 alpha, protected 100 percent of the mice from developing an inflammatory disorder that is very close to the human disease. These results are a stepping stone that leads to the clinic,” said the study’s corresponding author Thirumala-Devi Kanneganti, Ph.D., an associate member of the St. Jude Department of Immunology.

The SHP-1 protein protects against unneeded and unwanted inflammation by switching off the signaling system that governs the release of molecules called cytokines. These molecules drive inflammation. Although mutations in SHP-1 have been linked for decades to a variety of inflammatory and autoimmune disorders, including lupus and multiple sclerosis, until now the mechanism responsible was unknown.

To find the answer, researchers turned to a new SHP-1 mutant mouse model of the inflammatory human skin disorder neutrophilic dermatosis. The disease is characterized by skin inflammation and sometimes painful skin abnormalities, including ulcers. Corticosteroids, the centerpiece of current treatment, are associated with serious side effects.

Kanneganti and her colleagues showed that SHP-1 mutations work through an unexpected mechanism. The system features the RIP1 kinase and IL-1 alpha in prominent roles. Kinases are signaling molecules that can start the inflammatory process. The scientists found the SHP-1 mutation led to signaling through RIP1, which resulted in the release of IL-1 alpha and other cytokines that promote and sustain inflammation. Deleting either RIP1 or IL-1 alpha prevented excessive inflammation and inflammation-related tissue damage in the mutant mice and restored normal wound healing.

The experimental drug necrostatin 1 also protected mutant mice from inflammation-driven tissue damage, researchers reported. The drug was designed to block RIP1 activity.

Deleting other protein complexes and cytokines that control or fuel inflammation had no impact on the inflammation or disease symptoms in the mice, said first author John Lukens, Ph.D., a postdoctoral fellow in Kanneganti’s laboratory. That list included the molecules caspase 1, IL-1 beta and RIP3, which works with RIP1 to trigger a form of programed cell death that triggers inflammation.

Researchers noted that when IL-1 alpha was deleted, messaging through a protein complex called NF-kB also declined. NF-kB is a master regulator of inflammation. That observation offers further insight into the disease process, suggesting RIP1 and IL-1 alpha are in a feedback loop that fuels inflammation.

The other authors are Peter Vogel and Gordon Johnson, both of St. Jude; Michelle Kelliher, University of Massachusetts Medical School; Yoichiro Iwakura, University of Tokyo; and Mohamed Lamkanfi, Ghent University, Belgium.

The study was funded in part by grants (AR056296, CA163507 and AI101935) from the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude shares the discoveries it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.

 
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