A natural mechanism by which the body turns off inflammation may serve as a basis for the design of a new class of drugs against multiple sclerosis and other autoimmune diseases.
This mechanism -- demonstrated by a team of scientists led by Prof. Lawrence Steinman of the Weizmann Institute of Science and Stanford University Medical Center -- has already been used to block an autoimmune disease in laboratory animals, as reported in today's issue of Nature.
"A sore throat doesn't stay sore forever, and the redness produced by a positive reaction to a tuberculin skin test lasts only 48 to 72 hours, but it is unclear how the body turns off such inflammatory reactions," Prof. Steinman said.
"We have found what may be one of the body's signals for stopping inflammation, and we hope to use it to treat disease," he said.
The damage associated with autoimmune diseases occurs in several stages: first, immune system T cells attack a particular component in a certain tissue. This attack then triggers an abnormal build-up of an entire spectrum of immune cells, which affect other tissue components and cause severe inflammation -- a major aspect of autoimmune diseases.
Because such a wide variety of immune cells is involved, scientists believed that the only way to treat autoimmune diseases effectively was to suppress the entire immune system -- hardly an acceptable solution.
In the new study, the researchers showed that it may be possible to turn off the initial mechanism that triggers autoimmune processes without affecting the rest of the immune system. They used a certain protein fragment (referred to as the p87-99 analogue) to affect T cells which operate at the very outset of autoimmune disease.
Their original intention was to block the active site on the surface of these cells, preventing them from binding with and attacking myelin, the protective coating of nerves that is destroyed in multiple sclerosis. Yet they discovered that one of the protein fragments manufactured for this purpose -- the p87-99 analogue -- did not entirely block the active site on the T cells but prevented the damaging build-up of other immune cells.
The scientists found that this protein fragment works by spurring the T cells to release the signalling chemical interleukin-4, which chases the damaging immune cells away. The scientists believe this is one of the ways by which the body stops inflammation in a natural fashion.
Using the new protein fragment, they caused inflammatory lesions to regress and were even able to reverse the paralysis produced in laboratory mice by an autoimmune disease analogous to multiple sclerosis in humans.
Prof. Steinman conducted this study in collaboration with researchers from Stanford University Medical Center, Neurocrine Biosciences (La Jolla, California), DNAX Research Institute (Palo Alto, California), the U.S. National Institutes of Health, Cambridge University, U.K., and the Max-Delbrueck-Centrum for Molecular Medicine in Berlin
Scientists involved included Dr. Stefan Brocke of Stanford, Dr. Ari Waisman of the Weizmann Institute, Dr. Nicholas Ling of Neurocrine, and Dr.Anne O'Garre of DNAX.
This work was supported in part by the NIH, the Phil Allen Trust, the Emil Aaltonen Foundation, the Wellcome Trust, and by Neurocrine Biosciences, Inc.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.
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