5/15/97
CONTACT: Rosanne Spector, (415) 725-5374 or 723-6911; e-mail [email protected]
BROADCAST MEDIA CONTACT: M.A. Malone, (415) 723-6912 or 723-6911; e-mail [email protected]
COMMENT: Michael Shaw, (415) 723-7949; e-mail [email protected]
Improved treatment for autoimmune diseases
STANFORD -- The immune system adheres to a behavioral code that demands respect for the body's healthy cells and allows attack of only cancers and harmful microbial invaders -- usually. But sometimes immune cells break the rules and turn against normal parts of the body. When this happens, people experience the devastating effects of autoimmune disease.
Stanford investigators have succeeded in reforming delinquent immune cells that have turned against the body they are meant to protect. The researchers forced the misbehaving cells to carry the blueprint for a gene that squelches the destructive response. The researchers showed that mice destined to have an autoimmune disease benefit significantly from this treatment.
"This is the first time anyone has shown that these molecules can be delivered to a specific site, bypassing problems associated with delivering an immunosuppressive drug to the entire body," said Michael Shaw. Shaw is a postdoctoral fellow in the laboratory of Dr. Garry Fathman. "It means that we may be able to have the benefit of current therapies for autoimmune disease, without the side effects of global immunosuppression. Right now, patients' immune systems are suppressed to such an extent that they are much more susceptible to infections and some cancers. And there are also a host of other side effects, including obesity and loss of bone density," Shaw said.
The researchers are studying an autoimmune disease in mice that models the human disease multiple sclerosis. The mouse condition, called experimental autoimmune encephalitis (EAE), is an inflammatory autoimmune disease of the central nervous system (CNS). In both disorders, the immune system attacks a protein called myelin.
Myelin is part of the CNS electrical system, said Fathman, a professor of medicine (immunology and rheumatology) and senior author of the paper that appeared in the May issue of the Journal of Experimental Medicine. "The myelin acts as an insulator of the electrical impulses that travel through the nervous system, delivering messages to and from the brain. If you damage the myelin, you short out the nerve," he said. This interrupts nerve signals and creates a range of clinical problems ranging from double vision and stumbling to severe motor dysfunction and death.
The researchers engineered a retrovirus, replacing part of its normal genetic cargo with the instructions to make a molecule, called interleukin 4 (IL4), that turns down the immune response. IL4 is one of many cytokines, "hormone- like molecules used for communication," within the immune system, Shaw said. The investigators then coaxed the retrovirus to infect a line of T cells that homes to the central nervous system -- the site of inflammation in EAE. The idea was to trick the T cells into secreting a "shut-down" signal, IL4, in the vicinity of the inflammatory site.
The investigators infected the cell line in the test tube and then transferred the cells back into animals that were on their way to acquiring EAE. As predicted, mice containing the IL4-secreting T cells took longer to become ill than mice containing control T cells that did not produce IL4. Their symptoms were less severe as well.
Shaw said there are no technical barriers to applying the technique to humans, but there will have to be a few more studies in the mouse model before that happens.
The advantage of this method over the majority of approaches taken to control autoimmune disease lies in its ability to deliver a therapeutic molecule to a particular location in the body, Shaw said. This approach solves the major problem inherent to autoimmune disease treatment: Turning off the body's destructive attack against its normal cells while maintaining the body's ability to fend off dangerous intruders. Although systemic administration of chemicals such as IL4 is possible and staves off autoimmune attacks, it also leaves the animal or human susceptible to infection by harmful bacteria and viruses.
The method is not limited to treating EAE and, potentially, MS. "You can imagine applying this method to any inflammatory autoimmune disease -- diseases like rheumatoid arthritis and diabetes," Shaw said. "In fact, you can also imagine that it's applicable to other situations where you might want to alter the immune response. It would be very helpful to be able to heighten the immune response against cancer cells, for example, and to interfere with the immune attack of transplanted organs."
The researchers are now improving their new tool, trying to develop ways to control production of the therapeutic molecules within the body. "One worry is what happens when the immune cells finish their work and leave the site of inflammation," Shaw said. "They might suppress healthy immune responses elsewhere in the body. It would be helpful to have a T cell that could traffic through the body and not secrete anything until it encounters a signal at the inflammatory site. Then, once the inflammation is resolved, the stimulus would no longer be around and the cell would stop producing its cytokine." The technology for this already exists, Shaw said. "It's just a matter of adapting it to our system."
Shaw received a Multiple Sclerosis Society postdoctoral fellowship to carry out this work. The research is supported by a National Institutes of Health grant to Fathman. --es--
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