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Autoimmune Disease Treatment May Not Dampen Immune System
Date:6/19/2008

Targeting a key protein might reap rewards for people with asthma, MS, scientists say

THURSDAY, June 19 (HealthDay News) -- Researchers have uncovered cellular proteins that may be key to certain autoimmune and inflammatory diseases, according to a new study.

The findings, performed so far only in mice, point to potential new treatments for a range of human diseases that are mediated by immune system T-cells. These include many inflammatory and autoimmune disorders, illnesses that involve an immune system run amok.

More important, such a treatment might provide patients with all the benefits of existing drugs, without the general immune suppression that often accompanies them.

"It has an effect on an autoimmune disease -- a mouse model of multiple sclerosis -- and an inflammatory disease -- a mouse model of asthma -- but does not seem to interfere with protective immunity against toxoplasma, a parasite," said one expert, Dr. Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research in Baltimore.

"This is what everyone is driving for, to selectively block pathological [immune] responses but not normal responses," added the study's lead author, Dr. Richard Siegel of the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases.

The findings were published in the July issue of Immunity.

At the center of this effort are a pair of proteins, DR3 and TL1A. Expressed on the surface of white blood cells called T lymphocytes, DR3 induces T-cells to proliferate and release inflammatory cytokines (signaling proteins) when it binds TL1A, which is like the "key" to DR3's "lock."

TL1A and DR3 are also related to tumor necrosis factor (TNF), and its receptor, respectively. TNF has been implicated in inflammatory and autoimmune disease, and drugs that target TNF and its receptor are used to treat rheumatoid arthritis and inflammatory bowel disease and are generally quite effective, said Rose.

Still, they are not perfect.

"The problem with that treatment is it is not effective against all autoimmune diseases," he said. "But more importantly, it may predispose to infection, because you downgrade the entire inflammatory response."

Siegel, with colleagues at the U.S. National Institute of Allergy and Infectious Diseases and at Cardiff University in Wales, U.K., asked what would happen to mouse models of asthma and multiple sclerosis that were genetically engineered to lack DR3. (Asthma is an inflammatory condition largely attributed to a subset of T-cells called Th2; multiple sclerosis is an autoimmune disorder caused by two different T-cell populations, Th1 and Th17.)

The answer: Both disease pathologies were "reduced" in the DR3-deficient mice, said Siegel, and fewer T-cells were found in the tissues that should have been affected. Yet, the DR3-deficient animals did not suffer from a generalized immunodeficiency and thus were able to mount immune responses to both a chicken egg protein and the parasite that causes toxoplasmosis.

"The essence of the paper is that not only are DR3-deficient mice not horribly immunodeficient," said Siegel, "if you look at their immune system in general, it is normal."

Indeed, the animals appeared to have no shortage of T-cells capable of responding to the inflammation-inducing antigens. Instead, for whatever reason, they were not being activated and dividing in the tissues normally affected by disease (such as the lung in the asthma model).

"It looks as if, for reasons this article does not make clear, the cells do not proliferate in the target organ," said Rose. "They can proliferate elsewhere, but they do not elicit an inflammatory response in the target organ."

Siegel said the combination of anti-inflammatory activity in DR3-deficient mice with sustained immune system function is unusual, and suggests that DR3 might make a good drug target for a range of inflammatory and autoimmune diseases.

"This is potentially a huge finding," said Rose. "Companies would salivate to have something like this."

Yet Rose also noted that drugs against DR3 or TL1A likely would only help against diseases for which inflammation is the primary problem. "In autoimmune diseases in which antibodies play a major role [such as hemolytic anemia and Graves' disease], this probably would not be useful," he said.

Further, Rose noted that, in general, inflammation serves a useful, healthy purpose, immunologically speaking, and dampening it down might have undesirable effects. For example, there might be diseases or infections that could thrive in the absence of DR3 signaling.

One such case is tuberculosis, which can become active in individuals treated with TNF receptor blockers. Siegel said he is now testing to see whether the immune response to TB, or any other kind of infection, is weaker in mice without DR3 than normal mice.

A pair of recent studies -- one from the University of Miami and the other from M.D. Anderson Cancer Center in Houston and Biogen Idec in Cambridge, Mass. -- separately established a role for DR3/TL1A in both asthma and multiple sclerosis. The current study establishes that, in fact, the molecules do play a role in both diseases, said Siegel.

More information

For more on autoimmune disorders, visit MedlinePlus.



SOURCES: Richard M. Siegel, M.D., Ph.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.; Noel R. Rose, M.D., Ph.D., professor of pathology and molecular microbiology and immunology, and director, Johns Hopkins Center for Autoimmune Disease Research, Bloomberg School of Public Health, Baltimore, Md.; July 2008, Immunity


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