Re: ScienceDaily: Preventing Toxic Side Effects Of Inflammatory Disease Therapy

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Source: University of California - San Diego

Posted: February 13, 2006

Preventing Toxic Side Effects Of Inflammatory Disease Therapy

Researchers at the University of California, San Diego (UCSD) School

of Medicine have developed a mouse model that could help scientists

develop better drugs to fight autoimmune and inflammatory disorders

such as multiple sclerosis and rheumatoid arthritis.

Inflammation is a process by which the white blood cells and

chemicals of the immune system rally to protect the body from

infection and foreign substances such as bacteria and viruses. In

autoimmune diseases, however, this defense system triggers an

inflammatory response when there are no foreign substances to fight

off, or the defense system goes into " overdrive " and forgets how to

turn off. In these diseases, the body's normally protective immune

system attacks and damages its own healthy tissues.

UCSD researcher Mark H. Ginsberg, M.D., professor of Medicine at the

University of California, San Diego (UCSD) School of Medicine, and

his colleagues have identified a mechanism to selectively disrupt

signaling to recruit lymphocytes and monocytes -- white blood cells

sent to sites of inflammation to fight infection -- while maintaining

the body's other essential immune system functions. Their findings

appear online on February 9 in advance of print publication in the

March issue of the Journal of Clinical Investigation.

In the case of certain autoimmune diseases, the alpha 4 integrins

cause white blood cells to accumulate at the site of the disease,

resulting in inflammation. An integrin is a surface molecule found on

the exterior of cells that helps cells adhere and migrate. It is also

believed to be responsible for a role in cell signaling, which allows

cells to communicate with the extracellular environment. One of the

promising treatments for disorders such as multiple sclerosis,

inflammatory bowel disease and rheumatoid arthritis -- the alpha 4

integrin antagonist -- works by blocking cell adhesion. However, this

anti-inflammatory therapy could cause adverse side effects, such as

impairment of the immune system and the patient's ability to develop

new red and white blood cells in the bone marrow, a process called

hematopoiesis.

" Our goal was to identify a more specific target of alpha 4 integrin

molecules in order to interfere with their roles in disease

progression while sparing alpha4 functions required for normal

health, " said M. Rose, D.V.M., Ph.D., assistant professor of

medicine at UCSD, and co-author of the study.

The research team created mutant mice known as " alpha4(Y991A) mice, "

in which the alpha4 integrin can no longer bind to a signaling

protein inside the cell called paxillin. Previously generated alpha4

integrin deficient mutant mice died at birth because too many aspects

of alpha4 function were changed. The new alpha4(Y991A) mice have an

impairment only in the interaction between alpha4 and paxillin, and

thus have fewer effects on development. The researchers discovered

that, in contrast to normal mice, alpha4(Y991A) mice exposed to an

inflammatory stimulus recruited fewer circulating white blood cells

(B and T cells) to the region of exposure. However, the development

of new B and T cells was unaffected.

The authors suggest that these mice are a valuable tool to test

models of inflammatory and autoimmune diseases of humans, and that a

new class of pharmaceutical agents that target the specific

interaction of paxillin and alpha4 integrin could be important future

treatments of inflammatory disease.

" We were surprised to find that the mutation actually had very little

effect on the animal's development of lymphocytes, the white blood

cells that fight infection, " said Rose. " This could prove to be an

important first step in development of a more effective drug to

target alpha4 integrins in autoimmune and inflammatory disease of

humans. "

Additional co-authors include Kaushansky, M.D., Chloé C.

Féral, Jaewon Han, Norman Fox and Gregg J. Silverman, UCSD Department

of Medicine.

http://www.sciencedaily.com/releases/2006/02/060213093730.htm