RESEARCH - New cell-based targets for treating autoimmune inflammatory diseases

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From Arthritis Care Research News Alerts

New Cell-Based Targets for Treating Autoimmune Inflammatory Diseases

Posted 10/06/2006

Patients with systemic autoimmune diseases such as lupus and

rheumatoid arthritis (RA) often suffer loss of kidney function. When marked

by a crescent formation in the glomerulus - a tiny ball comprised of

capillary blood vessels integral to forming urine - kidney failure tends to

be rapidly progressive, irreversible, and fatal. Little is known about the

mechanism behind this crescent or its relationship to immune-mediated

inflammation.

To gain understanding, a team of researchers in Japan began by

analyzing a spontaneous mutant strain of EOD mice. Their study, published in

the September 2006 issue of Arthritis & Rheumatism

(http://www.interscience.wiley.com/journal/arthritis), indicates the

critical role of platelet function in this dire form of autoimmune kidney

disease, crescentic glomerulonenephritis (CGN). It also sheds light on the

involvement of Cno protein, a member of a large protein complex called

biogenesis of lysosome-related organelle complex 1 (BLOC-1), in the

development of an autoimmune disease.

Researchers isolated this mutant strain of mice from the

autoimmune-prone strain EOD, which stably develops fatal CGN. Then, using

blood samples, they thoroughly assessed blood cell count, immune function,

platelet function, and properties of various cell types and genes in these

mice, searching for clues to their marked improvement in CGN and ability to

survive about twice as long as wild-type EOD mice. Among the surprising

findings in the mutant mice was an ability to alter platelet functions.

While wild-type EOD mice displayed massive accumulations of platelets in the

glomerulus, the mutant mice did not, but they were more prone to bleeding.

Further investigation revealed a mutation in the cappuccino gene, which

encodes the Cno protein. Mutant platelets also showed abnormally low

aggregation in response to collagen and abnormally low rates of serotonin

storage.

These findings suggest links between the gene mutation, loss of

Cno protein expression, defect in platelet function, and the regression of

crescent formation in the glomerulus. What's more, these links are related

to BLOC-1, which controls lysosomes, tiny organelles that contain digestive

enzymes critical to maintaining healthy cell function.

" The profound role of BLOC-1 appears to be platelet-specific

among immuno-inflammatory cell types, " notes the study's lead author, Dr.

Masao Ono from the Tohoku University Graduate School of Medicine. " BLOC-1 is

a possible therapeutic target for suppression of platelet functions without

compromising physiologic immune responses. "

In another promising new study, using rats and gene-modified

mice, researchers in Turku, Finland, uncovered a new type of adhesion

molecule highly expressed on vessels of inflamed human synovial tissue. This

molecule, AOC3 (amine oxidase, copper-containing 3; also known as vascular

adhesion protein 1), works to spur inflammation by thwarting the

infiltration of leukocytes, vital white blood cells, into rheumatoid joints.

In an editorial describing the discovery and function of this adhesive

enzyme, Dr. Beat A. Imhof of the University of Geneva School of Medicine and

University Hospital, Geneva, Switzerland, indicates the potential

therapeutic value for rheumatoid arthritis patients. " Antiadhesive therapies

based on the use of small molecule inhibitors certainly represent an

economically interesting alternative to expensive biologic treatments, such

as humanized anti-adhesion molecule antibodies, which are currently being

developed for the treatment of inflammatory diseases, " Dr. Imhof notes.

Item is available via Wiley InterScience at

http://www.interscience.wiley.com/journal/arthritiscare.

Arthritis Care. 2006;54(9):2934-2943. ©2006 Wiley InterScience

http://www.medscape.com/viewarticle/545078

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