NEWS - Research points to new approach to RA therapy

[Guest guest]

Research points to new approach to RA therapy

Sep 14, 2004

Research carried out with blood cells and fibroblasts obtained from

rheumatoid arthritis (RA) patients has unveiled a new mechanism by which

antibodies trigger the migration of T cells into areas of inflammation [1].

Described in the September 1, 2004 issue of the Journal of Immunology, the

work opens up new targets for therapeutic intervention aimed at RA.

As a target for intervention, it is very attractive, as it is further

upstream and more specific than the TNF inhibitors that are currently used

in the treatment of RA, principal investigator Dr Terry

(Harbor-University of California, Los Angeles Medical Center, Torrance)

tells rheumawire. " If you take away the T cells, there isn't this outpouring

of TNF that you then need to dampen down. . . . I don't believe that

knocking out TNF is all good, as it's an important mediator in the body, and

blocking it may lead to untoward effects, such as infections and neoplasms. "

In their paper, et al describe how antibodies obtained from RA

patients directly activate synovial fibroblasts via activation of the

insulin growth factor receptor (IGF-1R) and enhancement of the expression of

2 cytokines, interleukin-16 (IL-16) and RANTES (regulated on activation

normal T cell expressed and secreted). explains that IL-16 is a very

specific activator of CD4+ T lymphocytes, while RANTES acts on a broader

array of lymphocytes, and between them they trigger T-cell migration into

areas of inflammation. The team has previously shown that the same pathway

exists in Graves disease and suspects that it may also be found in other

autoimmune diseases, such as diabetes and myasthenia gravis. " This newly

recognized mechanism may explain a previously unknown bridge between B-cell

activity and T lymphocytes trafficking in multiple diseases, " they comment.

Although all work described in the paper has been carried out in vitro, the

" implications are quite proximate to the disease, " says. " We're using

cells that have just come from the patients, which have not been engineered

in any way, and we have evidence that much of the molecular activation that

we've described is pretty much what is happening in the patients. "

The team is now elucidating further details of the mechanism involved,

tells rheumawire, " working out exactly how the antibodies interact with the

fibroblasts, how they activate IGF-1R, and how we can interrupt this

interaction. " The aim is to find points at which to target therapy, perhaps

with a monoclonal antibody. estimates that it will take another 2 to 3

years before this approach can be tested in clinical trials but believes

that it could make quite an impact clinically. " We predict that in early

disease, we could completely abrogate the disease process. We might

potentially be able to stop T cells from getting into the joints to begin

with, and so all of the destructive events that take place downstream of

this could be prevented. " In RA patients with full-blown disease, there is

already damage in the joints and it's unlikely that this approach could have

an impact on the tissue remodeling, scar tissue, etc. " But the disease is

episodic, and we may be able to prevent these episodes from recurring and

thus prevent further damage. "

Source

1. Pritchard J, Tsui S, Horst N, Cruikshank W, TJ. Synovial

fibroblasts from patients with rheumatoid arthritis, like fibroblasts from

Graves' disease, express high levels of IL-16 when treated with IGs against

insulin-like growth facto