RESEARCH - RA, contradictory immune responses explain different therapeutic effects

[Guest guest]

Rheumatoid arthritis, contradictory immune responses explain different

therapeutic effects

Main Category: Arthritis News

Article Date: 09 Nov 2005 - 0:00am (UK)

Using a humanized mouse model that mimics the effects of human rheumatoid

arthritis (RA), researchers have discovered that protein growth factors

called cytokines in the immune system have both pro- and anti-inflammatory

responses to RA that help explain why some patients respond to current

therapy and others don't. By pinpointing the unique immune mecha-nisms

involved in different forms of RA, the scientists hope to guide physicians

toward more precise individualized diagnosis of RA patients and more

effective therapies that target specific forms of the disease.

The findings were published online on October 20 and are reported in the

November issue of the Journal of Clinical Investigation. The research was

conducted at the Lowance Center for Human Immunology at Emory University

School of Medicine, and was led by rheumatologists Cornelia Weyand, MD, PhD,

and Jorg Goronzy, MD, PhD. The study's first author was Thor-sten M. Seyler.

Rheumatoid arthritis (RA) is a chronic and crippling inflammatory joint,

bone and cartilage disease affecting more than 2.1 million Americans. An

autoimmune disease, RA is characterized by an abnormal immune response in

which the immune system attacks healthy tissue, causing in-flammation of the

lining of the joints, called the synovium.

For the last 20 years researchers, including those at Emory, have worked to

identify path-ways and molecules that play a role in RA, resulting in new

therapies that target inflammatory growth factors and a marked improvement

in treatment success. However, even though not all RA patients respond well

to these therapies, they are applied universally, without accounting for

differ-ences in disease.

" We need to become much more sophisticated as rheumatologists in

understanding that RA is not all the same disease and that when we treat it

we will see very diverse results, " said Dr. Weyand. " Rheumatologists need to

develop diagnostic tools to capture differences in patients that have

meaning for the course of disease and for our therapeutic actions. "

Drs. Weyand and Goronzy have helped delineate three different subtypes of RA

disease over the past ten years. In diffuse RA, T and B lymphocytes seem to

infiltrate tissue randomly, re-sulting in autoimmune inflammation. In

aggregate synovitis, T and B cells meet each other in ag-gregates and

inflame the joints. In germinal center synovitis, T cells, B cells, and

other supporting cell populations go into the joints and acquire a highly

complex and organized micro-architecture that resembles conditions in an

inflamed lymph node.

Many therapies currently used to treat RA patients are based on new

knowledge about in-flammatory cytokines __ growth factor-like proteins that

stimulate the autoimmune process. Scien-tists have hypothesized that

rheumatoid lesions produce excessive amounts of such growth factors,

promoting lymphocyte proliferation and keeping alive the immune cells that

drive inflammation and perpetuate the autoimmune disease state.

The Emory scientists set out to explore differences in immune responses by

using their mouse model to study related types of cytokine protein known for

helping B lympocytes survive and differentiate. Two of these proteins, known

as APRIL (A proliferation inducing ligand) and BlyS (B-lymphcyte

stimulator), are the targets of new experimental drugs currently in early

phase clinical trials.

The researchers implanted human tissue from RA patients who had the three

different types of disease into mice engineered to lack a natural immune

response. They treated the mice with a soluble receptor called TACI that

" plucks " the growth factors APRIL and BlyS and " mops " them away from the

affected tissue.

The researchers found that in the mice carrying tissue from patients with

germinal center synovitis, the inflammatory lymph-node like structures

completely collapsed, effectively halting the inflammatory process. However,

in the other two types of disease just the opposite happened, and the growth

factors and inflammation actually increased.

" This was a very surprising result, " said Dr. Weyand. " We found that these

two factors do more than just support the growth and differentiation of B

cells. They also can bind to T lympho-cytes. In the tissues that had

worsening of disease, we found T cells binding APRIL and BLyS, telling us

that these T cells had actually been suppressing the disease. "

The conclusion? The factors APRIL and BlyS have multiple and complex effects

in rheu-matoid arthritis. In some types of disease they are critical in

keeping the inflammatory structures working and functioning, while in other

types of disease they seem to do just the opposite.

" Physicians and patients already have been aware that some people respond to

therapy while others do not, " Dr. Weyand says. " Our research helps us

explain why. These molecules have both pro- and anti-inflammatory activity,

and the trial-and-error method of treatment may not be best for the patient.

The goal of current RA treatment is to suppress the immune system, but we

need to recognize that nature has developed anti-inflammatory pathways that

we may be able to utilize. "

Dr. Weyand and Goronzy say the goal of their research is to learn more about

physiological ways of downregulating inflammation and strengthening them

instead of destroying the entire im-mune response. They also want to develop

molecular screening methods to distinguish RA pa-tients, ideally using a

simple blood test.

" We want to move away from making global, unsophisticated diagnoses and

design ther-apy plans for patients that match their particular needs, " says

Dr. Weyand. " We can gain clues from nature about how it inhibits

inflammation that will allow us to develop a whole new way of managing the

auto-immune response. "

Other study authors included Yong W. Park, Seisuke Takemura, from Emory's

Lowance Center for Human Immunology; J. Bram, Department of

Pediatrics and Adolescent Medi-cine, the Mayo Clinic; and J. Kurtin,

Department of Pathology, the Mayo Clinic.

The work was funded in part by the National Institutes of Health.

http://www.medicalnewstoday.com/medicalnews.php?newsid=33254

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

[Guest guest]

Good article. I wonder if that's the Emory here in Georgia. I am not

treated at Emory. I have done my share of studies already and just

want an experienced RA doc now. However, I may have to look into this

particular research a little more. I have also thought of relocating

to MD to be near s-Hopkins hospital. There is an arthritis center

there. I don't have any first-hand information on it, only what I

read. At least everything would be all in one place -- the doctor care,

the swim therapy, rehabilitation, etc. That's what I really want -- a

multiple approach in one place since getting around is an issue.

thanks,

Ebony