Contradictory immune responses explain different therapeutic effects in rheumatoid arthritis

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Public release date: 4-Nov-2005

Contact: Holly Korschun

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Emory University Health Sciences Center

Contradictory immune responses explain different therapeutic effects

in rheumatoid arthritis

ATLANTA -- Using a humanized mouse model that mimics the effects of

human rheuma-toid 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 pre-cise

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 ÐÐ 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 teest.

" 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.

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