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 �� 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; Richard J. Bram, Department of Pediatrics and Adolescent Medi-cine, the Mayo Clinic; and Paul J. Kurtin, Department of Pathology, the Mayo Clinic.

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