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RESEARCH BRIEFSStudy Suggests Surprising Cause of ArthritisCertain Carbohydrates Fingered as Trigger of Autoimmune Response Although there have been promising advances in treating the symptoms of rheumatoid arthritis, which affects hundreds of millions of people worldwide, the cause of arthritic inflammation, swelling, and joint destruction has remained elusive. Now researchers at Brigham and Women's Hospital and HMS have for the first time associated carbohydrates present in the body with the disease. Julia Ying Wang, lead researcher on the study and an HMS assistant professor of medicine at BWH, presented the findings on Aug. 21 at the American Chemical Society's national meeting in Boston. The work began with Wang exploring whether a particular class of carbohydrates, glycosaminoglycans (GAGs), trigger an immune response in the body. GAGs are a major component of joint cartilage, joint fluid, connective tissue, and skin. In collaboration with Michael Roehrl, a research assistant in the Department of Biological Chemistry and Molecular Pharmacology, she studied the effect of GAGs on mice. The animals experienced arthritic symptoms, including swelling, inflammation, and joint damage, about 30 days after injection with the carbohydrates. "This study shows that rheumatoid arthritis may result from the body's mishandling of its own carbohydrates that under normal circumstances would not be interpreted as a threat," Wang said. "We found that inflammatory cells that accumulate in arthritic joints attach themselves directly to the glycosaminoglycans. This accumulation of cells leads to painful inflammation and swelling in the affected tissue." In addition to their research with mice, Wang and Roehrl also examined human tissue taken from arthritis patients. They discovered the same type of glycosaminoglycan-binding cells in the human tissue, the first direct demonstration of such cells in humans. "The findings lead us to believe that rheumatoid arthritis may be an unusual immune response," Wang said. Given the findings, Wang said subsequent research would most likely focus on the development of drugs aimed at stopping the growth, expansion, or adhesion of immune cells that react to glycosaminoglycans. "This research is extremely promising," said John Mekalanos, professor and chairman of microbiology and molecular genetics at HMS. "This study also suggests plausible models for how bacterial infection might trigger arthritis and how we might go about reversing this debilitating condition with new therapies."
Double Transplant Helps Multiple Myeloma PatientsPatients suffering from both multiple myeloma and kidney failure could potentially benefit from two transplants--a kidney for their kidney failure and bone marrow for their cancer. But they have faced a dilemma. They are not eligible for kidney transplants because of their cancer, and their kidney failure renders them unable to tolerate the toxic aspects of bone marrow transplantation. A team of MGH researchers appears to have found a way to face the problem. Paradoxically, the method involves performing both transplants, kidney and bone marrow, in rapid succession. Megan Sykes, HMS professor of surgery and of medicine at Massachusetts General Hospital, and colleagues Thomas Spitzer, A. Benedict Cosimi, and David Sachs have tried this combined therapy on four multiple myeloma patients who developed kidney failure as a result of their cancer. In each case, the patient was given a kidney transplant and then infused with bone marrow from their donor. The first patient was treated in 1998 and the most recent received the combined therapy in the last few months. All are in remission from their cancer and all but one have successfully discontinued immunosuppressive drugs for their transplants. Sykes presented the findings on Aug. 30 at the Congress of the International Transplantation Society. Sykes and her colleagues have been working for years to find ways to disarm the immune system of transplant patients so they could accept bone marrow and other transplants. Working with Spitzer, HMS associate professor of medicine at MGH, the researchers developed a protocol of non-myeloablative bone marrow transplantation. The recipient's hematopoietic system is suppressed rather than totally destroyed, creating a state of mixed chimerism--a blending of immune cells from both donor and recipient. They plan to try the combined kidney and bone marrow transplant approach on more patients with both kidney failure and multiple myeloma. "Our results demonstrate that long-lasting tolerance can be induced with non-myeloablative bone marrow transplantation," said Sykes. "Our group is starting a new study of the induction of mixed chimerism for tolerance in patients without cancer who need kidney transplants." That investigation is being led by MGH colleagues Sachs, the Paul S. Russell/ Warner Lambert professor of surgery, and Cosimi, the Claude E. Welch professor of surgery. --Misia Landau
Allergy-producing Cells May Play Role in Rheumatoid ArthritisThe symptoms of rheumatoid arthritis--pain, loss of movement, disfigurement--are achingly clear, but the story of how this disease develops is one that scientists are still struggling to understand. Like most autoimmune diseases, rheumatoid arthritis begins when the immune system releases substances that target and inflame the body's own tissues, in this case the tender lining of the joints, or synovium. The inflamed tissue then releases enzymes that eat away at bone and cartilage, producing the disease's painful symptoms. But what enables arthritis-producing substances to start this process in the synovium?David M. Lee, HMS instructor in medicine at Brigham and Women's Hospital, Michael Brenner, the K. Frank Austen professor of medicine at HMS and BWH, and colleagues report in the Sept. 6 Science that they have identified a middleman, the immune system's mast cells. The findings, made with Diane Mathis and Christophe Benoist, both professors of medicine at Joslin Diabetes Center, and others, complement those of Julia Wang and Michael Roehrl (see above) on carbohydrates as potential systemic triggers of arthritis. "We are looking at different parts of the process," said Lee. Traditionally, mast cells, which reside in connective tissue and mucosa, have been associated with allergies and other inflammatory reactions. Yet they exhibit several characteristics that make them good candidates for the role of cellular middleman in rheumatoid arthritis. They express receptors for autoantibodies and complement that are known to cause the disease. What is more, they reside in the synovium. To see if they might actually play a role, Lee and his colleagues introduced arthritis-causing autoantibodies into two transgenic strains of mice, each lacking mast cells. They observed no signs of disease in the mutants. Next, they gave mutants infusions of mast cells prior to administering the autoantibodies. The mice developed symptoms of erosive arthritis. Lee and his colleagues were even able to catch the mast cells springing into action in the mutants' synovium. When activated, mast cells release granular constituents, a process called degranulation, which Lee and his colleagues observed one to two hours after administering the autoantibodies and prior to inflammation of the synovium. Degranulation was observed only in the mast cells of the synovium and not in other tissues. "They are there, they are activated, and they are important genetically," said Lee. It is not yet clear if mast cells play the same role in human rheumatoid arthritis. If they do, the findings could lead to a new therapeutic approach. "Mast cells have not been an important therapeutic target in the treatment of arthritis," he said. What makes the approach promising is the fact that mast cells are highly targetable. "We need to more precisely define their role in the mouse and in the human," he said. --Misia Landau |
