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Fred Hutchinson Cancer Research Center Study Shows Novel Agent Can Prevent Transplant Reactions and Promote Immunological Tolerance

Graft-versus-host disease (GVHD) continues to be a major complication for patients recovering after marrow transplantation. In a study conducted at the Fred Hutchinson Cancer Research Center, researchers found that by controlling the activation of specific T cells by blocking the anti-CD28 antibody, they could reduce or prevent GVHD.

CD28 is a T cell surface structure, the function of which is pivotal to determine whether a foreign antigen induces immunity or tolerance. Researchers used a mouse model to better understand how to block CD28 function and inhibit the occurrence of GVHD. They found evidence that treatment with an anti-CD28 antibody or other selective CD28 inhibitors could be applied to induce tolerance after transplantation. Results from this study were published in the May 1 issue of the Journal of Immunology.

According to Claudio Anasetti, M.D., member of the Clinical Research Division at the Hutchinson Center and lead researcher on the study, this information will lead to safer and more effective transplants. This study predicts that anti-human CD28 antibodies may be safer and more effective to prevent transplant reactions than other immunosuppressive agents currently available. The effect of anti-CD28 is restricted to T cells engaged with the specific transplant antigen, so that immune response to pathogens will be preserved.

"We expect that such an agent will be useful not only in transplantation of hematopoietic stem cells, a primary interest at Hutchinson Center, but also in the prevention of pancreatic islet, kidney, and other solid allograft rejection as well as the treatment of autoimmune diseases such as rheumatoid arthritis and diabetes," says Dr. Anasetti. "However, so far our research has focused on mouse models, the next step is human trials and now we can quickly move forward to these trials".

While this all sounds quite technical, it is actually simple. For patients it could mean an easier recovery after marrow transplantation. Bone marrow transplantation has been proven as a successful treatment for many people diagnosed with leukemia, lymphoma and a number of other blood and genetic disorders. While long-term survival after marrow transplantation has increased significantly over the years and many people survive to live healthy, happy and productive lives, a number have difficult recoveries, and in some cases chronic conditions or death, resulting from GVHD. This has been a major issue for researchers who are striving to improve bone marrow transplantation, and increase the applications for transplantation after high-dose regimens of chemotherapy and radiation. Researchers have worked for years to reduce the occurrence and control this complication. Currently, patients are treated with methotrexate, a steroid to reduce the chance that GVHD will occur.

Graft-versus-host disease is one of the more difficult and frequent complications occurring after a transplant. GVHD occurs when the donor marrow recognizes the patient's tissue as foreign. Transplanted white blood cells begin mounting an attack, even though the white blood cells types are the same, resulting in a number of symptoms ranging from mild to severe, and in some cases fatal. GVHD primarily affects the skin, liver and gastrointestinal tract of a patient. The most common symptoms are skin rashes, jaundice, liver disease and diarrhea.

Antibodies are proteins that play a key role in the body's immune system. When a foreign invader enters the body, antibodies identify this and defend the body against the invader. Researchers have worked to create laboratory-made antibodies that are equipped with the recognition capabilities of natural antibodies. The laboratory-made antibodies are called monoclonal antibodies. CD28 is such an antibody.

T cells, recognized as major components of the immune surveillance system, have three primary functions: to recognize and destroy abnormal or infected cells, to help other cells destroy infective organisms and to suppress the activity of other lymphocytes so they do not destroy normal tissue.

The Fred Hutchinson Cancer Research Center is recognized as a leader in the field of marrow transplantation. More than 400 marrow or stem cell transplants are performed each year for a number of diseases. Over the last 25 years many physicians now performing marrow transplants rotated through the Center to learn transplant techniques. The Hutchinson Center continues to improve and further develop this therapy. Are large part of this research is conducted in the laboratory where researchers are hoping to find ways to reduce complications and improve survival.

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The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Center's Web site at <www.fhcrc.org>.

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CONTACT: Susan Edmonds
Sedmonds@fhcrc.org

Fred Hutchinson Cancer Research Center is a world leader in research to prevent, detect and treat cancer and other life-threatening diseases.