Epstein Barr virus (EBV) is the cause of infectious mononucleosis and is associated with a number of cancers including lymphomas in transplant recipients. We have been studying EBV DNA in the blood of transplant recipients, patients with chronic active EBV disease, and in patients with other immunocompromising diseases. Severe aplastic anemia is often due to destruction of blood cell precursors by activated lymphocytes and is frequently treated with antibody-mediated immunosuppression. We collaborated with Phillip Scheinberg and A. John Barrett in the National Heart, Lung and Blood Institute to study EBV in the blood of patients with aplastic anemia undergoing immunosuppressive therapy. We found that EBV reactivated, with an increased level of EBV in the blood in 33% of patients receiving immunosuppressive therapy. Patients receiving rabbit anti-thymocyte globulin and cyclosporine had the highest level and longest duration of EBV reactivation when compared with patients receiving other types of immunosuppressive therapy. None of the patients who reactivated EBV developed disease associated with the virus.? ? Patients who receive transplants or who are immunocompromised from HIV are susceptible to developing EBV-associated lymphomas. Current therapy for this disease is limited and newer treatments are needed. We found that EBV-transformed B lymphocytes were more susceptible to killing by bortezomib, a drug currently licensed for the treatment of multiple myeloma. Bortezomib induced programmed cell death (apoptosis) of EBV-transformed B cells by inducing cleavage of caspases-8 and -9; apoptosis was inhibited by pretreatment with a caspase inhibitor. Bortezomib inhibited the NF-kappaB pathway which is important for the growth of many EBV-associated tumors. Bortezomib also inhibited the expression of several proteins, cIAP-1, cIAP-2 and XIAP, which are regulated by NF-kappaB, and function as inhibitors of apoptosis. Bortezomib significantly prolonged survival of severely immunodeficient (SCID) mice inoculated with EBV-transformed B cells. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.
Showing the most recent 10 out of 13 publications
