This project consists of interrelated studies of virus infection after marrow transplant, based on present concepts of the epidemiology, clinical manifestations, and immunology of these infections. The proposed studies primarily address cytomegalovirus (CMV) infection, since it is most common and most severe. There are four subprojects including: 1) trials for the prevention and treatment of herpesvirus infection, 2) studies of the biology and rapid diagnosis of CMV infection, 3) studies of the immunology of herpesvirus infection including efforts at specific immunization, and 4) specific adoptive immunotherapy of CMV infection with immune T-cells. The goals of the treatment trials include determination of the safety and efficacy of the acyclovir analogue 9-(2-hydroxy-1-(hydroxymethyl)ethoxymethyl) guanine in the treatment and prevention of CMV infection, prevention of primary CMV Infection using intravenous CMV immune globulin and leukocyte-depleted blood products in separate trials, and long-term acyclovir usage for prevention of varicella-zoster virus reactivation. The studies of the biology of CMV infection will define the clinical importance of CMV viremia in the predisposition to more serious CMV syndromes, an the usefulness of centrifugation cultures and nucleic acid probes in the diagnosis of CMV infection. The immunological studies will examine the usefulness of measurement of in vitro production of gamma-interferon and interleukin-2 in response to viral antigen stimulation for the identification of patients at higher risk of serious virus infection and determine the activity of these lymphokines in the augmentation of natural cytotoxicity against CMV-infected targets in vitro. Studies of pulmonary host defenses will phenotype the cells obtained by bronchopulmonary lavage and examine their role in the pathogenesis of CMV pneumonia. The ability of an HSV glycoprotein vaccine to stimulate virus-specific immune responses will be a first attempt to restore virus-specific responses without active virus infection. Finally, the studies of adoptive immunotherapy will explore the potential for expanding CMV-specific T-cells from the marrow donor in vitro for use in therapy of CMV infection in patients. This last study is the first attempt to apply the principles of adoptive immunotherapy developed in animal models to the treatment of a human disease. These combined studies are intended to define more clearly the pathogenesis of herpesvirus infections after marrow transplant and to reduce their significance by developing better regimens for treatment and prophylaxis.
Showing the most recent 10 out of 1845 publications
