Herpes viruses, particularly Cytomegalovirus and Epstein-Barr virus, are major causes of morbidity and mortality following allogeneic marrow transplantation. Recent developments in molecular and immunologically based diagnosis, particularly the polymerase chain reaction (PCR), and the use of monoclonal antibodies, as well as the recent use of adoptive human immunotherapy with virus-specific T-lymphocytes, offer new means of eliminating these infections as major complications of the severely immunocompromised patient. Toward this goal, this project has 2 specific aims. The concurrent utility of PCR and Cytomegalovirus antigen detection of Cytomegalovirus infection in peripheral blood of marrow transplant recipients will be assessed as early markers for the subsequent development of CMV-related disease. The goal is to develop methods for directing potentially toxic anti-viral prophylaxis to the group of patients at highest risk for CMV-related disease. Patients positive by either CMV-PCR or by CMV antigen detection in peripheral blood leukocytes will be randomized to receive either low-dose pre- emptive therapy with Ganciclovir or no treatment, to evaluate the safety, toxicity and efficacy of this mode of CMV disease prophylaxis. The feasibility of developing panels of CMV and EBV-specific cytotoxic T-cell clones, restricted to commonly inherited MHC Class 1 sequences, for use as """"""""generic"""""""" adoptive cellular immunotherapy for CMV or EBV infections, in patients sharing the same HLA Class 1 specificity will be evaluated. Methods of optimizing and simplifying the development of viral-specific cytotoxic T-cells (CTL) in-vitro will be investigated. In addition to using previously described methodologies, novel means for generating these clones will be pursued, including the use of retroviral gene transfer to transduce viral genes into hematopoietic progenitor cells and marrow stroma. Transduced macrophages and marrow stromal cells from long-term marrow cultures will be used to generate CTL, (""""""""Immunization by gene transfer""""""""). In addition new cytokine combinations and alternative means of antigen presentation will be evaluated to try to improve the efficiency of generating virus-specific T-cell clones. Studies will be conducted to investigate whether virus-specific T-cell clones, restricted to the most common HLA specificities seen in our marrow transplant population, might be used """"""""generically"""""""" as adoptive cellular immunotherapy for multiple allogeneic recipients inheriting the same HLA Class 1 antigen specificity. A panel of virus-specific clones, reactive against viral peptides presented in the context of the majority of known alleles of the most common HLA Class 1 specificities, might significantly facilitate the application of adoptive immunotherapy as a clinical tool.
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