This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epstein-Barr virus (EBV) is a latent herpes virus that infects over 90% of the population. Primary infection usually results in a mild, self-limiting illness that is followed by life-long virus latency in oral epithelial cells and in B cells. In hosts with impaired T-cell immunity, reactivation of EBV can lead to unchecked lymphoproliferation evolving to immunoblastic lymphoma. In recipients of allogeneic bone marrow from HLA-matched unrelated donors or mismatched related donors, the genetic disparity between donor and recipient results in a high risk of graft versus host disease (GvHD). In vitro T cell depletion of donor marrow effectively reduces this risk, but also delays immune recovery and increases the incidence of viral infections, including Epstein-Barr virus lymphoproliferative disease (EBV-LPD), resulting from the outgrowth of EBV transformed B cells. Risk factors for the development post-transplant of EBV-LPD are the use of marrow from a mismatched related or closely matched unrelated donor, T cell depletion of the donor marrow and intensive immunosuppression. The incidence of EBV-LPD ranges from 5% to 25% in patients with these predisposing features and responds poorly to chemotherapy or alpha interferon. Unselected populations of lymphocytes from the peripheral blood of the donor usually contain EBV-specific T cells and therefore, can be used to control EBV lymphoproliferative disease. However, the use of such therapy is limited by potentially fatal complications that arise from alloreactive T cells also present in the lymphocyte infusion. Inflammatory reactions to T cell therapy can also cause severe tissue damage in affected organs during a therapeutic response. One means of reducing the risk of GvHD is the use of antigen specific cytotoxic T lymphocytes rather than unmanipulated cells. This strategy was initially evaluated by investigators in Seattle, when cytomegalovirus (CMV)-specific CD8 T cell clones were administered to recipients of matched sibling grafts. There were no adverse effects from the adoptive transfer of these clones. Furthermore CMV specific immune responses were reconstituted and no patients developed CMV disease. Post-transplant EBV-LPD is an excellent model in which to evaluate the efficacy of adoptively transferred antigen-specific CTL. The tumor cells express all latent-cycle virus-encoded antigens (EBNAs 1,2,3A, 3B, 3C, LMP1, 2a and 2b), most of which are targets for virus-specific immune responses, as well as several co-stimulatory molecules that facilitate CTL generation. EBV-transformed B lymphoblastoid cell lines (LCL) that can readily be prepared from any donor provided a source not only of antigen-presenting cell that endogenously expresses the appropriate viral antigens, but also of autologous target cells bearing the tumor antigens for CTL testing. Furthermore, most donors are immune to EBV and carry a high frequency of EBV-specific CTL precursors.
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