EBV vaccination strategies are proposed which will be evaluated in severe combined immunodeficient mice engrafted with adult human immunocompetent cells (SCID-Adult Hu). One form of mouse-human chimera is generated by the inoculation of SCID mice with peripheral blood leukocytes from adult EBV negative donors. Another chimeric model is generated by the inoculation of bone marrow from healthy adult donors into neonatal or adult SCID mice. Both animal models support the engraftment of functional human B and T cells and with the provision of human hematopoietic factors to mice inoculated with human bone marrow, it has been shown that the murine microenvironment can support the engraftment of human stem cells which subsequently leads to a high level multi-lineage engraftment in the spleen, lymph node, peripheral blood and bone marrow. These recent advances in the transplantation of human immunocompetent cells into immunodeficient mice, and the ability of exogenous EBV to infect and transform human B cells residing in SCID mice provide a viable and unique opportunity to evaluate the efficacy of different EBV vaccination protocols. Each protocol will be tested in SCID-Adult Hu mice for the ability to induce immunity which protects the mice from EBV-induced disseminated lymphoproliferation. The first vaccination protocol to be tested focuses upon the use of a subunit preparation consisting of a truncated gp 350/220 protein. SCID-Adult Hu mice will be immunized with this viral envelope protein either in solution or covalently attached to a particulate carrier (liposomes or milk fat globules). A second protocol utilizes a transformation-defective EBV as the mutant immunogen. In the third vaccination protocol, SCID-Adult Hu mice are immunized with an autologous B-cell that has been transformed in vitro by EBV. In an effort to maximize the human lymphocyte response, the immunizing cells are also modified by gene transfer to produce and secrete human IL-2. In addition to testing the vaccination strategies, EBV mutants are being developed and assessed in vitro and in SCID-Adult Hu mice to investigate the significance of several EBV genes that lack known functions. The information obtained from these studies should contribute to the development of an attenuated live virus vaccine.
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