Immunology and Microbiology
First Thesis Advisor
John L. Sullivan, M.D.
T-Lymphocytes, Cytotoxic, Virus Diseases
Epstein-Barr virus (EBV) is associated with a spectrum of benign and malignant lymphoproliferative disorders, including acute infectious mononucleosis (IM), Burkitt's lymphoma (BL) and immunosuppression-associated B cell lymphoproliferative disease (LPD). Immunosurveillance mediated by virus-specific cytotoxic T lymphocytes is believed to protect immunocompetent hosts from EBV-associated lymphoma and LPD. Due to the lack of an adequate animal model, however, the precise immunologic mechanisms which provide this protection have not been directly demonstrated in vivo.
Human peripheral blood mononuclear cell-reconstituted C.B.-17-scid/scid mice (hu-PBMC-SCID mice) develop EBV-positive LPD following intraperitoneal injection of PBMC from EBV-seropositive donors. The SCID mouse disease mirrors human EBV-associated LPD in morphology, presence of the EBV genome, clonality, and patterns of expression of latent viral cellular differentiation antigens. The hu-PBMC-SCID mouse provides a unique small animal model of EBV+ LPD, and it was used in this study to examine the role of CD8+ CTL in controlling LPD. Survival time increase significantly when EBV-specific cytotoxic T-cell lines (CTL) are adoptive transferred into hu-PBMC-SCID mice, demonstrating suppression of LPD in vivoby a CTL-mediated virus-specific mechanism. Survival time also increases significantly with administration of alloreactive CTL lines, suggesting that a non-virus-specific mechanism also contributes to control of EBV-associated LPD by CTL.
NOD-SCID mice reconstituted with PBMC from donors with latent EBV infection develop EBV+ LPD with significantly less frequency than do C.B.17-SCID mice reconstituted with PBMC from the same donors. Administration of anti-CD8 mAb to these mice depletes human CD8+ cells and increases the incidence of LPD to 100%, demonstrating that CD8+ T cells are neccessary for protection from EBV-associated LPD. Adoptive transfer of human CD8+ T cells, but not CD4+ T cells, prevents LPD in CD8-depleted NOD-SCID mice. In vivo depletion of CD4+ T cells prevents engraftment of human T cells, and LPD does not develop in most mice after CD4+ cell depletion. These studies are the first to directly demonstrate both the protective role of CD8+ T cells and a requirement for CD4+ T cells in EBV -associated LPD in an in vivo model.
Cromwell, MA. The Role of T Lymphocytes in the hu-PBMC-SCID Mouse Model of Epstein-Barr Virus-Associated Lymphoproliferative Disease. (1995). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 158. DOI: 10.13028/9wsn-qg93. https://escholarship.umassmed.edu/gsbs_diss/158
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